Since the discovery of endothelin 1 (EDN1) in 1988, the role of endothelin ligands and their receptors in the regulation of blood pressure in normal and disease states has been extensively studied. However, endothelin signaling also plays crucial roles in the development of neural crest cell-derived tissues. Mechanisms of endothelin action during neural crest cell maturation have been deciphered using a variety of in vivo and in vitro approaches, with these studies elucidating the basis of human syndromes involving developmental differences resulting from altered endothelin signaling. In this Review, we describe the endothelin pathway and its functions during the development of neural crest-derived tissues. We also summarize how dysregulated endothelin signaling causes developmental differences and how this knowledge may lead to potential treatments for individuals with gene variants in the endothelin pathway.

More than 30 years ago, the first member of the endothelin peptide family, endothelin 1, was discovered based on its potent vasoconstrictive activity (Yanagisawa et al., 1988), followed by the discovery of two other endothelin peptides, endothelin 2 (EDN2) and endothelin 3 (EDN3) (Inoue et al., 1989), their receptors, endothelin receptor type A (EDNRA) (Arai et al., 1990) and type B (EDNRB) (Sakurai et al., 1990; Sakamoto et al., 1991) and their activating enzymes endothelin converting enzymes 1 and 2 (ECE1 and ECE2) (Xu et al., 1994; Emoto and Yanagisawa, 1995).

Endothelin signaling is a vertebrate-specific innovation that likely emerged in the common vertebrate ancestor, before the divergence of jawless (cyclostome) and jawed (gnathostome) vertebrate lineages (Hyndman and Evans, 2007; Martinez-Morales et al., 2007; Braasch et al., 2009; Kuraku et al., 2010), in parallel with neural crest cells (NCCs) (Box 1) (Square et al., 2016, 2020). Depending on the ligand, receptor and cell and tissue types involved, endothelin signaling can direct NCCs to migrate, proliferate, differentiate or maintain an undifferentiated state. Thus, endothelin signaling contributes to the functional diversity of NCCs, a crucial step in vertebrate evolution (Donoghue et al., 2008; Karim et al., 2021), and plays a conserved role in the development of tissues derived from NCCs, such as the craniofacial skeleton, cardiac outflow tract, pigmentation and the enteric nervous system (ENS) (Clouthier et al., 2010; Bondurand et al., 2018). Although the role of endothelin signaling in the development of these tissues and organs appears to work largely in a cell-autonomous manner in NCCs, it also appears that in some instances (including in melanocyte and ENS development), endothelin signaling is also required in non-NCCs to support NCC contributions to these tissues and organs (Wu et al., 1999; Barlow et al., 2003; Hou et al., 2004).

Box 1. Neural crest cells

NCCs are multipotent progenitors that give rise to an enormous diversity of cell types throughout the body (Tang and Bronner, 2020). NCCs first appear during neurulation, where they are induced from the border of the neural and non-neural ectoderm along the anterior-posterior axis of the embryo (Le Douarin and Kalcheim, 1999). NCCs from different axial levels take stereotyped migratory paths to specific regions of the developing embryo and give rise to specific cell types, tissues and organ systems (Szabo and Mayor, 2018) (Fig. 2). The craniofacial complex is derived from cranial NCCs that arise from the posterior midbrain and hindbrain (Serbedzija et al., 1992; Chai et al., 2000), whereas the cardiac outflow tract and septa are derived from cardiac NCCs, a subpopulation of vagal NCCs adjacent to somites 1-3 (Kirby et al., 1983; Jiang et al., 2000) (Fig. 2). Trunk melanocytes are derived from trunk NCCs (Mort et al., 2015), whereas the neurons and glia of the enteric nervous system are derived from the vagal and sacral NCCs (Le Douarin and Teillet, 1973) (Fig. 2).

Here, we describe the components of the endothelin signaling pathway and their respective functions during embryogenesis, while highlighting model organisms and genetic tools used in these investigations (Table 1). We also summarize endothelin-associated developmental differences in humans and approaches used to understand the genetic, cellular and molecular basis of disease (Table 2).

Table 1.

Summary of endothelin pathway mutant lines and phenotypes

Summary of endothelin pathway mutant lines and phenotypes
Summary of endothelin pathway mutant lines and phenotypes
Table 2.

Human developmental differences associated with alteration in EDN1-EDNRA signaling

Human developmental differences associated with alteration in EDN1-EDNRA signaling
Human developmental differences associated with alteration in EDN1-EDNRA signaling

Endothelin peptides

The endothelin family of peptides is comprised of EDN1, EDN2 and EDN3 in tetrapods (Barton and Yanagisawa, 2019) (Table 1; Fig. 1). Teleosts have a fourth endothelin peptide, EDN4, which was likely present in the common vertebrate ancestor but was lost in tetrapods (Braasch et al., 2009). The endothelin genes, EDN1, EDN2 and EDN3, encode an ∼200 amino acid preproEDN, which is a biologically inert precursor that is subsequently converted to a biologically active peptide by proteases. preproEDN is first cleaved by furin-like proteases to generate a 37-41 amino acid inactive precursor, referred to as big-EDN (Denault et al., 1995; Kim et al., 2012). Membrane-bound metalloproteases ECE1 and ECE2 then convert big-EDN into a mature, 21 amino acid peptide (Xu et al., 1994; Emoto and Yanagisawa, 1995). Expression of endothelin components is regulated by a number of events, including circadian regulation (Kozakai et al., 2014; Richards et al., 2014), cell sheer stress (Malek et al., 1993; Harrison et al., 1998) and epigenetics (Welch et al., 2013). The transcriptional regulation of EDN1 has been most extensively studied, with at least ten signaling pathways capable of influencing its expression (Stow et al., 2011). However, the transcriptional regulation of endothelin ligands during development is poorly understood.

Fig. 1.

The endothelin signaling pathway. The endothelin ligands endothelin 1 (EDN1), EDN2 and EDN3 are initially produced as inert precursors, prepro-EDN1-3, which are processed into big-EDN1-3 by furin or a furin-like protease before being secreted. Big-EDN1-3 are then converted to mature, bioactive peptides EDN1-3 by membrane-bound metalloproteases endothelin converting enzyme 1 (ECE1) and ECE2. Binding of EDN peptides to either the endothelin receptor type A (EDNRA) or EDNRB receptors stimulate signal transduction cascades mediated by heterotrimeric G proteins. EDNRA and EDNRB couple to all four families of Gα proteins, with each family inducing distinct intracellular signaling responses. EDNRA has differential binding affinities for EDN peptides [illustrated by solid (high affinity) and hatched (low affinity) arrows], whereas EDNRB binds non-selectively to all EDN peptides. cAMP, cyclic adenosine monophosphate; CDC42, cell division control protein 42 homolog; CREB, cAMP responsive element binding protein; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; IP3, inositol triphosphate; JNK, c-Jun N-terminal kinase; PAK, P21-activated kinase; PKA, protein kinase A; PKC, protein kinase C; PLCB, phospholipase Cβ; RhoA, Ras homolog gene family member A GTPase; RhoGEF, Rho guanine nucleotide exchange factor.

Fig. 1.

The endothelin signaling pathway. The endothelin ligands endothelin 1 (EDN1), EDN2 and EDN3 are initially produced as inert precursors, prepro-EDN1-3, which are processed into big-EDN1-3 by furin or a furin-like protease before being secreted. Big-EDN1-3 are then converted to mature, bioactive peptides EDN1-3 by membrane-bound metalloproteases endothelin converting enzyme 1 (ECE1) and ECE2. Binding of EDN peptides to either the endothelin receptor type A (EDNRA) or EDNRB receptors stimulate signal transduction cascades mediated by heterotrimeric G proteins. EDNRA and EDNRB couple to all four families of Gα proteins, with each family inducing distinct intracellular signaling responses. EDNRA has differential binding affinities for EDN peptides [illustrated by solid (high affinity) and hatched (low affinity) arrows], whereas EDNRB binds non-selectively to all EDN peptides. cAMP, cyclic adenosine monophosphate; CDC42, cell division control protein 42 homolog; CREB, cAMP responsive element binding protein; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; IP3, inositol triphosphate; JNK, c-Jun N-terminal kinase; PAK, P21-activated kinase; PKA, protein kinase A; PKC, protein kinase C; PLCB, phospholipase Cβ; RhoA, Ras homolog gene family member A GTPase; RhoGEF, Rho guanine nucleotide exchange factor.

Receptors

Endothelin peptides act on two receptor subtypes, EDNRA and EDNRB (Arai et al., 1990; Sakurai et al., 1990) (Fig. 1). Mammals have single genes for EDNRA and EDNRB, but some species have additional paralogs due to whole-genome duplication events. Zebrafish, for example, have two paralogs for ednra (ednraa and ednrab) and ednrb (ednrba and ednrbb), though at least ednraa and ednrab can act in a partially functionally redundant manner during craniofacial development (Nair et al., 2007). Avians also have two paralogs for Ednrb (Ednrb and Ednrb2), which display different expression patterns and functions during melanocyte development (Lecoin et al., 1998; Pla et al., 2005; Harris et al., 2008). Xenopus have an additional Endothelin receptor type C, though its function in development is unclear (Karne et al., 1993). Although progesterone can synergize with GATA2 to regulate Ednra expression (Zhang et al., 2013), as with endothelin ligands, transcriptional regulation of endothelin receptors during development is poorly understood.

EDNRA and EDNRB have different affinities for endothelin peptides. EDNRB is nonselective and binds to all EDN peptides with equal affinity, whereas EDNRA is selective and has the highest binding affinity for EDN1, moderate affinity for EDN2 and little to no affinity for EDN3 (Arai et al., 1990; Sakurai et al., 1990; Sakamoto et al., 1991). As EDN2 does not have an apparent role in embryonic development (Chang et al., 2013), this ligand will not be further discussed. The ligand selectivity for EDN1 is crucial for EDNRA function during development, as EDNRA nucleotide variants that enhance EDN3 binding affinity result in aberrant EDNRA signaling and developmental differences in mice and humans (discussed below) (Gordon et al., 2015; Sabrautzki et al., 2016; Kurihara et al., 2023). Endothelin peptide and receptor pairs involved in embryonic development can be classified into two general categories; EDN1-EDNRA, which drives craniofacial and outflow tract development, and EDN3-EDNRB, which drives melanocyte and ENS development. One of the key determinants that link these peptide-receptor pairs to specific developmental events is the coordinated expression of receptors and peptides in cells that are in close proximity (Nataf et al., 1996, 1998b; Brand et al., 1998; Clouthier et al., 1998; Yanagisawa et al., 1998a; Parichy et al., 2000; Barlow et al., 2003; Nair et al., 2007; Krauss et al., 2014; Square et al., 2016).

Heterotrimeric G proteins

Endothelin receptors are members of the Class A G protein-coupled receptor (GPCR) family (Isberg et al., 2016). GPCR signaling pathways are mediated by heterotrimeric G proteins, which are composed of a Gα subunit and an obligate Gβ/Gγ heterodimer (Gilman, 1987). There are four families of Gα subunits, Gq/11, Gi/o, Gs and G12/13, that each activate or inhibit specific signaling effectors to regulate the production of secondary messengers, activity of kinase pathways, or gene expression (Fig. 1) (Neves et al., 2002). One of the direct signaling effectors for Gq/11 is phospholipase Cβ (PLCB) isoforms, which generates the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG), which in turn stimulate intracellular calcium release and activation of calcium-dependent signaling pathways (Kadamur and Ross, 2013). Gs activates adenylyl cyclase (AC) isoforms, which leads to the production of cyclic AMP (cAMP) and activation of protein kinase A (PKA), whereas Gi/o attenuates this pathway by inhibiting AC. G12/13 activates RhoGTPases, which promote cell migration through regulation of actin-cytoskeleton dynamics. Both EDNRA and EDNRB can couple to all four Gα family members, though coupling preferences vary based on cell and tissue type (Aramori and Nakanishi, 1992; Takigawa et al., 1995; Kitamura et al., 1999; Kawanabe et al., 2002). In cranial and cardiac development, Gq/11 is the primary signaling mediator for EDNRA, though the contributions of other Gα families have not been ruled out (Sato et al., 2008). In melanocyte and ENS development, PKA is implicated downstream of EDNRB, but the roles of Gs or Gi/o in regulating PKA activity are unknown (Barlow et al., 2003; Hou et al., 2004; Goto et al., 2013; Bondurand et al., 2018).

Craniofacial development

Most of the bone, cartilage, connective tissue and portions of the nerves of the craniofacial complex are derived from cranial NCCs (Schilling and Le Pabic, 2014) (Fig. 2). NCCs migrate from the posterior midbrain and hindbrain rhombomeres (r) 1 and 2 into the mesenchyme of the first and second pharyngeal arches, transient bilateral structures on the ventral surface of the embryo (Serbedzija et al., 1992; Chai et al., 2000; Frisdal and Trainor, 2014). NCCs in the maxillary prominence of arch one are specified to adopt a maxillary identity, whereas cells in the mandibular portion of arch one are specified to adopt a mandibular identity (Minoux and Rijli, 2010) (Fig. 3A). The mandibular pharyngeal arch is further segmented along the dorsal-ventral axis into proximal, intermediate and distal patterning domains (Fig. 3A,B) that each give rise to specific lower jaw/middle ear structures (Fig. 3C).

Fig. 2.

Neural crest cell populations. All five subpopulations of neural crest cells (NCCs; top portion of each box) require either EDNRA (black) or EDNRB (purple) signaling for proper development of NCC-derived cells and structures (bottom portion of each box).

Fig. 2.

Neural crest cell populations. All five subpopulations of neural crest cells (NCCs; top portion of each box) require either EDNRA (black) or EDNRB (purple) signaling for proper development of NCC-derived cells and structures (bottom portion of each box).

Fig. 3.

Signaling during lower jaw development. (A,B) Lateral (A) and ventral (B) views of an E10.5 mouse embryo schematic; purple dashed boxes in A and B illustrate the embryo area that is further expanded in the colored cartoons. Areas of color highlight expression domains of selected transcription factors required for establishing positional identity of NCCs. Expression domains for ligands Edn1 and Bmp4 are also shown. The three primary domains of the mandibular arch [proximal (P), intermediate (I) and distal (D)] are denoted. EDN1-EDNRA signaling is required for gene expression in the distal and intermediate domains (e.g. Dlx5/6 and Hand2) but not in the proximal domain (Pou3f3 and Hey1). (C,D) Schematic of mouse skulls illustrating structures dependent on EDN1-EDNRA signaling. (C) In E18.5 wild-type embryos, the mandible (md) arises from the mandibular portion of arch 1 (blue). The maxilla (mx), palatine (p) and jugal (j) bones arise from the maxillary prominence of arch 1 (orange). (D) Loss of EDN1-EDNRA signaling results in homeotic transformation of the mandible into maxilla-, palatine- and jugal-like bones. In the skull base, the pterygoid (p) and alisphenoid (as) bones are also duplicated (grey). Duplicated bones are denoted with an asterisk. Middle ear structures, including the malleus (ma), incus (in) and tympanic ring (ty), are also malformed, hypoplastic or absent. bo, basioccipital; bs, basisphenoid; eo, exoccipital; et, ethmoid; f, frontal; h, hyoid; i, incisor; ip, interparietal; la, lacrimal; n, nasal; or, orbitosphenoid; pa, parietal; pe, petrosal; pm, premaxilla; ps, presphenoid; s, stapes; so, supraoccipital; sq, squamosal; tb, temporal bone; th, thyroid cartilage; v, vomer.

Fig. 3.

Signaling during lower jaw development. (A,B) Lateral (A) and ventral (B) views of an E10.5 mouse embryo schematic; purple dashed boxes in A and B illustrate the embryo area that is further expanded in the colored cartoons. Areas of color highlight expression domains of selected transcription factors required for establishing positional identity of NCCs. Expression domains for ligands Edn1 and Bmp4 are also shown. The three primary domains of the mandibular arch [proximal (P), intermediate (I) and distal (D)] are denoted. EDN1-EDNRA signaling is required for gene expression in the distal and intermediate domains (e.g. Dlx5/6 and Hand2) but not in the proximal domain (Pou3f3 and Hey1). (C,D) Schematic of mouse skulls illustrating structures dependent on EDN1-EDNRA signaling. (C) In E18.5 wild-type embryos, the mandible (md) arises from the mandibular portion of arch 1 (blue). The maxilla (mx), palatine (p) and jugal (j) bones arise from the maxillary prominence of arch 1 (orange). (D) Loss of EDN1-EDNRA signaling results in homeotic transformation of the mandible into maxilla-, palatine- and jugal-like bones. In the skull base, the pterygoid (p) and alisphenoid (as) bones are also duplicated (grey). Duplicated bones are denoted with an asterisk. Middle ear structures, including the malleus (ma), incus (in) and tympanic ring (ty), are also malformed, hypoplastic or absent. bo, basioccipital; bs, basisphenoid; eo, exoccipital; et, ethmoid; f, frontal; h, hyoid; i, incisor; ip, interparietal; la, lacrimal; n, nasal; or, orbitosphenoid; pa, parietal; pe, petrosal; pm, premaxilla; ps, presphenoid; s, stapes; so, supraoccipital; sq, squamosal; tb, temporal bone; th, thyroid cartilage; v, vomer.

Targeted deletion of Ece1, Edn1 or Ednra in mice results in neonatal lethality and numerous craniofacial anomalies, including retrognathia, homeotic transformation of the lower jaw into to upper jaw-like structures, mispositioning and malformation of the outer ears (pinnae), dysmorphic middle ear structures and malformation and mispositioning of the hyoid bone in the throat that results in mechanical asphyxia (Kurihara et al., 1994; Clouthier et al., 1998; Yanagisawa et al., 1998b; Ozeki et al., 2004) (Fig. 3D). In zebrafish, two large forward genetics screens yielded a collection of mutant alleles with ventral cartilage and jaw joint defects (Nusslein-Volhard, 2012), with several of these alleles mapping to genes that encode components of the EDN1-EDNRA pathway, including edn1, furina, plcb3 and mef2ca (Miller et al., 2000, 2007; Walker et al., 2006, 2007). Zebrafish embryos injected with morpholinos targeting edn1, ednraa or ednrab result in similar changes in ventral cartilages and loss of jaw joints (Kimmel et al., 2003; Nair et al., 2007). In humans, gene variants in signaling components within the EDN1-EDNRA pathway are associated with Auriculocondylar syndrome (Rieder et al., 2012; Clouthier et al., 2013; Gordon et al., 2013a; Kanai et al., 2022) and Mandibulofacial Dysostosis with Alopecia (Gordon et al., 2015; Kurihara et al., 2023), both of which present with facial differences, and Oro-Oto-Cardiac syndrome, which presents with both craniofacial and cardiovascular differences (Pritchard et al., 2020) (Table 2).

Distal and intermediate domain specification

The mandibular pharyngeal arch is classically divided into proximal, intermediate and distal domains, with distal and intermediate domain patterning dependent on autonomous EDNRA signaling in NCCs. In mice, Ednra is expressed in migrating and post-migratory cranial NCCs (Clouthier et al., 1998). Edn1 expression is observed in the ectoderm, mesoderm and endoderm of the mandibular pharyngeal arches (Clouthier et al., 1998; Yanagisawa et al., 1998a; Miller et al., 2000), though studies in mice and zebrafish illustrate that primarily ectodermal EDN1 drives arch patterning (Nair et al., 2007; Tavares et al., 2012) (Fig. 3A,B). Ece1 is expressed by the ectoderm and underlying arch mesenchyme (Yanagisawa et al., 1998a, 1998b; Tavares et al., 2017). Similar expression patterns for edn1 and ece1 are observed in zebrafish (Miller et al., 2000), with ece1a expression induced by Nkx2.5/Nkx2.7 (Ikle et al., 2017). The Dlx family members Dlx5 and Dlx6, essential components of the gene regulatory network (GRN) governing mandibular identity (Beverdam et al., 2002; Depew et al., 2002; Ozeki et al., 2004; Ruest et al., 2004; Talbot et al., 2010; Vieux-Rochas et al., 2010) (Fig. 3A,B) are induced upon EDNRA activation and are required for subsequent induction of the basic helix-loop-helix transcription factor Hand2 in the distal domain (anlage of incisors and most of the mandible) and Nkx3.2 and Dlx3 in the intermediate domain (malleus, incus and the proximal mandible) (Thomas et al., 1998; Clouthier et al., 2000; Charité et al., 2001; Miller et al., 2003; Fukuhara et al., 2004; Tucker et al., 2004; Talbot et al., 2010; Barron et al., 2011; Funato et al., 2016). Although EDNRA signaling activity may directly induce mandibular patterning genes, a study in zebrafish suggests a permissive mechanism where EDNRA downregulates expression of the Nr2f family of nuclear receptors, which normally repress the expression of mandibular patterning genes (Barske et al., 2018).

EDN1-EDNRA signaling is mediated in part by Gq/11 and its downstream effectors PLCB and myocyte enhancer factor 2 (Mef2c), a MADS Box transcription factor (Offermanns et al., 1998; Ivey et al., 2003; Dettlaff-Swiercz et al., 2005; Miller et al., 2007; Verzi et al., 2007; Walker et al., 2007; Kanai et al., 2022) (Fig. 1). Disruption of Gq/11, PLCB isoforms or Mef2c by targeted deletion or mutations causes downregulation of endothelin-dependent patterning genes and produces craniofacial phenotypes reminiscent of endothelin loss. In mice, endothelin induces expression of Mef2c by direct transcriptional regulation, which is mediated in part by Ca2+/calmodulin-dependent protein kinase II (CaMKII) (Hu et al., 2015). In zebrafish, the expression of mef2ca is independent of endothelin signaling, though it is required for transduction of Edn1-mediated signaling (Miller et al., 2007).

Timing and outcome of distal and intermediate domain specification

When EDN1-EDNRA signaling is attenuated in mouse and zebrafish, NCCs of the ventral and intermediate domains fail to establish a mandibular identity and instead adopt a maxillary identity, resulting in homeotic transformation of most lower jaw structures and soft tissue into upper jaw-like structures and tissues (Kimmel et al., 2003; Miller et al., 2003; Ozeki et al., 2004; Nair et al., 2007; Ruest and Clouthier, 2009; Zuniga et al., 2010; Tavares et al., 2017; Barske et al., 2018) (Fig. 3C,D). In zebrafish, the second arch-derived operculum bones are also duplicated at the expense of the branchiostegal rays (Kimmel et al., 2003). Similar changes are observed when Ednra signaling is disrupted in chick, frog and humans, indicating the conserved nature of this developmental mechanism (Kempf et al., 1998; Miller et al., 2000; Bonano et al., 2008; Pritchard et al., 2020; Kanai et al., 2022).

The window of necessity for EDN1-EDNRA signaling is between the arrival of NCCs in the arch and the termination of migration (Ruest and Clouthier, 2009). In wild-type mice, administration of an EDNRA-specific antagonist by gavage between embryonic day (E) 8.25 and E9.25 (either once or twice separated by 12 h) resulted in defects in jaw and middle ear structures, with treatment between E8.75 and E9.25 producing the strongest effect (Fukuhara et al., 2004; Ruest and Clouthier, 2009). Treatment after E9.5 had no effect on craniofacial development. Gene expression changes at E10.5 in the mandibular arch of antagonist-treated embryos and in cultured E10.5 mandibular arches treated in vitro with an antagonist (Fukuhara et al., 2004) were similar to those observed in Ednra−/− embryos. Conditional ablation of the Ednra gene in mice using the Wnt1-Cre strain, which is active around E8.0, also recapitulated the jaw phenotype of Ednra−/− embryos, while conditional ablation of the Ednra gene using the Hand2-Cre strain, which results in gene deletion after E9.25, did not disrupt jaw development. This further highlights the strict temporal requirement for EDNRA signaling in craniofacial development.

Dorsal domain patterning and interactions with endothelin signaling

The boundary between upper and lower jaw patterning domains is established by the antagonistic interactions between EDN1-EDNRA and JAGGED-NOTCH signaling pathways. NOTCH is a cell-surface receptor for JAGGED and other related transmembrane ligands (Mumm and Kopan, 2000). In zebrafish, Jag1b and Notch2 establish the dorsal patterning domain (for maxilla and upper face) while also antagonizing the Edn1-Ednra signaling pathway to correctly position the dorsal/intermediate domain of the first and second pharyngeal arches (Zuniga et al., 2010; Barske et al., 2016). In contrast, Edn1-Ednra signaling antagonizes Jag1b-Notch2 signaling by inhibiting expression of jag1b and transcriptional targets, such as hey1 (Zuniga et al., 2010; Barske et al., 2016). Absence of Edn1-Ednra signaling causes Jag1b-Notch2 signaling activity to expand ventrally, subsequently contributing to the observed homeotic transformations. JAGGED-NOTCH signaling may have species-specific roles in the dorsal arches; mouse embryos lacking Jag1 had midfacial hypoplasia, a persistent foramen in the frontal bone and defects in the hyoid bone; however, defects in the upper and lower jaw were not observed (Teng et al., 2017).

The regional confinement of both EDN1-EDNRA and JAGGED-NOTCH signaling is likely controlled by several mechanisms, one of which involves the transcription factor SIX1. In mice, SIX1 represses Edn1 expression in the dorsal portion of the first pharyngeal arch endoderm while also inducing Jag1 expression (Tavares et al., 2017) (Fig. 3A,B). Targeted inactivation of Six1 leads to an expansion of Edn1 expression along the dorsal endoderm, resulting in aberrant EDNRA signaling and downregulation of Jag1 expression in the proximal arch. Consequently, the zygomatic process of the maxilla expands into a pseudo-condylar process that inserts into the temporal mandibular joint (TMJ) adjacent to the true mandibular condyle.

Recent advances in further subdividing the mandibular arch

Although the mandibular arch has historically been divided into three primary domains, recent advances in single-cell RNA-sequencing in the mouse have illustrated that the arch can be subdivided further into at least 15 clusters of cells with distinct gene expression patterns (Xu et al., 2019; Yuan et al., 2020). This indicates that induction of EDNRA signaling leads to establishment of multiple developmental domains within the mandibular arch that likely drive patterning and development of distinct elements (or portions of distinct elements).

Signaling cross-talk between EDN1-EDNRA and other pathways

EDN1-EDNRA also works in concert with other signaling pathways to pattern the mandibular arch. In zebrafish, signaling by bone morphogenic protein (Bmp) ligands and Bmp receptors (Bmpr) initiates expression of edn1 in the ventral ectoderm (Alexander et al., 2011), which then upregulates expression of a Bmp antagonist, Gremlin 2, in the intermediate and dorsal domains, restricting Bmp activity to the ventral domain (Zuniga et al., 2011). This suggests that Bmp is first necessary to induce Edn1, with Bmp and Edn1 then adopting independent roles in establishing the ventral and intermediate domains, respectively. Although this has been supported by computational models (Meinecke et al., 2018), it is unclear why endogenous Bmp cannot compensate for complete loss of Edn1-Ednra signaling in mouse and zebrafish. This may be due in part to Bmp4 expression being dependent on EDN1-EDNRA signaling in mice (Ruest et al., 2004). Furthermore, loss of BMP signaling in mice causes lower jaw hypoplasia and malformations but does not result in the homeotic transformations observed in Edn1 and Ednra mutants (Bonilla-Claudio et al., 2012). Additional work is needed to clarify the relationship between BMP-BMPR and EDN1-EDNRA signaling pathways.

WNT signaling also appears to work upstream of or in parallel with BMP-BMPR and EDN1-EDNRA during mandibular arch patterning. Disruption of Wnt signaling in zebrafish leads to loss of ventral arch gene expression and expansion of dorsal gene expression into the ventral arch, resulting in craniofacial phenotypes resembling edn1 mutants (Alexander et al., 2014). These changes occur due to a likely requirement for WNT signaling in establishing competence of cranial NCCs to respond to Bmp and Edn1. In mice, targeted inactivation of a WNT co-receptor, Lrp6, disrupts arch gene expression and later lip fusion but does not affect lower jaw development (Pinson et al., 2000; Song et al., 2009). In addition, targeted deletion of R-spondin 2 (Rspo2), a positive regulator of WNT/β-catenin signaling, results in lower jaw defects in mice, potentially by regulating Edn1 expression either directly or through FGF8 (Jin et al., 2011). In addition, targeted deletion of Fgf8 in the pharyngeal arch ectoderm in mice disrupts expression of multiple mandibular arch patterning genes, including Edn1 (Trumpp et al., 1999). However, the resulting phenotype in Fgf8 mutant mice (arch hypoplasia and subsequent loss of most mandibular arch-derived structures) does not resemble the Edn1 mutant phenotype (Kurihara et al., 1994; Ozeki et al., 2004). These discrepancies motivate additional work to clarify the relationship between WNT, BMP, EDN1 and FGF8 signaling pathways. Finally, Sonic hedgehog signaling is a crucial downstream mediator of EDN1 activity, working with HAND2 to pattern the lower jaw (Elliott et al., 2020) while also confining BMP activity (Xu et al., 2019).

Cardiovascular development

EDN1-EDNRA signaling is required for several aspects of cardiac development, including remodeling of the cardiac outflow tract, ventricle septation and valve formation, as well as the cardiac conduction system.

Remodeling of the pharyngeal arch arteries

Each pharyngeal arch initially has an associated artery, with the paired arch arteries 1 and 2 regressing into capillary beds of the face and neck (Kirby and Waldo, 1995; Waldo et al., 1996). Paired right and left pharyngeal arch arteries (PAAs) 3, 4 and 6 give rise to the cardiac outflow tract (Kirby et al., 1997), comprised of the ascending aorta, aortic arch, common carotid arteries and portions of the subclavian arteries (Fig. 4A,B). This remodeling is driven by ventrally-migrating cardiac NCCs that surround the endothelial cells demarcating each nascent arch artery lumen (Fig. 5) and eventually form the smooth muscle portion of the vessels (tunica media) (Kuratani and Kirby, 1991; Hutson and Kirby, 2007; Waldo et al., 1996). The endothelium of PAAs 3, 4 and 6 express Edn1 and Ece1, providing paracrine signaling to the surrounding Ednra-expressing cardiac NCCs (Kurihara et al., 1995; Clouthier et al., 1998; Yanagisawa et al., 1998a,b; Jiang et al., 2000). Ece1 is also expressed in the mesenchyme surrounding the arch arteries (Yanagisawa et al., 1998a,b). In Ednra, Edn1 or Ece1 mouse mutants, cardiac NCCs surround the PAAs but cannot facilitate remodeling, resulting in a variety of arch artery defects (Kurihara et al., 1995; Clouthier et al., 1998; Yanagisawa et al., 1998a,b, 2000) (Fig. 4C-G). The mechanisms by which cardiac NCCs coordinate vessel remodeling is not fully understood.

Fig. 4.

Representative aortic arch malformations in Edn1−/−, Ednra−/− or Ece1−/− mouse embryos. (A) A normally remodeled outflow tract observed in E18.5 embryos. Thin dotted lines represent normal regression of vessels during outflow tract remodeling. (B) The normally remodeled outflow tract shown in A with arch artery (aa) origins for each structure noted in pink. (C-G) Abnormal regression of arch arteries and abnormal outflow tract patterning observed in Edn1−/−, Ednra−/− and Ece1−/− mouse embryos. Blue vessels represent abnormal persistence of vessels; thick dotted lines represent abnormal regression of vessels. (C) Abnormal regression of the right arch artery 4 (raa4) and persistence of the right ductus caroticus (rdc) results in a right subclavian artery (rsa) of cervical origin. (D) Abnormal regression of right and left arch arteries 4 (raa4 and laa4) leads to persistence of right and left ductus caroticus (rdc and ldc). The right dorsal aorta (rda) also persists. (E) Abnormal regression of right arch artery 4 leads to persistence of right dorsal aorta, resulting in a right subclavian artery of dorsal aorta origin. (F) Aberrant regression of left arch artery 6 (laa6) and persistence of right arch artery 6 (raa6) and right dorsal aorta results in a right-sided aortic arch (raoa). (G) Aberrant regression of the left and right arch arteries 4, the left arch artery 6 and the left dorsal aorta (lda) and aberrant persistence of the right arch artery 6, the right ductus caroticus and the right dorsal aorta resulting in a right-sided aortic arch. da, ductus arteriosus; lsa, left subclavian artery; laa3, left arch artery 3; raa3, right arch artery 3. Adapted with permission from Yanagisawa et al. (1998a).

Fig. 4.

Representative aortic arch malformations in Edn1−/−, Ednra−/− or Ece1−/− mouse embryos. (A) A normally remodeled outflow tract observed in E18.5 embryos. Thin dotted lines represent normal regression of vessels during outflow tract remodeling. (B) The normally remodeled outflow tract shown in A with arch artery (aa) origins for each structure noted in pink. (C-G) Abnormal regression of arch arteries and abnormal outflow tract patterning observed in Edn1−/−, Ednra−/− and Ece1−/− mouse embryos. Blue vessels represent abnormal persistence of vessels; thick dotted lines represent abnormal regression of vessels. (C) Abnormal regression of the right arch artery 4 (raa4) and persistence of the right ductus caroticus (rdc) results in a right subclavian artery (rsa) of cervical origin. (D) Abnormal regression of right and left arch arteries 4 (raa4 and laa4) leads to persistence of right and left ductus caroticus (rdc and ldc). The right dorsal aorta (rda) also persists. (E) Abnormal regression of right arch artery 4 leads to persistence of right dorsal aorta, resulting in a right subclavian artery of dorsal aorta origin. (F) Aberrant regression of left arch artery 6 (laa6) and persistence of right arch artery 6 (raa6) and right dorsal aorta results in a right-sided aortic arch (raoa). (G) Aberrant regression of the left and right arch arteries 4, the left arch artery 6 and the left dorsal aorta (lda) and aberrant persistence of the right arch artery 6, the right ductus caroticus and the right dorsal aorta resulting in a right-sided aortic arch. da, ductus arteriosus; lsa, left subclavian artery; laa3, left arch artery 3; raa3, right arch artery 3. Adapted with permission from Yanagisawa et al. (1998a).

Fig. 5.

Endothelin signaling during cardiovascular development. Cardiac NCCs (blue circles) expressing Ednra arise from the cardiac neural crest (cnc) region (green) at the level of somites 1-3 (s1-s3), migrating ventrally towards the heart through the circumpharyngeal region (cpr). They subsequently surround the lumens of paired pharyngeal arch arteries (aa) 3, 4 and 6, which are lined with endothelial cells expressing Edn1. Once there, asymmetric remodeling of the arch arteries occurs, with the cardiac NCC-derived mesenchyme forming the smooth muscle cells that surround the lumen. Cardiac NCC-derived mesenchyme also give rise to the aorticopulmonary septum (aps) that divides the cardiac outflow into aortic (ao) and pulmonary (p) trunks. A subset of cardiac NCCs continue into the conotruncus (lined with Edn1-expressing endothelial cells), where they later contribute to the semilunar and atrioventricular valves. ct, conotruncus; lda, left dorsal aorta; lv, left ventricle; nt, neural tube; rda, right dorsal aorta; rv, right ventricle. Adapted with permission from Hutson and Kirby (2007).

Fig. 5.

Endothelin signaling during cardiovascular development. Cardiac NCCs (blue circles) expressing Ednra arise from the cardiac neural crest (cnc) region (green) at the level of somites 1-3 (s1-s3), migrating ventrally towards the heart through the circumpharyngeal region (cpr). They subsequently surround the lumens of paired pharyngeal arch arteries (aa) 3, 4 and 6, which are lined with endothelial cells expressing Edn1. Once there, asymmetric remodeling of the arch arteries occurs, with the cardiac NCC-derived mesenchyme forming the smooth muscle cells that surround the lumen. Cardiac NCC-derived mesenchyme also give rise to the aorticopulmonary septum (aps) that divides the cardiac outflow into aortic (ao) and pulmonary (p) trunks. A subset of cardiac NCCs continue into the conotruncus (lined with Edn1-expressing endothelial cells), where they later contribute to the semilunar and atrioventricular valves. ct, conotruncus; lda, left dorsal aorta; lv, left ventricle; nt, neural tube; rda, right dorsal aorta; rv, right ventricle. Adapted with permission from Hutson and Kirby (2007).

Outflow septation and conotruncus development

A subset of cardiac NCCs continue past the arch arteries, migrating into the cardiac outflow cushions, where they form two prongs of condensed cells in the distal outflow cushions (Fig. 5) (Kirby et al., 1983, 1985; Kirby and Waldo, 1995). Along with a shelf of tissue in the aortic sac, they form the aorticopulmonary septation complex, which divides the singular outflow into the pulmonary and aortic outflows and aligns the outflows with the respective ventricles. NCCs also contribute to both semilunar and atrioventricular valves and form the muscular portion of the ventricular septum separating the right and left ventricles (Waldo et al., 1998). EDNRA signaling, acting through CDC42, is required for cardiac NCC migration through the outflow tract (Fritz et al., 2019), with its absence resulting in persistent truncus arteriosus (failure to separate the aortic and pulmonary outflows) (Clouthier et al., 1998; Yanagisawa et al., 1998a,b). Compared with Ednra, Edn1 and Ece1 mutant embryos, defects in aorticopulmonary septation are more severe in embryos lacking both ECE1 and ECE2 [Ece1/Ece2 double knockout (dko) embryos] (Yanagisawa et al., 2000). Conotruncal alignment defects are also observed in the absence of EDN1-EDNRA signaling, including overriding aorta and perimembranous interventricular septal defects (Clouthier et al., 1998). In addition, a majority of both Ece1 knockout embryos and Ece1/Ece2dko embryos die between E13.5 and E18.5. Both groups show poor endocardial cushion development along with peripheral dilation and general edema, suggesting that lethality arises from defects in atrioventricular valve development (Yanagisawa et al., 2000). The observed edema could also arise from poor myocardial development. Ednra−/− embryos have a thin myocardium (Clouthier et al., 1998; Asai et al., 2010), potentially due to an early requirement for EDNRA signaling in a region of the cardiac crescent from which ventricular myocardial cells arise (Abu-Issa and Kirby, 2007; Asai et al., 2010). Overall, these findings illustrate a broad requirement of EDN1-EDNRA signaling in cardiac NCC differentiation.

The cardiac conduction system

In the chick, endothelin signaling is required for cardiac conduction system development (Gourdie et al., 1998; Takebayashi-Suzuki et al., 2000; Hall et al., 2004). Embryonic myocytes ubiquitously express Ednra, whereas Edn1 and Ece1 are expressed by endocardial and arterial endothelial cells (Takebayashi-Suzuki et al., 2000). Such an arrangement argues for a role of Ednra signaling in myocardial development. Indeed, ectopic expression of Edn1 and Ece1 in myocytes results in cell-autonomous expression of Cx42, sMyHC and AMyHC, which are markers for Purkinje fibers, the impulse conducting cells of the heart (Takebayashi-Suzuki et al., 2000). This suggests that Ednra-expressing myocytes that are in direct association with Edn1/Ece1+ endothelial cells of the heart drives formation of the Purkinje lineage (Mikawa and Fischman, 1992; Takebayashi-Suzuki et al., 2000). The transcriptional regulation of Ece1 in this setting is not well understood, but it appears that biomechanical forces exerted during cardiac development induce Ece1 expression in a spatially restricted pattern necessary for proper conduction system architecture (Hall et al., 2004).

EDN3-EDNRB signaling is required for the development of melanocytes, which provide pigmentation to skin and hair and contribute to intermediate cells in the stria vascularis of the mammalian cochlea (Mort et al., 2015; Ritter and Martin, 2019) and the network of neurons and glia of the ENS that control the complex functions of the gastrointestinal tract (Schneider et al., 2019).

The roles of EDN3-EDNRB signaling in pigmentation and ENS development are widely conserved in vertebrates, though some species-specific differences exist. Spontaneous mutations in EDNRB that cause similar defects to pigmentation and/or ENS development have been identified in rat, horse, zebrafish, pig, goat and chicken (Bondurand et al., 2018). In humans, variants in EDN3, EDNRB or ECE1 are associated with isolated and syndromic Hirschsprung disease (HSCR) (Karim et al., 2021) (Box 2). Below, we discuss the roles of EDN3-EDNRB signaling in melanocyte and ENS development, highlighting species-specific differences.

Box 2. Isolated and syndromic Hirschsprung disease and the EDN3-EDNRB pathway

Hirschsprung disease (HSCR) is defined by aganglionosis of the colon that leads to tonic contraction of the aganglionic region, inability to pass stool or gas, and death if untreated (Heuckeroth, 2018). The clinical presentations of HSCR can vary, with aganglionosis confined distal to the sigmoid colon classified as short-segment HSCR and aganglionosis that extends proximal to the sigmoid colon classified as long-segment HSCR. The genetic basis of HSCR is complex. Numerous genes are associated with HSCR, including RET, SOX10, EDN3 and EDNRB, but in many cases the associated variants are neither necessary nor sufficient to cause disease (Amiel et al., 2008). In addition, colonic aganglionosis can occur in isolation or in conjunction with other congenital anomalies (syndromic HSCR) (Amiel et al., 2008).

Disease variants in EDN3, EDNRB or ECE1 are associated with isolated and syndromic HSCR. Isolated HSCR cases are often associated with autosomal dominant variants of EDN3 or EDNRB (Karim et al., 2021), whereas recessive variants of EDN3 or EDNRB are often associated with syndromic HSCR called Waardenburg Syndrome Type 4A (WAS type 4), characterized by sensorineural deafness and pigment differences, in addition to distal colon aganglionosis (McCallion and Chakravarti, 2001; Pingault et al., 2010). One case of an ECE1 disease variant has been reported for syndromic HSCR presenting with cardiac differences and autonomic dysfunction (Hofstra et al., 1999).

Disease variants for EDN3 or EDNRB are typically associated with short-segment HSCR (Tang et al., 2018), but bowel dysfunction likely extends beyond the aganglionic regions. Despite resection of the aganglionic bowel region (pull-through surgery), individuals continue to exhibit symptoms stemming from dysfunction in ganglionated regions (Yanchar and Soucy, 1999). The features and causative mechanisms of bowel dysfunction in these regions are being investigated using animal models for HSCR (Cheng et al., 2016; Bhave et al., 2021, 2022).

Animal models have also been instrumental in advancing development of stem cell-based regenerative therapies (Burns and Thapar, 2014). Recent studies have provided proof of concept that neurons, glial cells, and gut function can be partially restored in HSCR mouse models by transplantation of mouse- or human-derived stem cells (Hotta et al., 2016; Fan et al., 2023). Further work is needed to understand all factors required for complete functional innervation, such as the role of extracellular matrix components in enteric nervous system development (Druckenbrod and Epstein, 2009).

Melanocyte development

Melanocytes are derived from NCCs from all axial levels (Freyer et al., 2011; Mort et al., 2015) (Fig. 2), with the role of EDN3-EDNRB in melanocyte development best characterized in trunk NCC derivatives. After delamination from the neuroectoderm, trunk NCCs transiently accumulate in a region between the dorsal neural tube and somites called the migration staging area (MSA) before bifurcating into two migratory paths that each give rise to two distinct NCC populations (Erickson et al., 1992) (Fig. 6A). The first population follows a ventral migratory pathway and gives rise to the neurons and glia of the peripheral nervous system, whereas the second population takes a dorsolateral path and gives rise to melanocytes (Serbedzija et al., 1990; Erickson and Goins, 1995; Reedy et al., 1998; Dupin and Le Douarin, 2003; Thomas and Erickson, 2008). The melanocyte progenitors, or melanoblasts, eventually invade and colonize the dorsal surface of the embryo. Throughout this process, Ednrb is expressed in trunk NCCs and melanoblasts, with Edn3 expressed in the dorsal ectoderm (Nataf et al., 1996, 1998b; Lee et al., 2003; Hou et al., 2004). In zebrafish, melanocytes are derived from both ventral and dorsal-migrating trunk NCCs (Mort et al., 2015). In Xenopus, melanocytes are derived primarily from the ventral-migrating populations of NCCs (Theveneau and Mayor, 2012).

Fig. 6.

Melanocyte and enteric nervous system development. (A) Migratory paths of trunk NCCs. In mouse and chick embryos, the melanoblast population migrates dorsolaterally between the somites and developing epidermis to colonize the dorsal surface of the embryo. Trunk NCCs that migrate ventrally between the somites and neural tube give rise to neurons and glia of the peripheral nervous system. (B) Characteristic coat pigmentation defects in Edn3 and Ednrb mutant mice. Compared with wild-type mice (top left), lethal spotting mice (ls/ls; loss of Edn3 expression) exhibit extensive white spotting (top right). Pigmented patches are typically observed on the head and hip regions. Piebald mice (s/s; reduced Ednrb expression) exhibit mild coat color spotting (bottom left). White spotting is typically observed on the shoulder and hip regions. Spotted lethal mice (sl/sl; complete loss of Ednrb expression) exhibit severe coat pigmentation defects and are almost completely white (bottom right). (C) Migratory paths of NCCs through the fetal gut of a prototypical midgestation embryo. Vagal NCCs, or enteric NCCs (ENCC), traverse long distances to colonize the entire length of the developing gut. In mice, ENCCs enter the developing intestine at the foregut (indicated by black arrow adjacent somites 1-7) around E8.5-E9.5 and migrate in a rostral-caudal direction (indicated by purple arrow in midgut). Colonization of the gut is completed by E15.5. In mouse and chick embryos, sacral NCCs enter the posterior hindgut (indicated by the black arrow adjacent the cloaca) and colonize the proximal and distal colon. Areas of high EDN3 are denoted by purple-brown shading (the stomach, cecum and cloaca). EDN3-EDNRB signaling is required for ENCCs to migrate past the ileo-cecal junction and into the proximal colon (indicated by orange circle). Regions of the gut (foregut, midgut and hindgut) are color-coded. Adapted with permission from Nagy and Goldstein (2017).

Fig. 6.

Melanocyte and enteric nervous system development. (A) Migratory paths of trunk NCCs. In mouse and chick embryos, the melanoblast population migrates dorsolaterally between the somites and developing epidermis to colonize the dorsal surface of the embryo. Trunk NCCs that migrate ventrally between the somites and neural tube give rise to neurons and glia of the peripheral nervous system. (B) Characteristic coat pigmentation defects in Edn3 and Ednrb mutant mice. Compared with wild-type mice (top left), lethal spotting mice (ls/ls; loss of Edn3 expression) exhibit extensive white spotting (top right). Pigmented patches are typically observed on the head and hip regions. Piebald mice (s/s; reduced Ednrb expression) exhibit mild coat color spotting (bottom left). White spotting is typically observed on the shoulder and hip regions. Spotted lethal mice (sl/sl; complete loss of Ednrb expression) exhibit severe coat pigmentation defects and are almost completely white (bottom right). (C) Migratory paths of NCCs through the fetal gut of a prototypical midgestation embryo. Vagal NCCs, or enteric NCCs (ENCC), traverse long distances to colonize the entire length of the developing gut. In mice, ENCCs enter the developing intestine at the foregut (indicated by black arrow adjacent somites 1-7) around E8.5-E9.5 and migrate in a rostral-caudal direction (indicated by purple arrow in midgut). Colonization of the gut is completed by E15.5. In mouse and chick embryos, sacral NCCs enter the posterior hindgut (indicated by the black arrow adjacent the cloaca) and colonize the proximal and distal colon. Areas of high EDN3 are denoted by purple-brown shading (the stomach, cecum and cloaca). EDN3-EDNRB signaling is required for ENCCs to migrate past the ileo-cecal junction and into the proximal colon (indicated by orange circle). Regions of the gut (foregut, midgut and hindgut) are color-coded. Adapted with permission from Nagy and Goldstein (2017).

Melanocyte migration

Avian and rodent models have provided a great deal of insight into the role of EDN3-EDNRB signaling in melanoblast migration (Dupin and Le Douarin, 2003). In mice containing a lacZ cassette in the Ednrb locus (EdnrblacZ) (Lee et al., 2003), trunk NCCs first appear at the MSA around E10 and are specified into melanoblasts, indicated by the expression of dopachrome tautomerase (Dct) (Mackenzie et al., 1997). Subsequently, they migrate into and colonize the dorsal surface between E10 and E12.5. In EdnrblacZ/lacZ animals, lacZ+ and Dct+ melanoblasts appear in the MSA at E10 but fail to migrate into the dorsolateral path. These results indicate that EDN3/EDNRB signaling is required for dorsolateral migration of melanoblasts but not for fate specification of NCCs (Pavan and Tilghman, 1994; Lee et al., 2003). This is consistent with experiments in mice that show EDN3-EDNRB signaling is required between E10 and E12.5 for normal coat pigmentation (Shin et al., 1999).

EDN3-EDNRB signaling likely plays a cell-autonomous role in melanoblast migration (Druckenbrod et al., 2008), though the underlying mechanisms are not fully understood (Fig. 6B). Studies using avian models suggest that EDN3-EDNRB signaling serves a pathfinding role in the migratory process (Pla et al., 2005; Harris et al., 2008). Aves have two types of EDNRB receptors: Ednrb and its paralog Ednrb2 (Lecoin et al., 1998). Although trunk NCCs initially express Ednrb, the subpopulation that adopts a melanocyte fate downregulates Ednrb and upregulates Ednrb2, driving melanoblast migration through the dorsolateral pathway. While the extracellular environment of the dorsolateral pathway contains repulsive signaling molecules (Harris et al., 2008), melanoblasts appear to overcome these repulsive cues through the cooperative effects of Ednrb2 and EphB2, a gene that encodes for Ephrin receptor B2 (Harris et al., 2008). In contrast, trunk NCCs expressing Ednrb are unable to enter the dorsolateral pathway (Pla et al., 2005). Future work is needed to better understand the functional differences between Ednrb and Ednrb2 and whether similar signaling mechanisms underlie melanoblast migration in mammals.

Melanocyte maturation

Cell culture and explant assays have suggested that EDN3-EDNRB plays additional roles throughout different stages of melanocyte maturation (Saldana-Caboverde and Kos, 2010). In uncommitted trunk NCCs, EDN3-EDNRB inhibits differentiation and promotes proliferation (Lahav et al., 1996, 1998). After trunk NCCs have adopted a melanoblast identity, EDN3-EDNRB works cooperatively with KIT ligand and KIT tyrosine kinase to promote survival, proliferation and terminal differentiation to melanocytes (Lahav et al., 1998; Reid et al., 1996; Opdecamp et al., 1998; Ono et al., 1998; Hou et al., 2004; Aoki et al., 2005). Terminal differentiation is likely mediated by protein kinase C (PKC), a signaling effector downstream of EDNRB (Ono et al., 1998; Hou et al., 2004). The mechanism of signaling crosstalk between EDN3-EDNRB and KITL-KIT, and the G protein pathways that mediate PKC signaling in terminal differentiation, are not fully understood. Furthermore, it is unknown whether the effects of EDN3-EDNRB on cultured cells and explants also apply to trunk NCCs and melanoblasts in vivo. (Lahav et al., 1996, 1998; Reid et al., 1996; Opdecamp et al., 1998; Hou et al., 2004).

Enteric nervous system development

The ENS is comprised of neurons and glial cells that form a network of ganglions that regulate gastrointestinal functions such as peristalsis, secretion and absorption (Kang et al., 2021). These neurons and glial cells are derived from vagal and sacral NCCs, which we refer to collectively as enteric neural crest cells (ENCCs). Vagal NCCs contribute to the entire ENS, whereas contributions by the sacral NCCs are limited to a small proportion in the distal colon (Fig. 2, Fig. 6C) (Hutchins et al., 2018). In zebrafish, the ENS is likely derived exclusively from vagal NCCs (Kuil et al., 2020).

EDN3-EDNRB signaling is required for ENCCs to migrate into and colonize the hindgut, with loss of this signaling pathway resulting in an aganglionic distal colon and additional defects in ganglionated areas (Zaitoun et al., 2013; Cheng et al., 2016; Bondurand et al., 2018; Bhave et al., 2021). Similar defects are observed in humans with mutations in EDN3 or EDNRB (Box 2). Ednrb is expressed in both ENCCs and mesenchymal cells of the gut (Nataf et al., 1996, 1998a; Leibl et al., 1999; Wu et al., 1999; Barlow et al., 2003). Edn3 is expressed in the gut mesenchyme; in mice, expression occurs in a dynamic pattern over time, first being expressed in the midgut and hindgut (∼E10.5) before shifting to the cecum and proximal colon (∼E14.5) (Barlow et al., 2003) (Fig. 6C).

Distal colon aganglionosis in EDN3-EDNRB mutant animals is caused by the failure of ENCCs to migrate into the distal gut. ENCCs colonize the fetal gut in highly stereotyped migratory behavior in all model organisms studied thus far (reviewed by Bondurand et al., 2018; Kang et al., 2021). In mice, ENCCs derived from vagal NCCs adjacent to somites 1-7 enter the foregut around E9-E9.5 and advance through the intestine as a wavefront in a rostral-caudal direction (Young et al., 2004; Druckenbrod and Epstein, 2005) (Fig. 6C). By E11.5, the wavefront arrives at the edge of the ileo-cecal junction and stalls for ∼12 h before colonizing the hindgut (Kapur et al., 1995; Lee et al., 2003; Nishiyama et al., 2012). In Edn3 and Ednrb mutant mice, ENCCs reach the ileo-cecal junction but fail to advance into the hindgut (Kapur et al., 1992; Barlow et al., 2003; Kruger et al., 2003; Druckenbrod and Epstein, 2005) (Fig. 6C). Sacral NCCs also fail to properly colonize the distal colon in Ednrb mutant mice (Burns et al., 2000; Lee et al., 2003; Erickson et al., 2012). This ENCC migration defect is attributed to multiple mechanisms.

During gut development, proliferation and differentiation of ENCCs must be properly coordinated in order to maintain a sufficient pool of progenitor cells to colonize the entire gut (Nagy and Goldstein, 2006). This balance between proliferation versus differentiation is maintained in part by EDN3-EDNRB signaling, which promotes proliferation and inhibits differentiation of ENCCs (Lahav et al., 1996; Reid et al., 1996; Hearn et al., 1998; Wu et al., 1999). Loss of this signaling pathway causes premature differentiation of ENCCs into neurons and glial cells, thus depleting the pool of progenitor cells required to colonize the distal colon (Hearn et al., 1998; Wu et al., 1999; Lee et al., 2003; Bondurand et al., 2006; Nagy and Goldstein, 2006; Watanabe et al., 2017).

ENCC migration is also coordinated by functional interactions between EDN3-EDNRB and rearranged during transfection (RET) receptor tyrosine kinase and its ligand Glial cell line-derived neurotrophic factor (GDNF). GDNF-RET is a crucial signaling pathway in ENS development that is required for ENCC survival, proliferation and chemoattraction (Young et al., 2001; Natarajan et al., 2002). Both GDNF and EDN3 are highly expressed in the cecum when the ENCC wavefront arrives at the ileo-cecal junction and EDN3 not only augments the proliferative effects of GDNF but also antagonizes the chemoattractive properties of GDNF (Hearn et al., 1998; Barlow et al., 2003; Kruger et al., 2003; Nagy and Goldstein, 2006). This signaling crosstalk likely permits continued ENCC migration towards the hindgut. Further, the dual effects of EDN3-EDNRB on GDNF-RET signaling are mediated by inhibition of PKA, though the exact mechanisms of signal crosstalk is not yet fully understood (Barlow et al., 2003; Goto et al., 2013; Gazquez et al., 2016; Hao et al., 2019). EDNRB and RET also regulate one another's expression levels through a shared gene regulatory network (Chatterjee et al., 2016; Chatterjee and Chakravarti, 2019). The cis-regulatory elements (CREs) that control EDNRB and RET expression in ENCCs share binding motifs for transcription factors SOX10 and GATA2 (Chatterjee and Chakravarti, 2019). Further, expression of both Sox10 and Gata2 is positively regulated by EDN3-EDNRB and GDNF-RET signaling in a feedforward mechanism, suggesting that disruptions to one signaling pathway can also lead to disruptions to both. Further work is needed to better understand how interactions between EDN3-EDNRB and GDNF-RET at the levels of cell signaling and gene regulation impact ENCC biology during ENS development.

The ENCC migration defect is also likely caused by changes to the composition of extracellular matrix (ECM) proteins in the gut mesenchyme (Nagy and Goldstein, 2006). In Edn3 and Ednrb mutant animals, the expression of numerous ECM components such as collagens, proteoglycans, laminins and laminin receptors are upregulated in the distal colon (Tennyson et al., 1990; Rothman et al., 1996; Fu et al., 2020). Many of these ECM components inhibit ENCC migration in vitro, leading to the hypothesis that failure of ENCC migration into the distal hindgut is attributed in part to upregulation of inhibitory ECM components (Druckenbrod and Epstein, 2009). Contrary to this model, a recent study has found that a pro-migratory ECM component, laminin β1, is upregulated in the distal hindgut mesenchyme of conventional (Ednrblacz/lacz) and NCC-specific (Wnt1-Cre;Ednrbflex3/flex3) Ednrb knockout mice (Fu et al., 2020). Further, application of YIGSR, a pentapeptide mimic of the receptor binding region of laminin β1, on whole gut explants from E12.5 Wnt1-Cre;Ednrbflex3/flex3 mice restored ENCC colonization of the distal colon and promoted directional cell migration of ENCCs in midgut slice cultures from E12.5 wild-type mice in a GDNF-dependent manner. This effect was further enhanced by β1-integrin, another pro-migratory ECM component implicated to interact with EDN3-EDNRB (Gazquez et al., 2016). ENCCs in Ednrb mutant mice also exhibited downregulation and changes to subcellular localization of the 37/67-laminin receptor (a laminin β1 receptor). Elucidating the functional interactions between EDN3-EDNRB signaling and expression of ECM components will be essential for advancing stem cell-based regenerative therapies for HSCR (Box 2).

In addition to distal colon aganglionosis in Ednrb−/− mice, structural and functional deficits have also been reported in ganglionated regions of the proximal colon, small intestine and stomach (Ro et al., 2006; Roberts et al., 2008; Zaitoun et al., 2013; Cheng et al., 2016; Bhave et al., 2021). These regions display abnormal intestinal motor function and ENS structure, characterized by irregular proportions of nitrergic and cholinergic neurons and irregularities in the number and sizes of ganglia and neuronal fiber density (Cheng et al., 2016; Bhave et al., 2021). The causative mechanisms are unknown, though comparison of ENCC-derived neuronal subtypes in the small intestine between E14 wildtype and Ednrb−/− embryos using single cell RNA-seq data revealed that a cell cluster expressing Neurod6 and Gad2 is absent in Ednrb−/− embryos (Bhave et al., 2022). These genes represent markers of GABAergic neurons, but further work is needed to understand how the loss of these neurons lead to functional deficits in the ganglionated regions of Ednrb−/− mice.

Research over at least the last 30 years has clearly established that endothelin signaling is essential for many aspects of embryonic development, with its disruption contributing to congenital disorders in humans. In the case of HSCR, this knowledge has led to promising developments in a stem cell-based strategy to restore distal colon innervation. In addition, investigations across a wide variety of vertebrates have illustrated the deep evolutionary conservation of endothelin function in the development of tissues and organs that are fundamental for species survival. Looking ahead, new findings from endothelin research will be driven by ongoing innovations in genome editing tools, -omics, imaging technologies and biosensors for cell signaling. This next phase of endothelin research will undoubtedly provide novel insights into mechanisms of embryonic development, with major implications for improving the diagnosis and treatment of individuals with endothelin-associated congenital disorders.

The authors would like to thank the Walker family for sharing their experiences, the numerous scientists whose work is part of this review and Dr Masashi Yanagisawa, who supported and encouraged D.E.C. during the initiation of this work.

Funding

This work is supported in part by the National Institute of Dental and Craniofacial Research (DE029406 and DE032428 to S.M.K. and DE029091 to D.E.C.). Deposited in PMC for release after 12 months.

Abu-Issa
,
R.
and
Kirby
,
M. L.
(
2007
).
Heart field: from mesoderm to heart tube
.
Annu. Rev. Cell Dev. Biol.
23
,
45
-
68
.
Adameyko
,
I.
,
Lallemend
,
F.
,
Furlan
,
A.
,
Zinin
,
N.
,
Aranda
,
S.
,
Kitambi
,
S. S.
,
Blanchart
,
A.
,
Favaro
,
R.
,
Nicolis
,
S.
,
Lübke
,
M.
et al. 
(
2012
).
Sox2 and Mitf cross-regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest
.
Development
139
,
397
-
410
.
Alexander
,
C.
,
Zuniga
,
E.
,
Blitz
,
I. L.
,
Wada
,
N.
,
Le Pabic
,
P.
,
Javidan
,
Y.
,
Zhang
,
T.
,
Cho
,
K. W.
,
Crump
,
J. G.
and
Schilling
,
T. F.
(
2011
).
Combinatorial roles for BMPs and Endothelin 1 in patterning the dorsal-ventral axis of the craniofacial skeleton
.
Development
138
,
5135
-
5146
.
Alexander
,
C.
,
Piloto
,
S.
,
Le Pabic
,
P.
and
Schilling
,
T. F.
(
2014
).
Wnt signaling interacts with bmp and edn1 to regulate dorsal-ventral patterning and growth of the craniofacial skeleton
.
PLoS Genet.
10
,
e1004479
.
Amiel
,
J.
,
Sproat-Emison
,
E.
,
Garcia-Barcelo
,
M.
,
Lantieri
,
F.
,
Burzynski
,
G.
,
Borrego
,
S.
,
Pelet
,
A.
,
Arnold
,
S.
,
Miao
,
X.
,
Griseri
,
P.
et al. 
(
2008
).
Hirschsprung disease, associated syndromes and genetics: a review
.
J. Med. Genet.
45
,
1
-
14
.
Aoki
,
H.
,
Motohashi
,
T.
,
Yoshimura
,
N.
,
Yamazaki
,
H.
,
Yamane
,
T.
,
Panthier
,
J. J.
and
Kunisada
,
T
. (
2005
).
Cooperative and indispensable roles of endothelin 3 and KIT signalings in melanocyte development
.
Dev. Dyn.
233
,
407
-
417
.
Arai
,
H.
,
Hori
,
S.
,
Aramori
,
I.
,
Ohkubo
,
H.
and
Nakanishi
,
S.
(
1990
).
Cloning and expression of a cDNA encoding an endothelin receptor
.
Nature
348
,
730
-
732
.
Aramori
,
I.
and
Nakanishi
,
S.
(
1992
).
Coupling of two endothelin receptor subtypes to differing signal transduction in transfected Chinese hamster ovary cells
.
J. Biol. Chem.
267
,
12468
-
12474
.
Asai
,
R.
,
Kurihara
,
Y.
,
Fujisawa
,
K.
,
Sato
,
T.
,
Kawamura
,
Y.
,
Kokubo
,
H.
,
Tonami
,
K.
,
Nishiyama
,
K.
,
Uchijima
,
Y.
,
Miyagawa-Tomita
,
S.
et al. 
(
2010
).
Endothelin receptor type A expression defines a distinct cardiac subdomain within the heart field and is later implicated in chamber myocardium formation
.
Development
137
,
3823
-
3833
.
Barlow
,
A.
,
de Graaff
,
E.
and
Pachnis
,
V.
(
2003
).
Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET
.
Neuron
40
,
905
-
916
.
Barron
,
F.
,
Woods
,
C.
,
Kuhn
,
K.
,
Bishop
,
J.
,
Howard
,
M. J.
and
Clouthier
,
D. E.
(
2011
).
Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis
.
Development
138
,
2249
-
2259
.
Barske
,
L.
,
Askary
,
A.
,
Zuniga
,
E.
,
Balczerski
,
B.
,
Bump
,
P.
,
Nichols
,
J. T.
and
Crump
,
J. G.
(
2016
).
Competition between jagged-notch and endothelin1 signaling selectively restricts cartilage formation in the zebrafish upper face
.
PLoS Genet.
12
,
e1005967
.
Barske
,
L.
,
Rataud
,
P.
,
Behizad
,
K.
,
Del Rio
,
L.
,
Cox
,
S. G.
and
Crump
,
J. G.
(
2018
).
Essential role of Nr2f nuclear receptors in patterning the vertebrate upper jaw
.
Dev. Cell
44
,
337
-
347.e335
.
Barton
,
M.
and
Yanagisawa
,
M.
(
2019
).
Endothelin: 30 years from discovery to therapy
.
Hypertension
74
,
1232
-
1265
.
Baynash
,
A. G.
,
Hosoda
,
K.
,
Giaid
,
A.
,
Richardson
,
J. A.
,
Emoto
,
N.
,
Hammer
,
R. E.
and
Yanagisawa
,
M.
(
1994
).
Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons
.
Cell
79
,
1277
-
1285
.
Beverdam
,
A.
,
Merlo
,
G. R.
,
Paleari
,
L.
,
Mantero
,
S.
,
Genova
,
F.
,
Barbieri
,
O.
,
Janvier
,
P.
and
Levi
,
G.
(
2002
).
Jaw transformation with gain of symmetry after Dlx5/Dlx 6 inactivation: mirror of the past
.
Genesis
34
,
221
-
227
.
Bhave
,
S.
,
Arciero
,
E.
,
Baker
,
C.
,
Ho
,
W. L.
,
Guyer
,
R. A.
,
Hotta
,
R.
and
Goldstein
,
A. M.
(
2021
).
Pan-enteric neuropathy and dysmotility are present in a mouse model of short-segment Hirschsprung disease and may contribute to post-pullthrough morbidity
.
J. Pediatr. Surg.
56
,
250
-
256
.
Bhave
,
S.
,
Guyer
,
R. A.
,
Picard
,
N.
,
Omer
,
M.
,
Hotta
,
R.
and
Goldstein
,
A. M.
(
2022
).
Ednrb (-/-) mice with Hirschsprung disease are missing Gad2-expressing enteric neurons in the ganglionated small intestine
.
Front. Cell Dev. Biol.
10
,
917243
.
Bonano
,
M.
,
Tríbulo
,
C.
,
De Calisto
,
J.
,
Marchant
,
L.
,
Sánchez
,
S. S.
,
Mayor
,
R.
and
Aybar
,
M. J.
(
2008
).
A new role for the Endothelin-1/Endothelin-A receptor signaling during early neural crest specification
.
Dev. Biol.
323
,
114
-
129
.
Bondurand
,
N.
,
Natarajan
,
D.
,
Barlow
,
A.
,
Thapar
,
N.
and
Pachnis
,
V.
(
2006
).
Maintenance of mammalian enteric nervous system progenitors by SOX10 and endothelin 3 signalling
.
Development
133
,
2075
-
2086
.
Bondurand
,
N.
,
Dufour
,
S.
and
Pingault
,
V.
(
2018
).
News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders
.
Dev. Biol.
444
Suppl. 1
,
S156
-
s169
.
Bonilla-Claudio
,
M.
,
Wang
,
J.
,
Bai
,
Y.
,
Klysik
,
E.
,
Selever
,
J.
and
Martin
,
J. F.
(
2012
).
Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development
.
Development
139
,
709
-
719
.
Braasch
,
I.
,
Volff
,
J. N.
and
Schartl
,
M.
(
2009
).
The endothelin system: evolution of vertebrate-specific ligand-receptor interactions by three rounds of genome duplication
.
Mol. Biol. Evol.
26
,
783
-
799
.
Brand
,
M.
,
Le Moullec
,
J. M.
,
Corvol
,
P.
and
Gasc
,
J. M.
(
1998
).
Ontogeny of endothelins-1 and -3, their receptors, and endothelin converting enzyme-1 in the early human embryo
.
J. Clin. Invest.
101
,
549
-
559
.
Burns
,
A. J.
and
Thapar
,
N.
(
2014
).
Neural stem cell therapies for enteric nervous system disorders
.
Nat. Rev. Gastroenterol. Hepatol.
11
,
317
-
328
.
Burns
,
A. J.
,
Champeval
,
D.
and
Le Douarin
,
N. M.
(
2000
).
Sacral neural crest cells colonise aganglionic hindgut in vivo but fail to compensate for lack of enteric ganglia
.
Dev. Biol.
219
,
30
-
43
.
Chai
,
Y.
,
Jiang
,
X.
,
Ito
,
Y.
,
Bringas
,
P.
, Jr.
,
Han
,
J.
,
Rowitch
,
D. H.
,
Soriano
,
P.
,
McMahon
,
A. P.
and
Sucov
,
H. M.
(
2000
).
Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis
.
Development
127
,
1671
-
1679
.
Chang
,
I.
,
Bramall
,
A. N.
,
Baynash
,
A. G.
,
Rattner
,
A.
,
Rakheja
,
D.
,
Post
,
M.
,
Joza
,
S.
,
McKerlie
,
C.
,
Stewart
,
D. J.
,
McInnes
,
R. R.
et al. 
(
2013
).
Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice
.
J. Clin. Invest.
123
,
2643
-
2653
.
Charité
,
J.
,
McFadden
,
D. G.
,
Merlo
,
G. R.
,
Levi
,
G.
,
Clouthier
,
D. E.
,
Yanagisawa
,
M.
,
Richardson
,
J. A.
and
Olson
,
E. N.
(
2001
).
Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer
.
Genes Dev.
15
,
3039
-
3049
.
Chatterjee
,
S.
and
Chakravarti
,
A.
(
2019
).
A gene regulatory network explains RET-EDNRB epistasis in Hirschsprung disease
.
Hum. Mol. Genet.
28
,
3137
-
3147
.
Chatterjee
,
S.
,
Kapoor
,
A.
,
Akiyama
,
J. A.
,
Auer
,
D. R.
,
Lee
,
D.
,
Gabriel
,
S.
,
Berrios
,
C.
,
Pennacchio
,
L. A.
and
Chakravarti
,
A.
(
2016
).
Enhancer variants synergistically drive dysfunction of a gene regulatory network in Hirschsprung disease
.
Cell
167
,
355
-
368.e310
.
Cheng
,
L. S.
,
Schwartz
,
D. M.
,
Hotta
,
R.
,
Graham
,
H. K.
and
Goldstein
,
A. M.
(
2016
).
Bowel dysfunction following pullthrough surgery is associated with an overabundance of nitrergic neurons in Hirschsprung disease
.
J. Pediatr. Surg.
51
,
1834
-
1838
.
Clouthier
,
D. E.
,
Hosoda
,
K.
,
Richardson
,
J. A.
,
Williams
,
S. C.
,
Yanagisawa
,
H.
,
Kuwaki
,
T.
,
Kumada
,
M.
,
Hammer
,
R. E.
and
Yanagisawa
,
M.
(
1998
).
Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice
.
Development
125
,
813
-
824
.
Clouthier
,
D. E.
,
Williams
,
S. C.
,
Yanagisawa
,
H.
,
Wieduwilt
,
M.
,
Richardson
,
J. A.
and
Yanagisawa
,
M.
(
2000
).
Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice
.
Dev. Biol.
217
,
10
-
24
.
Clouthier
,
D. E.
,
Garcia
,
E.
and
Schilling
,
T. F.
(
2010
).
Regulation of facial morphogenesis by endothelin signaling: insights from mice and fish
.
Am. J. Med. Genet. A
152A
,
2962
-
2973
.
Clouthier
,
D. E.
,
Passos-Bueno
,
M. R.
,
Tavares
,
A. L.
,
Lyonnet
,
S.
,
Amiel
,
J.
and
Gordon
,
C. T.
(
2013
).
Understanding the basis of auriculocondylar syndrome: Insights from human, mouse and zebrafish genetic studies
.
Am. J. Med. Genet. C Semin. Med. Genet.
163c
,
306
-
317
.
Cushman
,
L. J.
,
Torres-Martinez
,
W.
and
Weaver
,
D. D.
(
2005
).
Johnson-McMillin syndrome: report of a new case with novel features
.
Birth Defects Res. A Clin. Mol. Teratol
73
,
638
-
641
.
Denault
,
J. B.
,
Claing
,
A.
,
D'Orleans-Juste
,
P.
,
Sawamura
,
T.
,
Kido
,
T.
,
Masaki
,
T.
and
Leduc
,
R.
(
1995
).
Processing of proendothelin-1 by human furin convertase
.
FEBS Lett.
362
,
276
-
280
.
Depew
,
M. J.
,
Lufkin
,
T.
and
Rubenstein
,
J. L.
(
2002
).
Specification of jaw subdivisions by Dlx genes
.
Science
298
,
381
-
385
.
Dettlaff-Swiercz
,
D. A.
,
Wettschureck
,
N.
,
Moers
,
A.
,
Huber
,
K.
and
Offermanns
,
S.
(
2005
).
Characteristic defects in neural crest cell-specific Gaq/Ga11- and Ga12/Ga13-deficient mice
.
Dev. Biol.
282
,
174
-
182
.
Donoghue
,
P. C.
,
Graham
,
A.
and
Kelsh
,
R. N.
(
2008
).
The origin and evolution of the neural crest
.
BioEssays
30
,
530
-
541
.
Druckenbrod
,
N. R.
and
Epstein
,
M. L.
(
2005
).
The pattern of neural crest advance in the cecum and colon
.
Dev. Biol.
287
,
125
-
133
.
Druckenbrod
,
N. R.
and
Epstein
,
M. L.
(
2009
).
Age-dependent changes in the gut environment restrict the invasion of the hindgut by enteric neural progenitors
.
Development
136
,
3195
-
3203
.
Druckenbrod
,
N. R.
,
Powers
,
P. A.
,
Bartley
,
C. R.
,
Walker
,
J. W.
and
Epstein
,
M. L
. (
2008
).
Targeting of endothelin receptor-B to the neural crest
.
Genesis
46
,
396
-
400
.
Dupin
,
E.
and
Le Douarin
,
N. M.
(
2003
).
Development of melanocyte precursors from the vertebrate neural crest
.
Oncogene
22
,
3016
-
3023
.
Elliott
,
K. H.
,
Chen
,
X.
,
Salomone
,
J.
,
Chaturvedi
,
P.
,
Schultz
,
P. A.
,
Balchand
,
S. K.
,
Servetas
,
J. D.
,
Zuniga
,
A.
,
Zeller
,
R.
,
Gebelein
,
B.
et al. 
(
2020
).
Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
.
eLife
9
,
e56450
.
Emoto
,
N.
and
Yanagisawa
,
M.
(
1995
).
Endothelin converting enzyme-2: a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum
.
J. Biol. Chem.
70
,
15262
-
15268
.
Erickson
,
C. A.
and
Goins
,
T. L.
(
1995
).
Avian neural crest cells can migrate in the dorsolateral path only if they are specified as melanocytes
.
Development
121
,
915
-
924
.
Erickson
,
C. A.
,
Duong
,
T. D.
and
Tosney
,
K. W.
(
1992
).
Descriptive and experimental analysis of the dispersion of neural crest cells along the dorsolateral path and their entry into ectoderm in the chick embryo
.
Dev. Biol.
151
,
251
-
272
.
Erickson
,
C. S.
,
Zaitoun
,
I.
,
Haberman
,
K. M.
,
Gosain
,
A.
,
Druckenbrod
,
N. R.
and
Epstein
,
M. L.
(
2012
).
Sacral neural crest-derived cells enter the aganglionic colon of Ednrb-/- mice along extrinsic nerve fibers
.
J. Comp. Neurol.
520
,
620
-
632
.
Fan
,
Y.
,
Hackland
,
J.
,
Baggiolini
,
A.
,
Hung
,
L. Y.
,
Zhao
,
H.
,
Zumbo
,
P.
,
Oberst
,
P.
,
Minotti
,
A. P.
,
Hergenreder
,
E.
,
Najjar
,
S.
et al. 
. (
2023
).
hPSC-derived sacral neural crest enables rescue in a severe model of Hirschsprung's disease
.
Cell Stem Cell
30
,
264
-
282.e9
.
Freyer
,
L.
,
Aggarwal
,
V.
and
Morrow
,
B. E.
(
2011
).
Dual embryonic origin of the mammalian otic vesicle forming the inner ear
.
Development
138
,
5403
-
5414
.
Frisdal
,
A.
and
Trainor
,
P. A.
(
2014
).
Development and evolution of the pharyngeal apparatus
.
Wiley Interdiscip Rev. Dev. Biol.
3
,
403
-
418
.
Fritz
,
K. R.
,
Zhang
,
Y.
and
Ruest
,
L. B.
(
2019
).
Cdc42 activation by endothelin regulates neural crest cell migration in the cardiac outflow tract
.
Dev. Dyn.
248
,
795
-
812
.
Fu
,
M.
,
Barlow-Anacker
,
A. J.
,
Kuruvilla
,
K. P.
,
Bowlin
,
G. L.
,
Seidel
,
C. W.
,
Trainor
,
P. A.
and
Gosain
,
A
. (
2020
).
37/67-laminin receptor facilitates neural crest cell migration during enteric nervous system development
.
FASEB J.
34
,
10931
-
10947
.
Fukuhara
,
S.
,
Kurihara
,
Y.
,
Arima
,
Y.
,
Yamada
,
N.
and
Kurihara
,
H.
(
2004
).
Temporal requirement of signaling cascade involving endothelin-1/endothelin receptor type A in branchial arch development
.
Mech. Dev.
121
,
1223
-
1233
.
Funato
,
N.
,
Kokubo
,
H.
,
Nakamura
,
M.
,
Yanagisawa
,
H.
and
Saga
,
Y.
(
2016
).
Specification of jaw identity by the Hand2 transcription factor
.
Sci. Rep.
6
,
28405
.
Gazquez
,
E.
,
Watanabe
,
Y.
,
Broders-Bondon
,
F.
,
Paul-Gilloteaux
,
P.
,
Heysch
,
J.
,
Baral
,
V.
,
Bondurand
,
N.
and
Dufour
,
S.
(
2016
).
Endothelin-3 stimulates cell adhesion and cooperates with β1-integrins during enteric nervous system ontogenesis
.
Sci. Rep.
6
,
37877
.
Gilman
,
A. G.
(
1987
).
G proteins: transducers of receptor-generated signals
.
Annu. Rev. Biochem.
56
,
615
-
649
.
Gordon
,
C. T.
,
Petit
,
F.
,
Kroisel
,
P. M.
,
Jakobsen
,
L.
,
Zechi-Ceide
,
R. M.
,
Oufadem
,
M.
,
Bole-Feysot
,
C.
,
Pruvost
,
S.
,
Masson
,
C.
,
Tores
,
F.
et al. 
(
2013a
).
Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears
.
Am. J. Hum. Genet.
93
,
1118
-
1125
.
Gordon
,
C. T.
,
Vuillot
,
A.
,
Marlin
,
S.
,
Gerkes
,
E.
,
Henderson
,
A.
,
Alkindy
,
A.
,
Holder-Espinasse
,
M.
,
Park
,
S. S.
,
Omarjee
,
A.
,
Sanchis-Borja
,
M.
et al. 
(
2013b
).
Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome
.
Am. J. Med. Genet., Part A.
50
,
174
-
186
.
Gordon
,
C. T.
,
Weaver
,
K. N.
,
Zechi-Ceide
,
R. M.
,
Madsen
,
E. C.
,
Tavares
,
A. L.
,
Oufadem
,
M.
,
Kurihara
,
Y.
,
Adameyko
,
I.
,
Picard
,
A.
,
Breton
,
S.
et al. 
(
2015
).
Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia
.
Am. J. Hum. Genet.
96
,
519
-
531
.
Goto
,
A.
,
Sumiyama
,
K.
,
Kamioka
,
Y.
,
Nakasyo
,
E.
,
Ito
,
K.
,
Iwasaki
,
M.
,
Enomoto
,
H.
and
Matsuda
,
M.
(
2013
).
GDNF and endothelin 3 regulate migration of enteric neural crest-derived cells via protein kinase A and Rac1
.
J. Neurosci.
33
,
4901
-
4912
.
Gourdie
,
R. G.
,
Wei
,
Y.
,
Kim
,
D.
,
Klatt
,
S. C.
and
Mikawa
,
T.
(
1998
).
Endothelin-induced conversion of embryonic heart muscle cells into impulse-conducting Purkinje fibers
.
Proc. Natl. Acad. Sci. USA
95
,
6815
-
6818
.
Greig
,
A. V.
,
Podda
,
S.
,
Thorne
,
C. H.
and
McCarthy
,
J. G.
(
2012
).
The question mark ear in patients with mandibular hypoplasia
.
Plast. Reconstr. Surg.
129
,
368e
-
369e
.
Hall
,
C. E.
,
Hurtado
,
R.
,
Hewett
,
K. W.
,
Shulimovich
,
M.
,
Poma
,
C. P.
,
Reckova
,
M.
,
Justus
,
C.
,
Pennisi
,
D. J.
,
Tobita
,
K.
,
Sedmera
,
D.
et al. 
(
2004
).
Hemodynamic-dependent patterning of endothelin converting enzyme 1 expression and differentiation of impulse-conducting Purkinje fibers in the embryonic heart
.
Development
131
,
581
-
592
.
Hao
,
M. M.
,
Bergner
,
A. J.
,
Nguyen
,
H. T. H.
,
Dissanayake
,
P.
,
Burnett
,
L. E.
,
Hopkins
,
C. D.
,
Zeng
,
K.
,
Young
,
H. M.
and
Stamp
,
L. A.
(
2019
).
Role of JNK, MEK and adenylyl cyclase signalling in speed and directionality of enteric neural crest-derived cells
.
Dev. Biol.
455
,
362
-
368
.
Harris
,
M. L.
,
Hall
,
R.
and
Erickson
,
C. A.
(
2008
).
Directing pathfinding along the dorsolateral path - the role of EDNRB2 and EphB2 in overcoming inhibition
.
Development
135
,
4113
-
4122
.
Harrison
,
V. J.
,
Ziegler
,
T.
,
Bouzourene
,
K.
,
Suciu
,
A.
,
Silacci
,
P.
and
Hayoz
,
D.
(
1998
).
Endothelin-1 and endothelin-converting enzyme-1 gene regulation by shear stress and flow-induced pressure
.
J. Cardiovasc. Pharmacol.
31
Suppl. 1
,
S38
-
S41
.
Hearn
,
C. J.
,
Murphy
,
M.
and
Newgreen
,
D.
(
1998
).
GDNF and ET-3 differentially modulate the numbers of avian enteric neural crest cells and enteric neurons in vitro
.
Dev. Biol.
197
,
93
-
105
.
Heuckeroth
,
R. O
. (
2018
).
Hirschsprung disease - integrating basic science and clinical medicine to improve outcomes
.
Nat. Rev. Gastroenterol. Hepatol.
15
,
152
-
167
.
Hofstra
,
R. M.
,
Valdenaire
,
O.
,
Arch
,
E.
,
Osinga
,
J.
,
Kroes
,
H.
,
Loffler
,
B. M.
,
Hamosh
,
A.
,
Meijers
,
C.
and
Buys
,
C. H.
(
1999
).
A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction
.
Am. J. Hum. Genet.
64
,
304
-
308
.
Hosoda
,
K.
,
Hammer
,
R. E.
,
Richardson
,
J. A.
,
Baynash
,
A. G.
,
Cheung
,
J. C.
,
Giaid
,
A.
and
Yanagisawa
,
M.
(
1994
).
Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice
.
Cell
79
,
1267
-
1276
.
Hotta
,
R.
,
Cheng
,
L. S.
,
Graham
,
H. K.
,
Pan
,
W.
,
Nagy
,
N.
,
Belkind-Gerson
,
J.
and
Goldstein
,
A. M
. (
2016
).
Isogenic enteric neural progenitor cells can replace missing neurons and glia in mice with Hirschsprung disease
.
Neurogastroenterol. Motil.
28
,
498
-
512
.
Hou
,
L.
,
Pavan
,
W. J.
,
Shin
,
M. K.
and
Arnheiter
,
H.
(
2004
).
Cell-autonomous and cell non-autonomous signaling through endothelin receptor B during melanocyte development
.
Development
131
,
3239
-
3247
.
Hu
,
J.
,
Verzi
,
M. P.
,
Robinson
,
A. S.
,
Tang
,
P. L.
,
Hua
,
L. L.
,
Xu
,
S. M.
,
Kwok
,
P. Y.
and
Black
,
B. L.
(
2015
).
Endothelin signaling activates Mef2c expression in the neural crest through a MEF2C-dependent positive-feedback transcriptional pathway
.
Development
142
,
2775
-
2780
.
Hutchins
,
E. J.
,
Kunttas
,
E.
,
Piacentino
,
M. L.
,
Howard
,
A. G. A. T.
,
Bronner
,
M. E.
and
Uribe
,
R. A.
(
2018
).
Migration and diversification of the vagal neural crest
.
Dev. Biol.
444
Suppl. 1
,
S98
-
S109
.
Hutson
,
M. R.
and
Kirby
,
M. L.
(
2007
).
Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations
.
Semin. Cell Dev. Biol.
18
,
101
-
110
.
Hyndman
,
K. A.
and
Evans
,
D. H.
(
2007
).
Endothelin and endothelin converting enzyme-1 in the fish gill: evolutionary and physiological perspectives
.
J. Exp. Biol.
210
,
4286
-
4297
.
Ikle
,
J. M.
,
Tavares
,
A. L.
,
King
,
M.
,
Ding
,
H.
,
Colombo
,
S.
,
Firulli
,
B. A.
,
Firulli
,
A. B.
,
Targoff
,
K. L.
,
Yelon
,
D.
and
Clouthier
,
D. E.
(
2017
).
Nkx2.5 regulates endothelin converting enzyme-1 during pharyngeal arch patterning
.
Genesis
55
,
dvg.23021
.
Inoue
,
A.
,
Yanagisawa
,
M.
,
Kimura
,
S.
,
Kasuya
,
Y.
,
Miyauchi
,
T.
,
Goto
,
K.
and
Masaki
,
T.
(
1989
).
The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes
.
Proc. Natl. Acad. Sci. USA
86
,
2863
-
2867
.
Isberg
,
V.
,
Mordalski
,
S.
,
Munk
,
C.
,
Rataj
,
K.
,
Harpsøe
,
K.
,
Hauser
,
A. S.
,
Vroling
,
B.
,
Bojarski
,
A. J.
,
Vriend
,
G.
and
Gloriam
,
D. E.
(
2016
).
GPCRdb: an information system for G protein-coupled receptors
.
Nucleic Acids Res.
44
,
D356
-
D364
.
Ivey
,
K.
,
Tyson
,
B.
,
Ukidwe
,
P.
,
McFadden
,
D. G.
,
Levi
,
G.
,
Olson
,
E. N.
,
Srivastava
,
D.
and
Wilkie
,
T. M.
(
2003
).
Galphaq and Galpha11 proteins mediate endothelin-1 signaling in neural crest-derived pharyngeal arch mesenchyme
.
Dev. Biol.
255
,
230
-
237
.
Jiang
,
X.
,
Rowitch
,
D. H.
,
Soriano
,
P.
,
McMahon
,
A. P.
and
Sucov
,
H. M.
(
2000
).
Fate of the mammalian cardiac neural crest
.
Development
127
,
1607
-
1616
.
Jin
,
Y. R.
,
Turcotte
,
T. J.
,
Crocker
,
A. L.
,
Han
,
X. H.
and
Yoon
,
J. K.
(
2011
).
The canonical Wnt signaling activator, R-spondin2, regulates craniofacial patterning and morphogenesis within the branchial arch through ectodermal-mesenchymal interaction
.
Dev. Biol.
352
,
1
-
13
.
Johnson
,
S. L.
,
Africa
,
D.
,
Walker
,
C.
and
Weston
,
J. A.
(
1995
).
Genetic control of adult pigment stripe development in zebrafish
.
Dev. Biol.
167
,
27
-
33
.
Kadamur
,
G.
and
Ross
,
E. M.
(
2013
).
Mammalian phospholipase C
.
Annu. Rev. Physiol.
75
,
127
-
154
.
Kanai
,
S. M.
,
Heffner
,
C.
,
Cox
,
T. C.
,
Cunningham
,
M. L.
,
Perez
,
F. A.
,
Bauer
,
A. M.
,
Reigan
,
P.
,
Carter
,
C.
,
Murray
,
S. A.
and
Clouthier
,
D. E.
(
2022
).
Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants
.
Dis. Model. Mech.
15
,
dmm049320
.
Kang
,
Y. N.
,
Fung
,
C.
and
Vanden Berghe
,
P.
(
2021
).
Gut innervation and enteric nervous system development: a spatial, temporal and molecular tour de force
.
Development
148
,
dev182543
.
Kapur
,
R. P.
,
Yost
,
C.
and
Palmiter
,
R. D.
(
1992
).
A transgenic model for studying development of the enteric nervous system in normal and aganglionic mice
.
Development
116
,
167
-
175
.
Kapur
,
R. P.
,
Sweetser
,
D. A.
,
Doggett
,
B.
,
Siebert
,
J. R.
and
Palmiter
,
R. D.
(
1995
).
Intercellular signals downstream of endothelin receptor-B mediate colonization of the large intestine by enteric neuroblasts
.
Development
121
,
3787
-
3795
.
Karim
,
A.
,
Tang
,
C. S.
and
Tam
,
P. K.
(
2021
).
The emerging genetic landscape of Hirschsprung disease and its potential clinical applications
.
Front. Pediatr.
9
,
638093
.
Karne
,
S.
,
Jayawickreme
,
C. K.
and
Lerner
,
M. R.
(
1993
).
Cloning and characterization of an endothelin-3 specific receptor (ETC receptor) from Xenopus laevis dermal melanophores
.
J. Biol. Chem.
268
,
19126
-
19133
.
Kawanabe
,
Y.
,
Okamoto
,
Y.
,
Nozaki
,
K.
,
Hashimoto
,
N.
,
Miwa
,
S.
and
Masaki
,
T.
(
2002
).
Molecular mechanism for endothelin-1-induced stress-fiber formation: analysis of G proteins using a mutant endothelin(A) receptor
.
Mol. Pharmacol.
61
,
277
-
284
.
Kempf
,
H.
,
Linares
,
C.
,
Corvol
,
P.
and
Gasc
,
J. M.
(
1998
).
Pharmacological inactivation of the endothelin type A receptor in the early chick embryo: a model of mispatterning of the branchial arch derivatives
.
Development
125
,
4931
-
4941
.
Kim
,
W.
,
Essalmani
,
R.
,
Szumska
,
D.
,
Creemers
,
J. W.
,
Roebroek
,
A. J.
,
D'Orleans-Juste
,
P.
,
Bhattacharya
,
S.
,
Seidah
,
N. G.
and
Prat
,
A.
(
2012
).
Loss of endothelial furin leads to cardiac malformation and early postnatal death
.
Mol. Cell. Biol.
32
,
3382
-
3391
.
Kimmel
,
C. B.
,
Miller
,
C. T.
and
Moens
,
C. B.
(
2001
).
Specification and morphogenesis of the zebrafish larval head skeleton
.
Dev. Biol.
233
,
239
-
257
.
Kimmel
,
C. B.
,
Ullmann
,
B.
,
Walker
,
M.
,
Miller
,
C. T.
and
Crump
,
J. G.
(
2003
).
Endothelin 1-mediated regulation of pharyngeal bone development in zebrafish
.
Development
130
,
1339
-
1351
.
Kirby
,
M. L.
and
Waldo
,
K. L.
(
1995
).
Neural crest and cardiovascular patterning
.
Circ. Res.
77
,
211
-
215
.
Kirby
,
M. L.
,
Gale
,
T. F.
and
Stewart
,
D. E.
(
1983
).
Neural crest cells contribute to aorticopulmonary septation
.
Science
220
,
1059
-
1061
.
Kirby
,
M. L.
,
Turnage
,
K. L.
and
Hays
,
B. M.
(
1985
).
Characterization of conotruncal malformations following ablation of “cardiac” neural crest
.
Anat. Rec,
213
,
87
-
93
.
Kirby
,
M. L.
,
Hunt
,
P.
,
Wallis
,
K. T.
and
Thorogood
,
P.
(
1997
).
Normal development of the cardiac outflow tract is not dependent on normal patterning of the aortic arch arteries
.
Dev. Dyn.
208
,
34
-
47
.
Kitamura
,
K.
,
Shiraishi
,
N.
,
Singer
,
W. D.
,
Handlogten
,
M. E.
,
Tomita
,
K.
and
Miller
,
R. T.
(
1999
).
Endothelin-B receptors activate Galpha13
.
Am. J. Physiol.
276
,
C930
-
C937
.
Kozakai
,
T.
,
Sakate
,
M.
,
Takizawa
,
S.
,
Uchide
,
T.
,
Kobayashi
,
H.
,
Oishi
,
K.
,
Ishida
,
N.
and
Saida
,
K.
(
2014
).
Effect of feeding behavior on circadian regulation of endothelin expression in mouse colon
.
Life Sci.
118
,
232
-
237
.
Krauss
,
J.
,
Frohnhofer
,
H. G.
,
Walderich
,
B.
,
Maischein
,
H. M.
,
Weiler
,
C.
,
Irion
,
U.
and
Nusslein-Volhard
,
C.
(
2014
).
Endothelin signalling in iridophore development and stripe pattern formation of zebrafish
.
Biol. Open
3
,
503
-
509
.
Krispin
,
S.
,
Nitzan
,
E.
,
Kassem
,
Y.
and
Kalcheim
,
C.
(
2010
).
Evidence for a dynamic spatiotemporal fate map and early fate restrictions of premigratory avian neural crest
.
Development
137
,
585
-
595
.
Kruger
,
G. M.
,
Mosher
,
J. T.
,
Tsai
,
Y. H.
,
Yeager
,
K. J.
,
Iwashita
,
T.
,
Gariepy
,
C. E.
and
Morrison
,
S. J.
(
2003
).
Temporally distinct requirements for endothelin receptor B in the generation and migration of gut neural crest stem cells
.
Neuron
40
,
917
-
929
.
Krystek
,
S. R.
, Jr.
,
Patel
,
P. S.
,
Rose
,
P. M.
,
Fisher
,
S. M.
,
Kienzle
,
B. K.
,
Lach
,
D. A.
,
Liu
,
E. C.
,
Lynch
,
J. S.
,
Novotny
,
J.
and
Webb
,
M. L.
(
1994
).
Mutation of peptide binding site in transmembrane region of a G protein-coupled receptor accounts for endothelin receptor subtype selectivity
.
J. Biol. Chem.
269
,
12383
-
12386
.
Kuil
,
L. E.
,
Chauhan
,
R. K.
,
Cheng
,
W. W.
,
Hofstra
,
R. M. W.
and
Alves
,
M. M
. (
2020
).
Zebrafish: a model organism for studying enteric nervous system development and disease
.
Front. Cell Dev. Biol.
8
,
629073
.
Kuraku
,
S.
,
Takio
,
Y.
,
Sugahara
,
F.
,
Takechi
,
M.
and
Kuratani
,
S.
(
2010
).
Evolution of oropharyngeal patterning mechanisms involving Dlx and endothelins in vertebrates
.
Dev. Biol.
341
,
315
-
323
.
Kuratani
,
S. C.
and
Kirby
,
M. L.
(
1991
).
Initial migration and distribution of the cardiac neural crest in the avian embryo: an introduction to the concept of the circumpharyngeal crest
.
Am. J. Anat.
191
,
215
-
227
.
Kurihara
,
Y.
,
Kurihara
,
H.
,
Suzuki
,
H.
,
Kodama
,
T.
,
Maemura
,
K.
,
Nagai
,
R.
,
Oda
,
H.
,
Kuwaki
,
T.
,
Cao
,
W.-H.
,
Kamada
,
N.
et al. 
(
1994
).
Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1
.
Nature
368
,
703
-
710
.
Kurihara
,
Y.
,
Kurihara
,
H.
,
Maemura
,
K.
,
Kuwaki
,
T.
,
Kumada
,
M.
and
Yazaki
,
Y.
(
1995
).
Impaired development of the thyroid and thymus in endothelin-1 knockout mice
.
J. Cardiovasc. Pharmacol.
26
Suppl. 3
,
S13
-
S16
.
Kurihara
,
Y.
,
Ekimoto
,
T.
,
Gordon
,
C. T.
,
Uchijima
,
Y.
,
Sugiyama
,
R.
,
Kitazawa
,
T.
,
Iwase
,
A.
,
Kotani
,
R.
,
Asai
,
R.
,
Pingault
,
V.
et al. 
(
2023
).
Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding
.
J. Clin. Invest.
133
,
e151536
.
Lahav
,
R.
,
Ziller
,
C.
,
Dupin
,
E.
and
Le Douarin
,
N. M.
(
1996
).
Endothelin 3 promotes neural crest cell proliferation and mediates a vast increase in melanocyte number in culture
.
Proc. Natl. Acad. Sci. USA
93
,
3892
-
3897
.
Lahav
,
R.
,
Dupin
,
E.
,
Lecoin
,
L.
,
Glavieux
,
C.
,
Champeval
,
D.
,
Ziller
,
C.
and
Le Douarin
,
N. M.
(
1998
).
Endothelin 3 selectively promotes survival and proliferation of neural crest-derived glial and melanocytic precursors in vitro
.
Proc. Natl. Acad. Sci. USA
95
,
14214
-
14219
.
Lang
,
M. R.
,
Patterson
,
L. B.
,
Gordon
,
T. N.
,
Johnson
,
S. L.
and
Parichy
,
D. M
. (
2009
).
Basonuclin-2 requirements for zebrafish adult pigment pattern development and female fertility
.
PLoS Genet.
5
,
e1000744
.
Le Douarin
,
N.
and
Kalcheim
,
C.
(
1999
).
The Neural Crest
.
Cambridge, UK; New York, NY, USA
:
Cambridge University Press
.
Le Douarin
,
N. M.
and
Teillet
,
M. A.
(
1973
).
The migration of neural crest cells to the wall of the digestive tract in avian embryo
.
J. Embryol. Exp. Morphol.
30
,
31
-
48
.
Lecoin
,
L.
,
Sakurai
,
T.
,
Ngo
,
M. T.
,
Abe
,
Y.
,
Yanagisawa
,
M.
and
Le Douarin
,
N. M.
(
1998
).
Cloning and characterization of a novel endothelin receptor subtype in the avian class
.
Proc. Natl. Acad. Sci. USA
95
,
3024
-
3029
.
Lee
,
J. A.
,
Elliott
,
J. D.
,
Sutiphong
,
J. A.
,
Friesen
,
W. J.
,
Ohlstein
,
E. H.
,
Stadel
,
J. M.
,
Gleason
,
J. G.
and
Peishoff
,
C. E.
(
1994
).
Tyr-129 is important to the peptide ligand affinity and selectivity of human endothelin type A receptor
.
Proc. Natl. Acad. Sci. USA
91
,
7164
-
7168
.
Lee
,
H. O.
,
Levorse
,
J. M.
and
Shin
,
M. K.
(
2003
).
The endothelin receptor-B is required for the migration of neural crest-derived melanocyte and enteric neuron precursors
.
Dev. Biol.
259
,
162
-
175
.
Leibl
,
M. A.
,
Ota
,
T.
,
Woodward
,
M. N.
,
Kenny
,
S. E.
,
Lloyd
,
D. A.
,
Vaillant
,
C. R.
and
Edgar
,
D. H.
(
1999
).
Expression of endothelin 3 by mesenchymal cells of embryonic mouse caecum
.
Gut
44
,
246
-
252
.
Lister
,
J. A.
,
Cooper
,
C.
,
Nguyen
,
K.
,
Modrell
,
M.
,
Grant
,
K.
and
Raible
,
D. W
. (
2006
).
Zebrafish Foxd3 is required for development of a subset of neural crest derivatives
.
Dev. Biol.
290
,
92
-
104
.
Lyon
,
M. F.
and
Searle
,
A. G.
(
1989
).
Genetic Variants and Strains of the Laboratory Mouse
.
Oxford
,
England
:
Oxford University Press
.
Lyons
,
G. E.
,
Micales
,
B. K.
,
Schwarz
,
J.
,
Martin
,
J. F.
and
Olson
,
E. N.
(
1995
).
Expression of mef2 genes in the mouse central nervous system suggests a role in neuronal maturation
.
J. Neurosci.
15
,
5727
-
5738
.
Mackenzie
,
M. A.
,
Jordan
,
S. A.
,
Budd
,
P. S.
and
Jackson
,
I. J.
(
1997
).
Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo
.
Dev. Biol.
192
,
99
-
107
.
Malek
,
A. M.
,
Greene
,
A. L.
and
Izumo
,
S.
(
1993
).
Regulation of endothelin 1 gene by fluid shear stress is transcriptionally mediated and independent of protein kinase C and cAMP
.
Proc. Natl. Acad. Sci. USA
90
,
5999
-
6003
.
Marivin
,
A.
,
Leyme
,
A.
,
Parag-Sharma
,
K.
,
DiGiacomo
,
V.
,
Cheung
,
A. Y.
,
Nguyen
,
L. T.
,
Dominguez
,
I.
and
Garcia-Marcos
,
M.
(
2016
).
Dominant-negative Galpha subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease
.
Sci. Signal.
9
,
ra37
.
Martinez-Morales
,
J. R.
,
Henrich
,
T.
,
Ramialison
,
M.
and
Wittbrodt
,
J.
(
2007
).
New genes in the evolution of the neural crest differentiation program
.
Genome Biol.
8
,
R36
.
McCallion
,
A. S.
and
Chakravarti
,
A.
(
2001
).
EDNRB/EDN3 and Hirschsprung disease type II
.
Pigment Cell Res.
14
,
161
-
169
.
Meinecke
,
L.
,
Sharma
,
P. P.
,
Du
,
H.
,
Zhang
,
L.
,
Nie
,
Q.
and
Schilling
,
T. F.
(
2018
).
Modeling craniofacial development reveals spatiotemporal constraints on robust patterning of the mandibular arch
.
PLoS Comput. Biol.
14
,
e1006569
.
Mikawa
,
T.
and
Fischman
,
D. A.
(
1992
).
Retroviral analysis of cardiac morphogenesis: discontinuous formation of coronary vessels
.
Proc. Natl. Acad. Sci. USA
89
,
9504
-
9508
.
Miller
,
C. T.
and
Kimmel
,
C. B.
(
2001
).
Morpholino phenocopies of endothelin 1 (sucker) and other anterior arch class mutations
.
Genesis
30
,
186
-
187
.
Miller
,
C. T.
,
Schilling
,
T. F.
,
Lee
,
K.-H.
,
Parker
,
J.
and
Kimmel
,
C. B.
(
2000
).
sucker encodes a zebrafish Endothelin-1 required for ventral pharyngeal arch development
.
Development
127
,
3815
-
3838
.
Miller
,
C. T.
,
Yelon
,
D.
,
Stainier
,
D. Y.
and
Kimmel
,
C. B.
(
2003
).
Two endothelin 1 effectors, hand2 and bapx1, pattern ventral pharyngeal cartilage and the jaw joint
.
Development
130
,
1353
-
1365
.
Miller
,
C. T.
,
Swartz
,
M. E.
,
Khuu
,
P. A.
,
Walker
,
M. B.
,
Eberhart
,
J. K.
and
Kimmel
,
C. B.
(
2007
).
mef2ca is required in cranial neural crest to effect Endothelin1 signaling in zebrafish
.
Dev. Biol.
308
,
144
-
157
.
Minoux
,
M.
and
Rijli
,
F. M.
(
2010
).
Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development
.
Development
137
,
2605
-
2621
.
Mort
,
R. L.
,
Jackson
,
I. J.
and
Patton
,
E. E.
(
2015
).
The melanocyte lineage in development and disease
.
Development
142
,
620
-
632
.
Mumm
,
J. S.
and
Kopan
,
R.
(
2000
).
Notch signaling: from the outside in
.
Dev. Biol.
228
,
151
-
165
.
Nagy
,
N.
and
Goldstein
,
A. M.
(
2006
).
Endothelin-3 regulates neural crest cell proliferation and differentiation in the hindgut enteric nervous system
.
Dev. Biol.
293
,
203
-
217
.
Nagy
,
N.
and
Goldstein
,
A. M.
(
2017
).
Enteric nervous system development: a crest cell's journey from neural tube to colon
.
Semin. Cell Dev. Biol.
66
,
94
-
106
.
Nair
,
S.
,
Li
,
W.
,
Cornell
,
R.
and
Schilling
,
T. F.
(
2007
).
Requirements for endothelin type-A receptors and endothelin-1 signaling in the facial ectoderm for the patterning of skeletogenic neural crest cells in zebrafish
.
Development
134
,
335
-
345
.
Nataf
,
V.
,
Lecoin
,
L.
,
Eichmann
,
A.
and
Le Douarin
,
N. M.
(
1996
).
Endothelin-B receptor is expressed by neural crest cells in the avian embryo
.
Proc. Natl. Acad. Sci. USA
93
,
9645
-
9650
.
Nataf
,
V.
,
Amemiya
,
A.
,
Yanagisawa
,
M.
and
Le Douarin
,
N. M.
(
1998a
).
The expression pattern of endothelin 3 in the avian embryo
.
Mech. Dev.
73
,
217
-
220
.
Nataf
,
V.
,
Grapin-Botton
,
A.
,
Amemiya
,
A.
,
Yanagisawa
,
M.
and
Le Douarin
,
N. M.
(
1998b
).
The expression patterns of endothelin-A receptor and endothelin 1 in the avian embryo
.
Mech. Dev.
75
,
145
-
149
.
Natarajan
,
D.
,
Marcos-Gutierrez
,
C.
,
Pachnis
,
V.
and
de Graaff
,
E.
(
2002
).
Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis
.
Development
129
,
5151
-
5160
.
Neves
,
S. R.
,
Ram
,
P. T.
and
Iyengar
,
R.
(
2002
).
G protein pathways
.
Science
296
,
1636
-
1639
.
Nishiyama
,
C.
,
Uesaka
,
T.
,
Manabe
,
T.
,
Yonekura
,
Y.
,
Nagasawa
,
T.
,
Newgreen
,
D. F.
,
Young
,
H. M.
and
Enomoto
,
H.
(
2012
).
Trans-mesenteric neural crest cells are the principal source of the colonic enteric nervous system
.
Nat. Neurosci.
15
,
1211
-
1218
.
Nusslein-Volhard
,
C.
(
2012
).
The zebrafish issue of development
.
Development
139
,
4099
-
4103
.
Offermanns
,
S.
,
Zhao
,
L. P.
,
Gohla
,
A.
,
Sarosi
,
I.
,
Simon
,
M. I.
and
Wilkie
,
T. M.
(
1998
).
Embryonic cardiomyocyte hypoplasia and craniofacial defects in G alpha q/G alpha 11-mutant mice
.
EMBO J.
17
,
4304
-
4312
.
Ono
,
H.
,
Kawa
,
Y.
,
Asano
,
M.
,
Ito
,
M.
,
Takano
,
A.
,
Kubota
,
Y.
,
Matsumoto
,
J.
and
Mizoguchi
,
M
. (
1998
).
Development of melanocyte progenitors in murine Steel mutant neural crest explants cultured with stem cell factor, endothelin-3, or TPA
.
Pigment Cell Res.
11
,
291
-
298
.
Opdecamp
,
K.
,
Kos
,
L.
,
Arnheiter
,
H.
and
Pavan
,
W. J.
(
1998
).
Endothelin signalling in the development of neural crest-derived melanocytes
.
Biochem. Cell Biol.
76
,
1093
-
1099
.
Ozeki
,
H.
,
Kurihara
,
Y.
,
Tonami
,
K.
,
Watatani
,
S.
and
Kurihara
,
H.
(
2004
).
Endothelin-1 regulates the dorsoventral branchial arch patterning in mice
.
Mech. Dev.
121
,
387
-
395
.
Parichy
,
D. M.
,
Ransom
,
D. G.
,
Paw
,
B.
,
Zon
,
L. I.
and
Johnson
,
S. L.
(
2000
).
An orthologue of the kit-related gene fms is required for development of neural crest-derived xanthophores and a subpopulation of adult melanocytes in the zebrafish, Danio rerio
.
Development
127
,
3031
-
3044
.
Pavan
,
W. J.
and
Tilghman
,
S. M.
(
1994
).
Piebald lethal (sl) acts early to disrupt the development of neural crest-derived melanocytes
.
Proc. Natl. Acad. Sci. USA
91
,
7159
-
7163
.
Pingault
,
V.
,
Ente
,
D.
,
Dastot-Le Moal
,
F.
,
Goossens
,
M.
,
Marlin
,
S.
and
Bondurand
,
N.
(
2010
).
Review and update of mutations causing Waardenburg syndrome
.
Hum. Mutat.
31
,
391
-
406
.
Pinson
,
K. I.
,
Brennan
,
J.
,
Monkley
,
S.
,
Avery
,
B. J.
and
Skarnes
,
W. C.
(
2000
).
An LDL-receptor-related protein mediates Wnt signalling in mice
.
Nature
407
,
535
-
538
.
Piotrowski
,
T.
,
Schilling
,
T. F.
,
Brand
,
M.
,
Jiang
,
Y.-J.
,
Heisenberg
,
C.-P.
,
Beuchle
,
D.
,
Grandel
,
H.
,
van Eeden
,
F. J. M.
,
Furutani-Seiki
,
M.
,
Granato
,
M.
et al. 
(
1996
).
Jaw and branchial arch mutants in zebrafish II. anterior arches and cartilage differentiation
.
Development
123
,
345
-
356
.
Pla
,
P.
,
Alberti
,
C.
,
Solov'eva
,
O.
,
Pasdar
,
M.
,
Kunisada
,
T.
and
Larue
,
L.
(
2005
).
Ednrb2 orients cell migration towards the dorsolateral neural crest pathway and promotes melanocyte differentiation
.
Pigment Cell Res.
18
,
181
-
187
.
Pritchard
,
A. B.
,
Kanai
,
S. M.
,
Krock
,
B.
,
Schindewolf
,
E.
,
Oliver-Krasinski
,
J.
,
Khalek
,
N.
,
Okashah
,
N.
,
Lambert
,
N. A.
,
Tavares
,
A. L. P.
,
Zackai
,
E.
et al. 
(
2020
).
Loss-of-function of Endothelin receptor type A results in Oro-Oto-Cardiac syndrome
.
Am. J. Med. Genet. A
182
,
1104
-
1116
.
Reedy
,
M. V.
,
Faraco
,
C. D.
and
Erickson
,
C. A.
(
1998
).
The delayed entry of thoracic neural crest cells into the dorsolateral path is a consequence of the late emigration of melanogenic neural crest cells from the neural tube
.
Dev. Biol.
200
,
234
-
246
.
Reid
,
K.
,
Turnley
,
A. M.
,
Maxwell
,
G. D.
,
Kurihara
,
Y.
,
Kurihara
,
H.
,
Bartlett
,
P. F.
and
Murphy
,
M.
(
1996
).
Multiple roles for endothelin in melanocyte development: regulation of progenitor number and stimulation of differentiation
.
Development
122
,
3911
-
3919
.
Richards
,
J.
,
Welch
,
A. K.
,
Barilovits
,
S. J.
,
All
,
S.
,
Cheng
,
K. Y.
,
Wingo
,
C. S.
,
Cain
,
B. D.
and
Gumz
,
M. L.
(
2014
).
Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1
.
Life Sci.
118
,
255
-
262
.
Rieder
,
M. J.
,
Green
,
G. E.
,
Park
,
S. S.
,
Stamper
,
B. D.
,
Gordon
,
C. T.
,
Johnson
,
J. M.
,
Cunniff
,
C. M.
,
Smith
,
J. D.
,
Emery
,
S. B.
,
Lyonnet
,
S.
et al. 
(
2012
).
A human homeotic transformation tesulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome
.
Am. J. Hum. Genet.
90
,
907
-
914
.
Ritter
,
K. E.
and
Martin
,
D. M.
(
2019
).
Neural crest contributions to the ear: Implications for congenital hearing disorders
.
Hear. Res.
376
,
22
-
32
.
Ro
,
S.
,
Hwang
,
S. J.
,
Muto
,
M.
,
Jewett
,
W. K.
and
Spencer
,
N. J.
(
2006
).
Anatomic modifications in the enteric nervous system of piebald mice and physiological consequences to colonic motor activity
.
Am. J. Physiol. Gastrointest. Liver Physiol.
290
,
G710
-
G718
.
Roberts
,
R. R.
,
Bornstein
,
J. C.
,
Bergner
,
A. J.
and
Young
,
H. M.
(
2008
).
Disturbances of colonic motility in mouse models of Hirschsprung's disease
.
Am. J. Physiol. Gastrointest. Liver Physiol.
294
,
G996
-
g1008
.
Romanelli Tavares
,
V. L.
,
Gordon
,
C. T.
,
Zechi-Ceide
,
R. M.
,
Kokitsu-Nakata
,
N. M.
,
Voisin
,
N.
,
Tan
,
T. Y.
,
Heggie
,
A. A.
,
Vendramini-Pittoli
,
S.
,
Propst
,
E. J.
,
Papsin
,
B. C.
et al. 
(
2015
).
Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect
.
Eur. J. Hum. Genet.
23
,
481
-
485
.
Rothman
,
T. P.
,
Chen
,
J.
,
Howard
,
M. J.
,
Costantini
,
F.
,
Schuchardt
,
A.
,
Pachnis
,
V.
and
Gershon
,
M. D
. (
1996
).
Increased expression of laminin-1 and collagen (IV) subunits in the aganglionic bowel of ls/ls, but not c-ret -/- mice
.
Dev. Biol.
178
,
498
-
513
.
Ruest
,
L. B.
and
Clouthier
,
D. E.
(
2009
).
Elucidating timing and function of endothelin-A receptor signaling during craniofacial development using neural crest cell-specific gene deletion and receptor antagonism
.
Dev. Biol.
328
,
94
-
108
.
Ruest
,
L. B.
,
Xiang
,
X.
,
Lim
,
K. C.
,
Levi
,
G.
and
Clouthier
,
D. E.
(
2004
).
Endothelin-A receptor-dependent and -independent signaling pathways in establishing mandibular identity
.
Development
131
,
4413
-
4423
.
Sabrautzki
,
S.
,
Sandholzer
,
M. A.
,
Lorenz-Depiereux
,
B.
,
Brommage
,
R.
,
Przemeck
,
G.
,
Vargas Panesso
,
I. L.
,
Vernaleken
,
A.
,
Garrett
,
L.
,
Baron
,
K.
,
Yildirim
,
A. O.
et al. 
(
2016
).
Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation
.
Mamm. Genome
27
,
587
-
598
.
Sakamoto
,
A.
,
Yanagisawa
,
M.
,
Sakurai
,
T.
,
Takuwa
,
Y.
,
Yanagisawa
,
H.
and
Masaki
,
T.
(
1991
).
Cloning and functional expression of human cDNA for the ETB endothelin receptor
.
Biochem. Biophys. Res. Commun.
178
,
656
-
663
.
Sakurai
,
T.
,
Yanagisawa
,
M.
,
Takuwa
,
Y.
,
Miyazaki
,
H.
,
Kimura
,
S.
,
Goto
,
K.
and
Masaki
,
T.
(
1990
).
Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor
.
Nature
348
,
732
-
735
.
Saldana-Caboverde
,
A.
and
Kos
,
L
. (
2010
).
Roles of endothelin signaling in melanocyte development and melanoma
.
Pigment Cell Melanoma Res.
23
,
160
-
170
.
Sato
,
T.
,
Kawamura
,
Y.
,
Asai
,
R.
,
Amano
,
T.
,
Uchijima
,
Y.
,
Dettlaff-Swiercz
,
D. A.
,
Offermanns
,
S.
,
Kurihara
,
Y.
and
Kurihara
,
H.
(
2008
).
Recombinase-mediated cassette exchange reveals the selective use of Gq/G11-dependent and -independent endothelin 1/endothelin type A receptor signaling in pharyngeal arch development
.
Development
135
,
755
-
765
.
Scarparo
,
A. C.
,
Isoldi
,
M. C.
,
de Lima
,
L.
,
Visconti
,
M. A.
and
Castrucci
,
A. M. L.
(
2007
).
Expression of endothelin receptors in frog, chicken, mouse and human pigment cells
.
Comp. Biochem. Physiol. A Mol. Integr. Physiol.
147
,
640
-
646
.
Schilling
,
T. F.
and
Le Pabic
,
P.
(
2014
).
Neural crest cells in craniofacial skeletal development
. In
Neural Crest Cells
(ed.
P. A.
Trainor
), pp.
127
-
151
:
Academic Press
.
Schneider
,
S.
,
Wright
,
C. M.
and
Heuckeroth
,
R. O.
(
2019
).
Unexpected roles for the second brain: enteric nervous system as master regulator of bowel function
.
Annu. Rev. Physiol.
81
,
235
-
259
.
Serbedzija
,
G. N.
,
Fraser
,
S. E.
and
Bronner-Fraser
,
M.
(
1990
).
Pathways of trunk neural crest cell migration in the mouse embryo as revealed by vital dye labelling
.
Development
108
,
605
-
612
.
Serbedzija
,
G. N.
,
Bronner-Fraser
,
M.
and
Fraser
,
S. E.
(
1992
).
Vital dye analysis of cranial neural crest cell migration in the mouse embryo
.
Development
116
,
297
-
307
.
Shin
,
M. K.
,
Levorse
,
J. M.
,
Ingram
,
R. S.
and
Tilghman
,
S. M.
(
1999
).
The temporal requirement for endothelin receptor-B signalling during neural crest development
.
Nature
402
,
496
-
501
.
Shkalim
,
V.
,
Eliaz
,
N.
,
Linder
,
N.
,
Merlob
,
P.
and
Basel-Vanagaite
,
L.
(
2008
).
Autosomal dominant isolated question mark ear
.
Am. J. Med. Genet. A
146A
,
2280
-
2283
.
Silvers
,
W. K.
(
1979
).
The Coat Colors of Mice
.
New York, NY
:
Springer-Verlag
.
Song
,
L.
,
Li
,
Y.
,
Wang
,
K.
,
Wang
,
Y. Z.
,
Molotkov
,
A.
,
Gao
,
L.
,
Zhao
,
T.
,
Yamagami
,
T.
,
Wang
,
Y.
,
Gan
,
Q.
et al. 
(
2009
).
Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion
.
Development
136
,
3161
-
3171
.
Square
,
T.
,
Jandzik
,
D.
,
Cattell
,
M.
,
Hansen
,
A.
and
Medeiros
,
D. M.
(
2016
).
Embryonic expression of endothelins and their receptors in lamprey and frog reveals stem vertebrate origins of complex Endothelin signaling
.
Sci. Rep.
6
,
34282
.
Square
,
T. A.
,
Jandzik
,
D.
,
Massey
,
J. L.
,
Romášek
,
M.
,
Stein
,
H. P.
,
Hansen
,
A. W.
,
Purkayastha
,
A.
,
Cattell
,
M. V.
and
Medeiros
,
D. M.
(
2020
).
Evolution of the endothelin pathway drove neural crest cell diversification
.
Nature
585
,
563
-
568
.
Stow
,
L. R.
,
Jacobs
,
M. E.
,
Wingo
,
C. S.
and
Cain
,
B. D.
(
2011
).
Endothelin-1 gene regulation
.
FASEB J.
25
,
16
-
28
.
Szabo
,
A.
and
Mayor
,
R.
(
2018
).
Mechanisms of neural crest migration
.
Annu. Rev. Genet.
52
,
43
-
63
.
Takebayashi-Suzuki
,
K.
,
Yanagisawa
,
M.
,
Gourdie
,
R. G.
,
Kanzawa
,
N.
and
Mikawa
,
T.
(
2000
).
In vivo induction of cardiac Purkinje fiber differentiation by coexpression of preproendothelin-1 and endothelin converting enzyme-1
.
Development
127
,
3523
-
3532
.
Takigawa
,
M.
,
Sakurai
,
T.
,
Kasuya
,
Y.
,
Abe
,
Y.
,
Masaki
,
T.
and
Goto
,
K.
(
1995
).
Molecular identification of guanine-nucleotide-binding regulatory proteins which couple to endothelin receptors
.
Eur. J. Biochem.
228
,
102
-
108
.
Talbot
,
J. C.
,
Johnson
,
S. L.
and
Kimmel
,
C. B.
(
2010
).
hand2 and Dlx genes specify dorsal, intermediate and ventral domains within zebrafish pharyngeal arches
.
Development
137
,
2507
-
2517
.
Tang
,
W.
and
Bronner
,
M. E.
(
2020
).
Neural crest lineage analysis: from past to future trajectory
.
Development
147
,
dev193193
.
Tang
,
C. S.
,
Li
,
P.
,
Lai
,
F. P.
,
Fu
,
A. X.
,
Lau
,
S. T.
,
So
,
M. T.
,
Lui
,
K. N.
,
Li
,
Z.
,
Zhuang
,
X.
,
Yu
,
M.
et al. 
(
2018
).
Identification of genes associated with Hirschsprung disease, based on whole-genome sequence analysis, and potential effects on enteric nervous system development
.
Gastroenterology
155
,
1908
-
1922.e1905
.
Tavares
,
A. L. P.
,
Garcia
,
E. L.
,
Kuhn
,
K.
,
Woods
,
C. M.
,
Williams
,
T.
and
Clouthier
,
D. E.
(
2012
).
Ectodermal-derived Endothelin1 is required for patterning the distal and intermediate domains of the mouse mandibular arch
.
Dev. Biol.
371
,
47
-
56
.
Tavares
,
A. L. P.
,
Cox
,
T. C.
,
Maxson
,
R. M.
,
Ford
,
H. L.
and
Clouthier
,
D. E.
(
2017
).
Negative regulation of endothelin signaling by SIX1 is required for proper maxillary development
.
Development
144
,
2021
-
2031
.
Teng
,
C. S.
,
Yen
,
H. Y.
,
Barske
,
L.
,
Smith
,
B.
,
Llamas
,
J.
,
Segil
,
N.
,
Go
,
J.
,
Sanchez-Lara
,
P. A.
,
Maxson
,
R. E.
and
Crump
,
J. G.
(
2017
).
Requirement for Jagged1-Notch2 signaling in patterning the bones of the mouse and human middle ear
.
Sci. Rep.
7
,
2497
.
Tennyson
,
V. M.
,
Payette
,
R. F.
,
Rothman
,
T. P.
and
Gershon
,
M. D
. (
1990
).
Distribution of hyaluronic acid and chondroitin sulfate proteoglycans in the presumptive aganglionic terminal bowel of ls/ls fetal mice: an ultrastructural analysis
.
J. Comp. Neurol.
291
,
345
-
362
.
Theveneau
,
E.
and
Mayor
,
R.
(
2012
).
Neural crest delamination and migration: from epithelium-to-mesenchyme transition to collective cell migration
.
Dev. Biol.
366
,
34
-
54
.
Thomas
,
A. J.
and
Erickson
,
C. A.
(
2008
).
The making of a melanocyte: the specification of melanoblasts from the neural crest
.
Pigment Cell Melanoma Res.
21
,
598
-
610
.
Thomas
,
T.
,
Yamagishi
,
H.
,
Overbeek
,
P. A.
,
Olson
,
E. N.
and
Srivastava
,
D.
(
1998
).
The bHLH factors, dHAND and eHAND, specify pulmonary and systemic cardiac ventricles independent of left-right sidedness
.
Dev. Biol.
196
,
228
-
236
.
Trumpp
,
A.
,
Depew
,
M. J.
,
Rubenstein
,
J. L.
,
Bishop
,
J. M.
and
Martin
,
G. R.
(
1999
).
Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch
.
Genes Dev.
13
,
3136
-
3148
.
Tucker
,
A. S.
,
Watson
,
R. P.
,
Lettice
,
L. A.
,
Yamada
,
G.
and
Hill
,
R. E.
(
2004
).
Bapx1 regulates patterning in the middle ear: altered regulatory role in the transition from the proximal jaw during vertebrate evolution
.
Development
131
,
1235
-
1245
.
Uchide
,
T.
,
Masuda
,
H.
,
Mitsui
,
Y.
and
Saida
,
K.
(
1999
).
Gene expression of vasoactive intestinal contractor/endothelin-2 in ovary, uterus and embryo: comprehensive gene expression profiles of the endothelin ligand-receptor system revealed by semi-quantitative reverse transcription-polymerase chain reaction analysis in adult mouse tissues and during late embryonic development
.
J. Mol. Endocrinol.
22
,
161
-
171
.
Vegas
,
N.
,
Demir
,
Z.
,
Gordon
,
C. T.
,
Breton
,
S.
,
Romanelli Tavares
,
V. L.
,
Moisset
,
H.
,
Zechi-Ceide
,
R.
,
Kokitsu-Nakata
,
N. M.
,
Kido
,
Y.
,
Marlin
,
S.
et al. 
(
2022
).
Further delineation of auriculocondylar syndrome based on 14 novel cases and reassessment of 25 published cases
.
Hum. Mutat.
43
,
582
-
594
.
Verzi
,
M. P.
,
Agarwar
,
P.
,
Brown
,
C.
,
McCulley
,
D. J.
,
Schwarz
,
J. J.
and
Black
,
B. L.
(
2007
).
The transcription factor MEF2C is required for craniofacial development
.
Dev. Cell
12
,
645
-
652
.
Vieux-Rochas
,
M.
,
Mantero
,
S.
,
Heude
,
E.
,
Barbieri
,
O.
,
Astigiano
,
S.
,
Couly
,
G.
,
Kurihara
,
H.
,
Levi
,
G.
and
Merlo
,
G. R.
(
2010
).
Spatio-temporal dynamics of gene expression of the Edn1-Dlx5/6 pathway during development of the lower jaw
.
Genesis
48
,
262
-
373
.
Wakaoka
,
T.
,
Motohashi
,
T.
,
Hayashi
,
H.
,
Kuze
,
B.
,
Aoki
,
M.
,
Mizuta
,
K.
,
Kunisada
,
T.
and
Ito
,
Y.
(
2013
).
Tracing Sox10-expressing cells elucidates the dynamic development of the mouse inner ear
.
Hear. Res.
302
,
17
-
25
.
Waldo
,
K. L.
,
Kumiski
,
D.
and
Kirby
,
M. L.
(
1996
).
Cardiac neural crest is essential for the persistence rather than the formation of an arch artery
.
Dev. Dyn.
205
,
281
-
292
.
Waldo
,
K. L.
,
Miyagawa-Tomita
,
S.
,
Kumiski
,
D.
and
Kirby
,
M. L.
(
1998
).
Cardiac neural crest cells provide a new insight into septation of the outflow tract: Aortic sac to ventricular septal closure
.
Dev. Biol.
196
,
129
-
144
.
Walker
,
M. B.
,
Miller
,
C. T.
,
Talbot
,
J. C.
,
Stock
,
D. W.
and
Kimmel
,
C. B.
(
2006
).
Zebrafish furin mutants reveal intricacies in regulating Endothelin1 signaling in craniofacial patterning
.
Dev. Biol.
295
,
194
-
205
.
Walker
,
M. B.
,
Miller
,
C. T.
,
Swartz
,
M. E.
,
Eberhart
,
J. K.
and
Kimmel
,
C. B.
(
2007
).
phospholipase C, beta 3 is required for Endothelin1 regulation of pharyngeal arch patterning in zebrafish
.
Dev. Biol.
304
,
194
-
207
.
Watanabe
,
Y.
,
Stanchina
,
L.
,
Lecerf
,
L.
,
Gacem
,
N.
,
Conidi
,
A.
,
Baral
,
V.
,
Pingault
,
V.
,
Huylebroeck
,
D.
and
Bondurand
,
N.
(
2017
).
Differentiation of mouse enteric nervous system progenitor cells is controlled by endothelin 3 and requires regulation of Ednrb by SOX10 and ZEB2
.
Gastroenterology
152
,
1139
-
1150.e1134
.
Welch
,
A. K.
,
Jacobs
,
M. E.
,
Wingo
,
C. S.
and
Cain
,
B. D.
(
2013
).
Early progress in epigenetic regulation of endothelin pathway genes
.
Br. J. Pharmacol.
168
,
327
-
334
.
Wu
,
J. J.
,
Chen
,
J. X.
,
Rothman
,
T. P.
and
Gershon
,
M. D.
(
1999
).
Inhibition of in vitro enteric neuronal development by endothelin-3: mediation by endothelin B receptors
.
Development
126
,
1161
-
1173
.
Xu
,
D.
,
Emoto
,
N.
,
Giaid
,
A.
,
Slaughter
,
C.
,
Kaw
,
S.
,
deWit
,
D.
and
Yanagisawa
,
M.
(
1994
).
ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1
.
Cell
78
,
473
-
485
.
Xu
,
J.
,
Liu
,
H.
,
Lan
,
Y.
,
Adam
,
M.
,
Clouthier
,
D. E.
,
Potter
,
S.
and
Jiang
,
R.
(
2019
).
Hedgehog signaling patterns the oral-aboral axis of the mandibular arch
.
Elife
8
,
e40315
.
Yamada
,
T.
,
Ohtani
,
S.
,
Sakurai
,
T.
,
Tsuji
,
T.
,
Kunieda
,
T.
and
Yanagisawa
,
M.
(
2006
).
Reduced expression of the endothelin receptor type B gene in piebald mice caused by insertion of a retroposon-like element in intron 1
.
J. Biol. Chem.
281
,
10799
-
10807
.
Yanagi
,
K.
,
Morimoto
,
N.
,
Iso
,
M.
,
Abe
,
Y.
,
Okamura
,
K.
,
Nakamura
,
T.
,
Matsubara
,
Y.
and
Kaname
,
T.
(
2021
).
A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND1
.
J. Hum. Genet.
66
,
1029
-
1034
.
Yanagisawa
,
M.
,
Kurihara
,
H.
,
Kimura
,
S.
,
Tomobe
,
Y.
,
Kobayashi
,
M.
,
Mitsui
,
Y.
,
Yazaki
,
Y.
,
Goto
,
K.
and
Masaki
,
T.
(
1988
).
A novel potent vasoconstrictor peptide produced by vascular endothelial cells
.
Nature
332
,
411
-
415
.
Yanagisawa
,
H.
,
Hammer
,
R. E.
,
Richardson
,
J. A.
,
Williams
,
S. C.
,
Clouthier
,
D. E.
and
Yanagisawa
,
M.
(
1998a
).
Role of Endothelin-1/Endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice
.
J. Clin. Invest.
102
,
22
-
33
.
Yanagisawa
,
H.
,
Yanagisawa
,
M.
,
Kapur
,
R. P.
,
Richardson
,
J. A.
,
Williams
,
S. C.
,
Clouthier
,
D. E.
,
de Wit
,
D.
,
Emoto
,
N.
and
Hammer
,
R. E.
(
1998b
).
Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene
.
Development
125
,
825
-
836
.
Yanagisawa
,
H.
,
Hammer
,
R. E.
,
Richardson
,
J. A.
,
Emoto
,
N.
,
Williams
,
S. C.
,
Takeda
,
S.
,
Clouthier
,
D. E.
and
Yanagisawa
,
M.
(
2000
).
Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development
.
J. Clin. Invest.
105
,
1373
-
1382
.
Yanchar
,
N. L.
and
Soucy
,
P.
(
1999
).
Long-term outcome after Hirschsprung's disease: patients’ perspectives
.
J. Pediatr. Surg.
34
,
1152
-
1160
.
Young
,
H. M.
,
Hearn
,
C. J.
,
Farlie
,
P. G.
,
Canty
,
A. J.
,
Thomas
,
P. Q.
and
Newgreen
,
D. F.
(
2001
).
GDNF is a chemoattractant for enteric neural cells
.
Dev. Biol.
229
,
503
-
516
.
Young
,
H. M.
,
Bergner
,
A. J.
,
Anderson
,
R. B.
,
Enomoto
,
H.
,
Milbrandt
,
J.
,
Newgreen
,
D. F.
and
Whitington
,
P. M.
(
2004
).
Dynamics of neural crest-derived cell migration in the embryonic mouse gut
.
Dev. Biol.
270
,
455
-
473
.
Yuan
,
Y.
,
Loh
,
Y. E.
,
Han
,
X.
,
Feng
,
J.
,
Ho
,
T. V.
,
He
,
J.
,
Jing
,
J.
,
Groff
,
K.
,
Wu
,
A.
and
Chai
,
Y.
(
2020
).
Spatiotemporal cellular movement and fate decisions during first pharyngeal arch morphogenesis
.
Sci. Adv.
6
,
eabb0119
.
Zaitoun
,
I.
,
Erickson
,
C. S.
,
Barlow
,
A. J.
,
Klein
,
T. R.
,
Heneghan
,
A. F.
,
Pierre
,
J. F.
,
Epstein
,
M. L.
and
Gosain
,
A.
(
2013
).
Altered neuronal density and neurotransmitter expression in the ganglionated region of Ednrb null mice: implications for Hirschsprung's disease
.
Neurogastroenterol. Motil.
25
,
e233
-
e244
.
Zechi-Ceide
,
R. M.
,
Guion-Almeida
,
M. L.
,
Jehee
,
F. S.
,
Rocha
,
K.
and
Passos-Bueno
,
M. R.
(
2010
).
Mandibulofacial dysostosis, severe lower eyelid coloboma, cleft palate, and alopecia: A new distinct form of mandibulofacial dysostosis or a severe form of Johnson-McMillin syndrome?
Am. J. Med. Genet. A
152A
,
1838
-
1840
.
Zhang
,
Y.
,
Knutsen
,
G. R.
,
Brown
,
M. D.
and
Ruest
,
L. B.
(
2013
).
Control of endothelin-a receptor expression by progesterone is enhanced by synergy with Gata2
.
Mol. Endocrinol.
27
,
892
-
908
.
Zuniga
,
E.
,
Stellabotte
,
F.
and
Crump
,
J. G.
(
2010
).
Jagged-Notch signaling ensures dorsal skeletal identity in the vertebrate face
.
Development
137
,
1843
-
1852
.
Zuniga
,
E.
,
Rippen
,
M.
,
Alexander
,
C.
,
Schilling
,
T. F.
and
Crump
,
J. G.
(
2011
).
Gremlin 2 regulates distinct roles of BMP and Endothelin 1 signaling in dorsoventral patterning of the facial skeleton
.
Development
138
,
5147
-
5156
.

Competing interests

The authors declare no competing or financial interests.