Special Issue: The Origins and Mechanisms of Developmental Disorders
Challenges and opportunities at the interface of birth defects, human genetics and developmental biology
Summary: This Spotlight summarizes conclusions from The Company of Biologists Workshop ‘Understanding Human Birth Defects in the Genomic Age’ held in the UK in November 2019, identifying key hurdles in the field, as well as priorities for overcoming them.
Summary: This Spotlight discusses the methods for and the advantages of using Drosophila in the diagnosis of rare human diseases and identification of associated pathogenic mechanisms. Examples include human microcephaly.
Summary: This Spotlight discusses the role of gene-environment interactions in birth defects, argues for better alignment of research approaches with complex etiology, and prescribes strategies for discovery of new interactions.
Summary: This Spotlight highlights the opportunities, tools and resources available to developmental biologists to engage with human genetics databases, researchers and patients to advance the study of congenital disorders.
Summary: This Primer summarizes discoveries in heart development that have led to a revolution in understanding organogenesis and gene regulation, and how this is being applied to investigating regeneration of the diseased heart.
Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1
Summary: In utero lentiviral transgenics reveal the afadin/nectin complex is essential for palatogenesis, while exogenous expression of a human NECTIN1 mutation suggests it harbors dominant interfering activity.
Mitf-family transcription factor function is required within cranial neural crest cells to promote choroid fissure closure
Summary: Analysis of zebrafish Mitf-family member mutants, alongside embryological manipulations and rescue experiments, reveals that without Mitf-family function, cNCC localization and function in the choroid fissure is disrupted, thus contributing to colobomas.
The neurodevelopmental disorder risk gene DYRK1A is required for ciliogenesis and control of brain size in Xenopus embryos
Summary: The autism and Down syndrome risk gene DYRK1A localizes to ciliary components and mitotic spindles, and is required for ciliogenesis and cell cycle control during embryonic Xenopus development.
Summary: The primary role of Hippo-YAP/TAZ signalling in cartilage development is in control of tissue morphogenesis, rather than in control of cell proliferation or cell fate.
Mitchell-Riley syndrome iPSCs exhibit reduced pancreatic endoderm differentiation due to a mutation in RFX6
Summary: Mutations in RFX6 cause the rare disorder Mitchell-Riley syndrome, which is characterised by pancreatic hypoplasia and neonatal diabetes, and is due to an early failure to form pancreatic endoderm.
Summary: This study reveals evidence that excess GDNF-RET signaling can lead to phenotypic diversity in the enteric nervous system, including both aganglionosis and intestinal ganglioneuromas.
Summary: Loss of the plant homeodomain finger 6 (PHF6) protein in mice causes reversible postnatal growth retardation, mediated at least in part through neuroendocrine signaling.
The Fgf8 subfamily (Fgf8, Fgf17 and Fgf18) is required for closure of the embryonic ventral body wall
Summary: This study demonstrates that three related FGFs (FGF8, FGF17 and FGF18) cooperate in the essential, but understudied, process of embryonic ventral body wall closure in amniotes.
Deficiency and overexpression of Rtl1 in the mouse cause distinct muscle abnormalities related to Temple and Kagami-Ogata syndromes
Summary: Rtl1 plays an important role in fetal and neonatal skeletal muscle development. Abnormal expression of human RTL1 is the major cause of the muscle symptoms observed in Temple and Kagami-Ogata syndromes.
Temporal-specific roles of fragile X mental retardation protein in the development of the hindbrain auditory circuit
Summary: Deficiency of an RNA-binding protein, FMRP, negatively affects how auditory axons travel through the developing brainstem and establish proper synaptic connectivity in a timely manner.
Summary: Defects in minor splicing result in short limbs that maintain patterning. This study shows how the minor spliceosome might regulate limb size but not morphogenesis in disease and domestication.
NPC1 deficiency impairs cerebellar postnatal development of microglia and climbing fiber refinement in a mouse model of Niemann–Pick disease type C
Summary: Genetic deficiency of Npc1 impairs postnatal development of microglia and climbing fiber synaptic pruning in the mouse cerebellum.
Stromal β-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor
Summary: Stromal activation of β-catenin drives gene expression changes similar to those in human Wilms' tumors, suggesting that aberrant signaling from the stroma may contribute to tumorigenesis.
The KMT2D Kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology
Summary: Chromatin-modifying enzymes are mutated in a wide array of craniofacial disorders. This study contrasts KMT2D and UTX neural crest differentiation function as sources of variation in facial gestalt for Kabuki syndrome.
Msx1 deficiency interacts with hypoxia and induces a morphogenetic regulation during mouse lip development
Summary: Msx1 mutations cause morphological changes in the lip-forming region of mouse embryos, and interact with hypoxia and Pax9 deficiency in cleft lip formation.
A mutation affecting laminin alpha 5 polymerisation gives rise to a syndromic developmental disorder
Summary: This study describes a mutation in laminin alpha 5 that causes a complex, multi-system developmental disorder, which helps to define the importance of laminin polymerisation to organ development.
The FOXJ1 target Cfap206 is required for sperm motility, mucociliary clearance of the airways and brain development
Summary: Evolutionarily conserved CFAP206 modulates ciliary beat frequency in multiciliated cells in Xenopus and mouse, and is required for radial spoke arrangement in mouse sperm flagella.
RNF220 is required for cerebellum development and regulates medulloblastoma progression through epigenetic modulation of Shh signaling
Summary: RNF220 targets EED for degradation, contributing full Shh activation through an epigenetic mechanism during cerebellum development and medulloblastoma progression.
Cleft lip and cleft palate in Esrp1 knockout mice is associated with alterations in epithelial-mesenchymal crosstalk
Summary: Alterations in epithelial-mesenchymal crosstalk underlie the lip and palate formation defects caused by ablation of the epithelial-specific splicing factor Esrp1.
Summary: Animal models for generalized lymphatic anomaly or Gorham–Stout disease reveal that lymphatics in bone arise from pre-existing lymphatics and that rapamycin suppresses the development of lymphatics in bone.