ABSTRACT Over 50 years after its discovery in early chick embryos, the concept of epithelial-mesenchymal transition (EMT) is now widely applied to morphogenetic studies in both physiological and pathological contexts. Indeed, the EMT field has witnessed exponential growth in recent years, driven primarily by a rapid expansion of cancer-oriented EMT research. This has led to EMT-based therapeutic interventions that bear the prospect of fighting cancer, and has given developmental biologists new impetus to investigate EMT phenomena more closely and to find suitable models to address emerging EMT-related questions. Here, and in the accompanying poster, I provide a brief summary of the current status of EMT research and give an overview of EMT models that have been used in developmental studies. I also highlight dynamic epithelialization and de-epithelialization events that are involved in many developmental processes and that should be considered to provide a broader perspective of EMT. Finally, I put forward a set of criteria to separate morphogenetic phenomena that are EMT-related from those that are not.

ABSTRACT The transforming growth factor β (TGFβ) signaling family is evolutionarily conserved in metazoans. The signal transduction mechanisms of TGFβ family members have been expansively investigated and are well understood. During development and homeostasis, numerous TGFβ family members are expressed in various cell types with temporally changing levels, playing diverse roles in embryonic development, adult tissue homeostasis and human diseases by regulating cell proliferation, differentiation, adhesion, migration and apoptosis. Here, we discuss the molecular mechanisms underlying signal transduction and regulation of the TGFβ subfamily pathways, and then highlight their key functions in mesendoderm induction, dorsoventral patterning and laterality development, as well as in the formation of several representative tissues/organs.

ABSTRACT The lateral plate mesoderm (LPM) forms the progenitor cells that constitute the heart and cardiovascular system, blood, kidneys, smooth muscle lineage and limb skeleton in the developing vertebrate embryo. Despite this central role in development and evolution, the LPM remains challenging to study and to delineate, owing to its lineage complexity and lack of a concise genetic definition. Here, we outline the processes that govern LPM specification, organization, its cell fates and the inferred evolutionary trajectories of LPM-derived tissues. Finally, we discuss the development of seemingly disparate organ systems that share a common LPM origin.

ABSTRACT Over the past 5 years, several studies have begun to uncover the links between the classical signal transduction pathways and the physical mechanisms that are used to sculpt branched tissues. These advances have been made, in part, thanks to innovations in live imaging and reporter animals. With modern research tools, our conceptual models of branching morphogenesis are rapidly evolving, and the differences in branching mechanisms between each organ are becoming increasingly apparent. Here, we highlight four branched epithelia that develop at different spatial scales, within different surrounding tissues and via divergent physical mechanisms. Each of these organs has evolved to employ unique branching strategies to achieve a specialized final architecture.

ABSTRACT Regulatory landscapes have been defined in vertebrates as large DNA segments containing diverse enhancer sequences that produce coherent gene transcription. These genomic platforms integrate multiple cellular signals and hence can trigger pleiotropic expression of developmental genes. Identifying and evaluating how these chromatin regions operate may be difficult as the underlying regulatory mechanisms can be as unique as the genes they control. In this brief article and accompanying poster, we discuss some of the ways in which regulatory landscapes operate, illustrating these mechanisms using genes important for vertebrate development as examples. We also highlight some of the techniques available to researchers for analysing regulatory landscapes.

ABSTRACT Collective cell migration is the coordinated movement of a physically connected group of cells and is a prominent driver of development and metastasis. Interactions between cells within migrating collectives, and between migrating cells and other cells in the environment, play key roles in stimulating motility, steering and sometimes promoting cell survival. Similarly, diverse heterotypic interactions and collective behaviors likely contribute to tumor metastasis. Here, we describe a sampling of cells that migrate collectively in vivo , including well-established and newer examples. We focus on the under-appreciated property that many – perhaps most – collectively migrating cells move as cooperating groups of distinct cell types.

ABSTRACT The Hippo signalling pathway and its transcriptional co-activator targets Yorkie/YAP/TAZ first came to attention because of their role in tissue growth control. Over the past 15 years, it has become clear that, like other developmental pathways (e.g. the Wnt, Hedgehog and TGFβ pathways), Hippo signalling is a ‘jack of all trades’ that is reiteratively used to mediate a range of cellular decision-making processes from proliferation, death and morphogenesis to cell fate determination. Here, and in the accompanying poster, we briefly outline the core pathway and its regulation, and describe the breadth of its roles in animal development.

ABSTRACT The phytohormone auxin influences virtually all aspects of plant growth and development. Auxin transport across membranes is facilitated by, among other proteins, members of the PIN-FORMED (PIN) and the structurally similar PIN-LIKES (PILS) families, which together govern directional cell-to-cell transport and intracellular accumulation of auxin. Canonical PIN proteins, which exhibit a polar localization in the plasma membrane, determine many patterning and directional growth responses. Conversely, the less-studied non-canonical PINs and PILS proteins, which mostly localize to the endoplasmic reticulum, attenuate cellular auxin responses. Here, and in the accompanying poster, we provide a brief summary of current knowledge of the structure, evolution, function and regulation of these auxin transport facilitators.

ABSTRACT Retinoic acid (RA), a metabolite of retinol (vitamin A), functions as a ligand for nuclear RA receptors (RARs) that regulate development of chordate animals. RA-RARs can activate or repress transcription of key developmental genes. Genetic studies in mouse and zebrafish embryos that are deficient in RA-generating enzymes or RARs have been instrumental in identifying RA functions, revealing that RA signaling regulates development of many organs and tissues, including the body axis, spinal cord, forelimbs, heart, eye and reproductive tract. An understanding of the normal functions of RA signaling during development will guide efforts for use of RA as a therapeutic agent to improve human health. Here, we provide an overview of RA signaling and highlight its key functions during development.

ABSTRACT Vascular endothelial growth factors (VEGFs) are best known for their involvement in orchestrating the development and maintenance of the blood and lymphatic vascular systems. VEGFs are secreted by a variety of cells and they bind to their cognate tyrosine kinase VEGF receptors (VEGFRs) in endothelial cells to elicit various downstream effects. In recent years, there has been tremendous progress in elucidating different VEGF/VEGFR signaling functions in both the blood and lymphatic vascular systems. Here, and in the accompanying poster, we present key elements of the VEGF/VEGFR pathway and highlight the classical and newly discovered functions of VEGF signaling in blood and lymphatic vessel development and pathology.

ABSTRACT The Wnt-β-catenin signaling pathway is an evolutionarily conserved cell-cell communication system that is important for stem cell renewal, cell proliferation and cell differentiation both during embryogenesis and during adult tissue homeostasis. Genetic or epigenetic events leading to hypo- or hyper-activation of the Wnt-β-catenin signaling cascade have also been associated with human diseases such as cancer. Understanding how this pathway functions is thus integral for developing therapies to treat diseases or for regenerative medicine approaches. Here, and in the accompanying poster, we provide an overview of Wnt-β-catenin signaling and briefly highlight its key functions during development and adult tissue homeostasis.

ABSTRACT The membrane receptor Toll and the related Toll-like receptors (TLRs) are best known for their universal function in innate immunity. However, Toll/TLRs were initially discovered in a developmental context, and recent studies have revealed that Toll/TLRs carry out previously unanticipated functions in development, regulating cell fate, cell number, neural circuit connectivity and synaptogenesis. Furthermore, knowledge of their molecular mechanisms of action is expanding and has highlighted that Toll/TLRs function beyond the canonical NF-κB pathway to regulate cell-to-cell communication and signalling at the synapse. Here, we provide an overview of Toll/TLR signalling and discuss how this signalling pathway regulates various aspects of development across species.

ABSTRACT The phytohormone cytokinin plays diverse roles in plant development, influencing many agriculturally important processes, including growth, nutrient responses and the response to biotic and abiotic stresses. Cytokinin levels in plants are regulated by biosynthesis and inactivation pathways. Cytokinins are perceived by membrane-localized histidine-kinase receptors and are transduced through a His-Asp phosphorelay to activate a family of transcription factors in the nucleus. Here, and in the accompanying poster, we summarize the current understanding of cytokinin metabolism, transport and signaling, and discuss how this phytohormone regulates changes in gene expression to mediate its pleiotropic effects.

ABSTRACT Pluripotent stem cell (PSC)-derived organoids are miniature, three-dimensional human tissues generated by the application of developmental biological principles to PSCs in vitro . The approach to generate organoids uses a combination of directed differentiation, morphogenetic processes, and the intrinsically driven self-assembly of cells that mimics organogenesis in the developing embryo. The resulting organoids have remarkable cell type complexity, architecture and function similar to their in vivo counterparts. In the past five years, human PSC-derived organoids with components of all three germ layers have been generated, resulting in the establishment of a new human model system. Here, and in the accompanying poster, we provide an overview of how principles of developmental biology have been essential for generating human organoids in vitro , and how organoids are now being used as a primary research tool to investigate human developmental biology.

The plant hormone auxin triggers complex growth and developmental processes. Its underlying molecular mechanism of action facilitates rapid switching between transcriptional repression and gene activation through the auxin-dependent degradation of transcriptional repressors. The nuclear auxin signaling pathway consists of a small number of core components. However, in most plants each component is represented by a large gene family. The modular construction of the pathway can thus produce diverse transcriptional outputs depending on the cellular and environmental context. Here, and in the accompanying poster, we outline the current model for TIR1/AFB-dependent auxin signaling with an emphasis on recent studies.

Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously. Here, we summarize new insights into Slit-Robo evolutionary and system-dependent diversity, receptor-ligand interactions, signaling crosstalk and receptor activation.

Distinct combinations of transcription factors are necessary to elicit cell fate changes in embryonic development. Yet within each group of fate-changing transcription factors, a subset called ‘pioneer factors’ are dominant in their ability to engage silent, unmarked chromatin and initiate the recruitment of other factors, thereby imparting new function to regulatory DNA sequences. Recent studies have shown that pioneer factors are also crucial for cellular reprogramming and that they are implicated in the marked changes in gene regulatory networks that occur in various cancers. Here, we provide an overview of the contexts in which pioneer factors function, how they can target silent genes, and their limitations at regions of heterochromatin. Understanding how pioneer factors regulate gene expression greatly enhances our understanding of how specific developmental lineages are established as well as how cell fates can be manipulated.

ABSTRACT Mammalian pluripotency is the ability to give rise to all somatic cells as well as the germ cells of an adult mammal. It is a unique feature of embryonic epiblast cells, existing only transiently, as cells pass through early developmental stages. By contrast, pluripotency can be captured and stabilized indefinitely in cell culture and can also be reactivated in differentiated cells via nuclear reprogramming. Pluripotent stem cells (PSCs) are the in vitro carriers of pluripotency and they can inhabit discrete pluripotent states depending on the stage at which they were derived and their culture conditions. Here, and in the accompanying poster, we provide a summary of mammalian pluripotency both in vivo and in vitro , and highlight recent and future applications of PSCs for basic and translational research.

The Hedgehog (Hh) signalling pathway is one of the key regulators of metazoan development. Hh proteins have been shown to play roles in many developmental processes and have become paradigms for classical morphogens. Dysfunction of the Hh pathway underlies a number of human developmental abnormalities and diseases, making it an important therapeutic target. Interest in Hh signalling thus extends across many fields, from evo-devo to cancer research and regenerative medicine. Here, and in the accompanying poster, we provide an outline of the current understanding of Hh signalling mechanisms, highlighting the similarities and differences between species.

Glia account for more than half of the cells in the mammalian nervous system, and the past few decades have witnessed a flood of studies that detail novel functions for glia in nervous system development, plasticity and disease. Here, and in the accompanying poster, we review the origins of glia and discuss their diverse roles during development, in the adult nervous system and in the context of disease.