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The notochord is a structure required for support and patterning of all chordate embryos, from sea squirts to humans. An increasing amount of information on notochord development and on the molecular strategies that ensure its proper morphogenesis has been gleaned through studies in the sea squirt Ciona. This invertebrate chordate offers a fortunate combination of experimental advantages, ranging from translucent, fast-developing embryos to a compact genome and impressive biomolecular resources. These assets have enabled the rapid identification of numerous notochord genes and cis-regulatory regions, and provide a rather unique opportunity to reconstruct the gene regulatory network that controls the formation of this developmental and evolutionary chordate landmark. This chapter summarizes the morphogenetic milestones that punctuate notochord formation in Ciona, their molecular effectors, and the current knowledge of the gene regulatory network that ensures the accurate spatial and temporal orchestration of these processes., (© 2020 Elsevier Inc. All rights reserved.)

Vertebrate limb bud outgrowth and patterning is controlled by two instructive signaling centers, the apical ectodermal ridge (AER) and the polarizing region in the posterior limb bud mesenchyme. Molecular analysis of limb bud development has identified a self-regulatory signaling system that operates between the AER and mesenchyme and orchestrates the dynamic progression of limb bud outgrowth and patterning. The first focus of this review are the gene regulatory networks (GRNs) and interactions that control the positioning of the fore- and hindlimb fields along the primary body axis, establish the initial axis polarity and control the precise positioning of the signaling centers. These early processes are largely controlled by activating and inhibiting interactions among types of transcriptional regulators expressed in specific territories. The second focus deals with the dynamic interactions among the GRNs that control limb bud patterning and outgrowth by responding to inputs from the self-regulatory limb bud signaling system. The final part describes the GRN interactions regulating digit morphogenesis and the Turing-type system that controls the periodicity of the digit ray pattern. This review highlights the significant progress made toward an integrative analysis and understanding of the morpho-regulatory systems that orchestrate patterning and outgrowth of vertebrate limb buds in time and space., (© 2020 Elsevier Inc. All rights reserved.)

In vertebrates, the hindbrain serves as a highly conserved complex coordination center for regulating many fundamental activities of the central nervous system, such as respiratory rhythms, sleep patterns and equilibrium, and it also plays an important role in craniofacial development. The basic ground plan that underlies the diverse functions of the hindbrain and its neural crest derivatives is established and patterned by a process of segmentation. Through a dynamic series of signaling and regulatory interactions the developing hindbrain is transiently compartmentalized into a set of seven segmental units, termed rhombomeres. The nested expression of the Hox family of transcription factors is tightly coupled to the process of segmentation and provides a molecular code for specifying the unique regional properties of the hindbrain and its neural crest derived craniofacial structures. The high degree of similarity in hindbrain architecture between diverse vertebrates has enabled cross-species regulatory analysis. This has facilitated the experimental assembly of the signaling and regulatory interactions, which underlie the process of segmentation, into a Hox-dependent gene regulatory network (GRN) model. This hindbrain GRN is a key regulatory feature of head patterning, conserved to the base of vertebrate evolution. This regulatory framework also serves as a basis for comparing and contrasting GRNs that govern cranial neural crest formation and axial patterning and provide insight into regulatory mechanisms associated with the evolution of novel vertebrate traits. The purpose of this review is to discuss the majorfeatures of the GRN for hindbrain segmentation and its relationship to the broader functional role of the hindbrain in patterning head development., (© 2020 Elsevier Inc. All rights reserved.)

Although the human body appears superficially symmetrical with regard to the left-right (L-R) axis, most visceral organs are asymmetric in terms of their size, shape, or position. Such morphological asymmetries of visceral organs, which are essential for their proper function, are under the control of a genetic pathway that operates in the developing embryo. In many vertebrates including mammals, the breaking of L-R symmetry occurs at a structure known as the L-R organizer (LRO) located at the midline of the developing embryo. This symmetry breaking is followed by transfer of an active form of the signaling molecule Nodal from the LRO to the lateral plate mesoderm (LPM) on the left side, which results in asymmetric expression of Nodal (a left-side determinant) in the left LPM. Finally, L-R asymmetric morphogenesis of visceral organs is induced by Nodal-Pitx2 signaling. This review will describe our current understanding of the mechanisms that underlie the generation of L-R asymmetry in vertebrates, with a focus on mice.

Sensory placodes and neural crest cells are among the key cell populations that facilitated the emergence and diversification of vertebrates throughout evolution. Together, they generate the sensory nervous system in the head: both form the cranial sensory ganglia, while placodal cells make major contributions to the sense organs-the eye, ear and olfactory epithelium. Both are instrumental for integrating craniofacial organs and have been key to drive the concentration of sensory structures in the vertebrate head allowing the emergence of active and predatory life forms. Whereas the gene regulatory networks that control neural crest cell development have been studied extensively, the signals and downstream transcriptional events that regulate placode formation and diversity are only beginning to be uncovered. Both cell populations are derived from the embryonic ectoderm, which also generates the central nervous system and the epidermis, and recent evidence suggests that their initial specification involves a common molecular mechanism before definitive neural, neural crest and placodal lineages are established. In this review, we will first discuss the transcriptional networks that pattern the embryonic ectoderm and establish these three cell fates with emphasis on sensory placodes. Second, we will focus on how sensory placode precursors diversify using the specification of otic-epibranchial progenitors and their segregation as an example., (© 2020 Elsevier Inc. All rights reserved.)

The neural crest (NC) is a transitory embryonic structure of vertebrates that gives rise to an astonishing variety of derivatives, encompassing both neural and mesenchymal cell types. Neural crest cells (NCCs) are an excellent model to study how environmental factors modulate features such as cell multipotentiality and differentiation. Tests with multifunctional substrates that allow NCCs to express their full potential, while promoting cell subcloning, are needed to advance knowledge about NCC self-renewal and to foster future biotechnological approaches. Here we show that a self-assembled peptide named PuraMatrix TM is an excellent substrate that allows the differentiation of NCCs based on the identification of seven different cell types. Depending on the PuraMatrix TM concentration employed, different frequencies and quantities of a given cell type were obtained. It is noteworthy that an enormous quantity and diversity of mesenchymal phenotypes, such as chondrocytes, could be observed. The quantity of adipocytes and osteocytes also increased with the use of mesenchymal differentiation factors (MDF), but PuraMatrix TM alone can support the appearance of these mesenchymal cell types. PuraMatrix TM will promote advances in studies related to multipotentiality, self-renewal and control of NCC differentiation, since it is an extremely simple and versatile material which can be employed for both in vivo and in vitro experiments.

The pharyngeal arches are a prominent and significant feature of vertebrate embryos. These are visible as a series of bulges on the lateral surface of the embryonic head. In humans, and other amniotes, there are five pharyngeal arches numbered 1, 2, 3, 4 and 6; note the missing '5'. This is the standard scheme for the numbering of these structures, and it is a feature of modern anatomy textbooks. In this article, we discuss the rationale behind this odd numbering, and consider its origins. One reason given is that there is a transient 5th arch that is never fully realized, while another is that this numbering reflects considerations from comparative anatomy. We show here, however, that neither of these reasons has substance. There is no evidence from embryology for a '5th' arch, and the comparative argument does not hold as it does not apply across the vertebrates. We conclude that there is no justification for this strange numbering. We suggest that the pharyngeal arches should simply be numbered 1, 2, 3, 4 and 5 as this would be in keeping with the embryology and with the general numbering of the pharyngeal arches across the vertebrates., (© 2019 Anatomical Society.)

The vertebrate anteroposterior axis forms through elongation of multiple tissues during embryogenesis. This process is based on tissue-autonomous mechanisms of force generation and intertissue mechanical coupling whose failure leads to severe developmental anomalies such as body truncation and spina bifida. Similar to other morphogenetic modules, anteroposterior body extension requires both the rearrangement of existing materials-such as cells and extracellular matrix-and the local addition of new materials, i.e., anisotropic growth, through cell proliferation, cell growth, and matrix deposition. Numerous signaling pathways coordinate body axis formation via regulation of cell behavior during tissue rearrangements and/or volumetric growth. From a physical perspective, morphogenesis depends on both cell-generated forces and tissue material properties. As the spatiotemporal variation of these mechanical parameters has recently been explored in the context of vertebrate body elongation, the study of this process is likely to shed light on the cross talk between signaling and mechanics during morphogenesis.

Polycomb group (PcG) proteins are transcriptional repressors that are important regulators of cell fate during embryonic development. Among them, Ezh2 is responsible for catalyzing the epigenetic repressive mark H3K27me3 and is essential for animal development. The ability of zebrafish embryos lacking both maternal and zygotic ezh2 to form a normal body plan provides a unique model for comprehensively studying Ezh2 function during early development in vertebrates. By using a multi-omics approach, we found that Ezh2 is required for the deposition of H3K27me3 and is essential for proper recruitment of Polycomb group protein Rnf2. However, despite the complete absence of PcG-associated epigenetic mark and proteins, only minor changes in H3K4me3 deposition and gene and protein expression occur. These changes were mainly due to local dysregulation of transcription factors outside their normal expression boundaries. Altogether, our results in zebrafish show that Polycomb-mediated gene repression is important immediately after the body plan is formed to maintain spatially restricted expression profiles of transcription factors, and we highlight the differences that exist in the timing of PcG protein action between vertebrate species., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

In Bilaterians, commissural neurons project their axons across the midline of the nervous system to target neurons on the opposite side. In mammals, midline crossing at the level of the hindbrain and spinal cord requires the Robo3 receptor which is transiently expressed by all commissural neurons. Unlike other Robo receptors, mammalian Robo3 receptors do not bind Slit ligands and promote midline crossing. Surprisingly, not much is known about Robo3 distribution and mechanism of action in other vertebrate species. Here, we have used whole-mount immunostaining, tissue clearing and light-sheet fluorescent microscopy to study Robo3 expression pattern in embryonic tissue from diverse representatives of amniotes at distinct stages, including squamate (African house snake), birds (chicken, duck, pigeon, ostrich, emu and zebra finch), early postnatal marsupial mammals (fat-tailed dunnart), and eutherian mammals (mouse and human). The analysis of this rich and unique repertoire of amniote specimens reveals conserved features of Robo3 expression in midbrain, hindbrain and spinal cord commissural circuits, which together with subtle but meaningful modifications could account for species-specific evolution of sensory-motor and cognitive capacities. Our results also highlight important differences of precerebellar nuclei development across amniotes., (© 2019 Wiley Periodicals, Inc.)

Background: p63 is an evolutionarily ancient transcription factor essential to vertebrate tooth development. Our recent gene expression screen comparing wild-type and "toothless" p63 -/- mouse embryos implicated in tooth development several new genes that we hypothesized act downstream of p63 in dental epithelium, where p63 is also expressed., Results: Via in situ hybridization and immunohistochemistry, we probed mouse embryos (embryonic days 10.5-14.5) and spotted gar fish embryos (14 days postfertilization) for these newly linked genes, Cbln1, Cldn23, Fermt1, Krt15, Pltp and Prss8, which were expressed in mouse and gar dental epithelium. Loss of p63 altered expression levels but not domains. Expression was comparable between murine upper and lower tooth organs, implying conserved gene functions in maxillary and mandibular dentitions. Our meta-analysis of gene expression databases supported that these genes act within a p63-driven gene regulatory network important to tooth development in mammals and more evolutionary ancient vertebrates (fish, amphibians)., Conclusions: Cbln1, Cldn23, Fermt1, Krt15, Pltp, and Prss8 were expressed in mouse and fish dental epithelium at placode, bud, and/or cap stages. We theorize that these genes participate in cell-cell adhesion, cell polarity, and extracellular matrix signaling to support dental epithelium integrity, folding, and epithelial-mesenchymal cross talk during tooth development., (© 2019 Wiley Periodicals, Inc.)

Glia are abundant components of animal nervous systems. Recognized 170 years ago, concerted attempts to understand these cells began only recently. From these investigations glia, once considered passive filler material in the brain, have emerged as active players in neuron development and activity. Glia are essential for nervous system function, and their disruption leads to disease. The nematode Caenorhabditis elegans possesses glial types similar to vertebrate glia, based on molecular, morphological, and functional criteria, and has become a powerful model in which to study glia and their neuronal interactions. Facile genetic and transgenic methods in this animal allow the discovery of genes required for glial functions, and effects of glia at single synapses can be monitored by tracking neuron shape, physiology, or animal behavior. Here, we review recent progress in understanding glia-neuron interactions in C. elegans . We highlight similarities with glia in other animals, and suggest conserved emerging principles of glial function.

Chrondrocranium, the cartilaginous skull, is one of the major innovations that underlie evolution of the vertebrate head. Control of the induction and shaping of the cartilage is a key for the formation of the facial bones and largely defines facial shape. The appearance of cartilage in the head enabled many new functions such as protection of central nervous system and sensory structures, support of the feeding apparatus and formation of muscle attachment points ensuring faster and coordinated jaw movements. Here we review the evolution of cartilage in the cranial region and discuss shaping of the chondrocranium in different groups of vertebrates., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Craniofacial muscles, muscles that move the eyes, control facial expression and allow food uptake and speech, have long been regarded as a variation on the general body muscle scheme. However, evidence has accumulated that the function of head muscles, their developmental anatomy and the underlying regulatory cascades are distinct. This article reviews the key aspects of craniofacial muscle and muscle stem cell formation and discusses how this differs from the trunk programme of myogenesis; we show novel RNAseq data to support this notion. We also trace the origin of head muscle in the chordate ancestors of vertebrates and discuss links with smooth-type muscle in the primitive chordate pharynx. We look out as to how the special properties of head muscle precursor and stem cells, in particular their competence to contribute to the heart, could be exploited in regenerative medicine., (Copyright © 2017. Published by Elsevier Ltd.)

Contemporary papers and book chapters on nephrology open with the assumption that human kidney development passes through three morphological stages: pronephros, mesonephros, and metanephros. Current knowledge of the human pronephros, however, appears to be based on only a hand full of human specimens. The ongoing use of variations in the definition of a pronephros hampers the interpretation of study results. Because of the increased interest in the anamniote pronephros as a genetic model for kidney organogenesis we aimed to provide an overview of the literature concerning kidney development and to clarify the existence of a pronephros in human embryos. We performed an extensive literature survey regarding vertebrate renal morphology and we investigated histological sections of human embryos between 2 and 8 weeks of development. To facilitate better understanding of the literature about kidney development, a referenced glossary with short definitions was composed. The most striking difference between pronephros versus meso- and metanephros is found in nephron architecture. The pronephros consists exclusively of non-integrated nephrons with external glomeruli, whereas meso- and metanephros are composed of integrated nephrons with internal glomeruli. Animals whose embryos have comparatively little yolk at their disposal and hence have a free-swimming larval stage do develop a pronephros that is dedicated to survival in aquatic environments. Species in which embryos do not have a free-swimming larval stage have embryos that are supplied with a large amount of yolk or that develop within the body of the parent. In those species the pronephros is usually absent, incompletely developed, and apparently functionless. Non-integrated nephrons were not identified in histological sections of human embryos. Therefore, we conclude that a true pronephros is not detectable in human embryos although the most cranial part of the amniote excretory organ is often confusingly referred to as pronephros. The term pronephros should be avoided in amniotes unless all elements for a functional pronephros are undeniably present., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

The endoderm is a progenitor tissue that, in humans, gives rise to the majority of internal organs. Over the past few decades, genetic studies have identified many of the upstream signals specifying endoderm identity in different model systems, revealing them to be divergent from invertebrates to vertebrates. However, more recent studies of the cell behaviours driving endodermal morphogenesis have revealed a surprising number of shared features, including cells undergoing epithelial-to-mesenchymal transitions (EMTs), collective cell migration, and mesenchymal-to-epithelial transitions (METs). In this Review, we highlight how cross-organismal studies of endoderm morphogenesis provide a useful perspective that can move our understanding of this fascinating tissue forward., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Gene regulatory networks account for the ability of the genome to program development in complex multi-cellular organisms. Such networks are based on principles of gene regulation by combinations of transcription factors that bind to specific cis-regulatory DNA sites to activate transcription. These cis-regulatory regions mediate logic processing at each network node, enabling progressive increases in organismal complexity with development. Gene regulatory network explanations of development have been shown to account for patterning and cell type diversification in fly and sea urchin embryonic systems, where networks are characterized by fast coupling between transcriptional inputs and changes in target gene transcription rates, and crucial cis-regulatory elements are concentrated relatively close to the protein coding sequences of the target genes, thus facilitating their identification. Stem cell-based development in post-embryonic mammalian systems also depends on gene networks, but differs from the fly and sea urchin systems. First, the number of regulatory elements per gene and the distances between regulatory elements and the genes they control are considerably larger, forcing searches via genome-wide transcription factor binding surveys rather than functional assays. Second, the intrinsic timing of network state transitions can be slowed considerably by the need to undo stem-cell chromatin configurations, which presumably add stability to stem-cell states but retard responses to transcription factor changes during differentiation. The dispersed, partially redundant cis-regulatory systems controlling gene expression and the slow state transition kinetics in these systems already reveal new insights and opportunities to extend understanding of the repertoire of gene networks and regulatory system logic., (Copyright © 2019. Published by Elsevier B.V.)

In jawed vertebrates (gnathostomes), Hox genes play an important role in patterning head and jaw formation, but mechanisms coupling Hox genes to neural crest (NC) are unknown. Here we use cross-species regulatory comparisons between gnathostomes and lamprey, a jawless extant vertebrate, to investigate conserved ancestral mechanisms regulating Hox2 genes in NC. Gnathostome Hoxa2 and Hoxb2 NC enhancers mediate equivalent NC expression in lamprey and gnathostomes, revealing ancient conservation of Hox upstream regulatory components in NC. In characterizing a lamprey hoxα2 NC/hindbrain enhancer, we identify essential Meis, Pbx, and Hox binding sites that are functionally conserved within Hoxa2/Hoxb2 NC enhancers. This suggests that the lamprey hoxα2 enhancer retains ancestral activity and that Hoxa2/Hoxb2 NC enhancers are ancient paralogues, which diverged in hindbrain and NC activities. This identifies an ancestral mechanism for Hox2 NC regulation involving a Hox-TALE regulatory circuit, potentiated by inputs from Meis and Pbx proteins and Hox auto-/cross-regulatory interactions.

Pbx genes encode transcription factors that belong to the TALE (three-amino-acid loop extension) superclass of homeodomain proteins. We have witnessed a surge in information about the roles of this gene family as leading actors in the transcriptional control of development. PBX proteins represent a clear example of how transcription factors can regulate developmental processes by combinatorial properties, acting within multimeric complexes to implement activation or repression of transcription depending on their interaction partners. Here, we revisit long-emphasized functions of PBX transcription factors as cofactors for HOX proteins, major architects of the body plan. We further discuss new knowledge on roles of PBX proteins in different developmental contexts as upstream regulators of Hox genes-as factors that interact with non-HOX proteins and can work independently of HOX-as well as potential pioneer factors. Committed to building a perfect body, PBX proteins govern regulatory networks that direct essential morphogenetic processes and organogenesis in vertebrate development. Perturbations of PBX-dependent networks can cause human congenital disease and cancer., (© 2019 Selleri et al.; Published by Cold Spring Harbor Laboratory Press.)

The neural crest (NC) in embryos of vertebrates represents a cell population formed at the border of the neural plate. These cells retain pluripotency, express a set of specific markers, and become multipotent upon their migration away from the neural tube to give rise to numerous derivatives. The genes specific for vertebrate NC appeared in evolution long before vertebrates. Abnormal development of NC cells causes numerous pathologies in humans.

Gene regulatory networks underlying cellular pluripotency are controlled by a core circuitry of transcription factors in mammals, including POU5F1. However, the evolutionary origin and transformation of pluripotency-related transcriptional networks have not been elucidated in deuterostomes. PR domain-containing protein 14 (PRDM14) is specifically expressed in pluripotent cells and germ cells, and is required for establishing embryonic stem cells (ESCs) and primordial germ cells in mice. Here, we compared the functions and expression patterns of PRDM14 orthologues within deuterostomes. Amphioxus PRDM14 and zebrafish PRDM14, but not sea urchin PRDM14, compensated for mouse PRDM14 function in maintaining mouse ESC pluripotency. Interestingly, sea urchin PRDM14 together with sea urchin CBFA2T, an essential partner of PRDM14 in mouse ESCs, complemented the self-renewal defect in mouse Prdm14 KO ESCs. Contrary to the Prdm14 expression pattern in mouse embryos, Prdm14 was expressed in motor neurons of amphioxus embryos, as observed in zebrafish embryos. Thus, Prdm14 expression in motor neurons was conserved in non-tetrapod deuterostomes and the co-option of the PRDM14-CBFA2T complex from motor neurons into pluripotent cells may have maintained the transcriptional network for pluripotency during vertebrate evolution.This article has an associated 'The people behind the papers' interview., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

In certain vertebrate species, the developing embryo breaks left-right symmetry in a transient organising structure: the "Left-Right Organiser" (LRO) known as the "node" in mice, and "Kupffer's vesicle" in fish. Directional cilia-driven flow is integral to this symmetry-breaking process, however the mechanism by which this flow is translated into an asymmetric signal remains contested; the principal theories are either flow transport of vesicles containing morphogens, or flow mechanosensing by cilia. Whilst some recent work favours the morphogen theory, other findings seem to support mechanosensing. In this study, we consider a hypothesis whereby the cilia themselves drive the release of morphogen-carrying extracellular vesicles (EVs) into the LRO; namely, that fluid stresses on the cell membrane induce/enhance exocytosis of EVs. Using a mathematical model, we calculate significant wall normal and shear stresses for a range of typical cilium parameter values comparable to levels capable of enhancing exocytosis. This mechanism may be able to reconcile the apparently conflicting experimental evidence., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Jawed vertebrates have inner ears with three semicircular canals, the presence of which has been used as a key to understanding evolutionary relationships. Ostracoderms, the jawless stem gnathostomes, had only two canals and lacked the lateral canal 1-3 . Lampreys, which are modern cyclostomes, are generally thought to possess two semicircular canals whereas the hagfishes-which are also cyclostomes-have only a single canal, which used to be regarded as a more primitive trait 1,4 . However, recent molecular and developmental analyses have strongly supported the monophyly of cyclostomes 5-7 , which has left the evolutionary trajectory of the vertebrate inner ear unclear 8 . Here we show the differentiation of the otic vesicle of the lamprey Lethenteron camtschaticum and inshore hagfish Eptatretus burgeri. This is the first time, to our knowledge, that the development of the hagfish inner ear is reported. We found that canal development in the lamprey starts with two depressions-which is reminiscent of the early developmental pattern of the inner ear in modern gnathostomes. These cyclostome otic vesicles show a pattern of expression of regulatory genes, including OTX genes, that is comparable to that of gnathosomes. Although two depressions appear in the lamprey vesicle, they subsequently fuse to form a single canal that is similar to that of hagfishes. Complete separation of the depressions results in anterior and posterior canals in gnathostomes. The single depression of the vesicle in hagfishes thus appears to be a secondarily derived trait. Furthermore, the lateral canal in crown gnathostomes was acquired secondarily-not by de novo acquisition of an OTX expression domain, but by the evolution of a developmental program downstream of the OTX genes.

In tetrapods, the scapular and pelvic girdles perform the important function of anchoring the limbs to the trunk of the body and facilitating the movement of each appendage. This shared function, however, is one of relatively few similarities between the scapula and pelvis, which have significantly different morphologies, evolutionary histories, embryonic origins, and underlying genetic pathways. The scapula evolved in jawless fish prior to the pelvis, and its embryonic development is unique among bones in that it is derived from multiple progenitor cell populations, including the dermomyotome, somatopleure, and neural crest. Conversely, the pelvis evolved several million years later in jawed fish, and it develops from an embryonic somatopleuric cell population. The genetic networks controlling the formation of the pelvis and scapula also share similarities and differences, with a number of genes shaping only one or the other, while other gene products such as PBX transcription factors act as hierarchical developmental regulators of both girdle structures. Here, we provide a detailed review of the cellular processes and genetic networks underlying pelvis and scapula formation in tetrapods, while also highlighting unanswered questions about girdle evolution and development., (© 2019 Elsevier Inc. All rights reserved.)

During development, the vertebrate embryo undergoes significant morphological changes which lead to its future body form and functioning organs. One of these noticeable changes is the extension of the body shape along the antero-posterior (A-P) axis. This A-P extension, while taking place in multiple embryonic tissues of the vertebrate body, involves the same basic cellular behaviors: cell proliferation, cell migration (of new progenitors from a posterior stem zone), and cell rearrangements. However, the nature and the relative contribution of these different cellular behaviors to A-P extension appear to vary depending upon the tissue in which they take place and on the stage of embryonic development. By focusing on what is known in the neural and mesodermal tissues of the bird embryo, I review the influences of cellular behaviors in posterior tissue extension. In this context, I discuss how changes in distinct cell behaviors can be coordinated at the tissue level (and between tissues) to synergize, build, and elongate the posterior part of the embryonic body. This multi-tissue framework does not only concern axis elongation, as it could also be generalized to morphogenesis of any developing organs.

Skeletal muscle powers all movement of the vertebrate body and is distributed in multiple regions that have evolved distinct functions. Axial muscles are ancestral muscles essential for support and locomotion of the whole body. The evolution of the head was accompanied by development of cranial muscles essential for eye movement, feeding, vocalization, and facial expression. With the evolution of paired fins and limbs and their associated muscles, vertebrates gained increased locomotor agility, populated the land, and acquired fine motor skills. Finally, unique muscles with specialized functions have evolved in some groups, and the diaphragm which solely evolved in mammals to increase respiratory capacity is one such example. The function of all these muscles requires their integration with the other components of the musculoskeletal system: muscle connective tissue (MCT), tendons, bones as well as nerves and vasculature. MCT is muscle's closest anatomical and functional partner. Not only is MCT critical in the adult for muscle structure and function, but recently MCT in the embryo has been found to be crucial for muscle development. In this review, we examine the important role of the MCT in axial, head, limb, and diaphragm muscles for regulating normal muscle development, discuss how defects in MCT-muscle interactions during development underlie the etiology of a range of birth defects, and explore how changes in MCT development or communication with muscle may have led to the modification and acquisition of new muscles during vertebrate evolution., (© 2019 Elsevier Inc. All rights reserved.)

Cell-to-cell communication is fundamental for embryo development and subsequent tissue homeostasis. This communication is often mediated by a small number of signaling pathways in which a secreted ligand binds to the surface of a target cell, thereby activating signal transduction. In vertebrate neural development, these signaling mechanisms are repeatedly used to obtain different and context-dependent outcomes. Part of the versatility of these communication mechanisms depends on their finely tuned regulation that controls timing, spatial localization, and duration of the signaling. The existence of secreted antagonists, which prevent ligand-receptor interaction, is an efficient mechanism to regulate some of these pathways. The Hedgehog family of signaling proteins, however, activates a pathway that is controlled largely by the positive or negative activity of membrane-bound proteins such as Cdon, Boc, Gas1, or Megalin/LRP2. In this review, we will use the development of the vertebrate retina, from its early specification to neurogenesis, to discuss whether there is an advantage to the use of such regulators, pointing to unresolved or controversial issues., Competing Interests: No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

The developing nervous system depends upon precise regulation of oxygen levels. Hypoxia, the condition of low oxygen concentration, can interrupt developmental sequences and cause a range of molecular, cellular and neuronal changes and injuries. The roles and effects of hypoxia on the central nervous system (CNS) are poorly characterized, even though hypoxia is simultaneously a normal component of development, a potentially abnormal environmental stressor in some settings, and a clinically important complication, for example of prematurity. Work over the past decade has revealed that hypoxia causes specific disruptions in the development of CNS connectivity, altering axon pathfinding and synapse development. The goals of this article are to review hypoxia's effects on the development of CNS connectivity, including its genetic and molecular mediators, and the changes it causes in CNS circuitry and function due to regulated as well as unintended mechanisms. The transcription factor HIF1α is the central mediator of the CNS response to hypoxia (as it is elsewhere in the body), but hypoxia also causes a dysregulation of gene expression. Animals appear to have evolved genetic and molecular responses to hypoxia that result in functional behavioral alterations to adapt to the changes in oxygen concentration during CNS development. Understanding the molecular pathways underlying both the normal and abnormal effects of hypoxia on CNS connectivity may reveal novel insights into common neurodevelopmental disorders. In addition, this Review explores the current gaps in knowledge, and suggests important areas for future studies., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Receptor tyrosine kinase-mediated growth factor signaling is essential for proper formation and development of the neural crest. The many ligands and receptors implicated in these processes signal through relatively few downstream pathways, frequently converging on the MAPK and PI3K pathways. Despite decades of study, there is still considerable uncertainty about where and when these signaling pathways are required and how they elicit particular responses. This review summarizes our current understanding of growth factor-induced MAPK and PI3K signaling in the neural crest., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The neural crest (NC) is a transient, multipotent and migratory cell population that generates an astonishingly diverse array of cell types during vertebrate development. These cells, which originate from the ectoderm in a region lateral to the neural plate in the neural fold, give rise to neurons, glia, melanocytes, chondrocytes, smooth muscle cells, odontoblasts and neuroendocrine cells, among others. Neurocristopathies (NCP) are a class of pathologies occurring in vertebrates, especially in humans that result from the abnormal specification, migration, differentiation or death of neural crest cells during embryonic development. Various pigment, skin, thyroid and hearing disorders, craniofacial and heart abnormalities, malfunctions of the digestive tract and tumors can also be considered as neurocristopathies. In this review we revisit the current classification and propose a new way to classify NCP based on the embryonic origin of the affected tissues, on recent findings regarding the molecular mechanisms that drive NC formation, and on the increased complexity of current molecular embryology techniques., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cell competition is a biological mechanism conserved from Drosophila to vertebrates wherein neighboring cells compare their relative fitness status resulting in the elimination of less fit cells by those with higher fitness. This is an active process that is essential for embryonic and organ development, tissue homeostasis, delay of ageing and in various disease models such as cancer. Recent research is beginning to unravel the various mechanisms of cell competition and the sensing of fitness status. Fitness fingerprints, death receptors, mechanical cell competition and a set of unknown genetic or signaling pathways are emerging as important pathways governing the mechanisms for cell to compare their relative fitness levels. In this review we are providing an account of recent advances which help summarize the mechanisms of operation and growing role of cell competition in regulation of oncogenesis in vertebrates., (Copyright © 2018. Published by Elsevier Ltd.)

Arising within the neural tube between the cranial and trunk regions of the body axis, the vagal neural crest shares interesting similarities in its migratory routes and derivatives with other neural crest populations. However, the vagal neural crest is also unique in its ability to contribute to diverse organs including the heart and enteric nervous system. This review highlights the migratory routes of the vagal neural crest and compares them across multiple vertebrates. We also summarize recent advances in understanding vagal neural crest ontogeny and discuss the contribution of this important neural crest population to the cardiovascular system and endoderm-derived organs, including the thymus, lungs and pancreas., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The endothelin system is a vertebrate-specific innovation with important roles in regulating the cardiovascular system and renal and pulmonary processes, as well as the development of the vertebrate-specific neural crest cell population and its derivatives. This system is comprised of three structurally similar 21-amino acid peptides that bind and activate two G-protein coupled receptors. In 1994, knockouts of the Edn3 and Ednrb genes revealed their crucial function during development of the enteric nervous system and melanocytes, two neural-crest derivatives. Since then, human and mouse genetics, combined with cellular and developmental studies, have helped to unravel the role of this signaling pathway during development and adulthood. In this review, we will summarize the known functions of the EDN3/EDNRB pathway during neural crest development, with a specific focus on recent scientific advances, and the enteric nervous system in normal and pathological conditions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The neural crest is a transient population of cells that forms within the developing central nervous system and migrates away to generate a wide range of derivatives throughout the body during vertebrate embryogenesis. These cells are of evolutionary and clinical interest, constituting a key defining trait in the evolution of vertebrates and alterations in their development are implicated in a high proportion of birth defects and craniofacial abnormalities. In the hindbrain and the adjacent cranial neural crest cells (cNCCs), nested domains of Hox gene expression provide a combinatorial'Hox-code' for specifying regional properties in the developing head. Hox genes have been shown to play important roles at multiple stages in cNCC development, including specification, migration, and differentiation. However, relatively little is known about the underlying gene-regulatory mechanisms involved, both upstream and downstream of Hox genes. Furthermore, it is still an open question as to how the genes of the neural crest GRN are linked to Hox-dependent pathways. In this review, we describe Hox gene expression, function and regulation in cNCCs with a view to integrating these genes within the emerging gene regulatory network for cNCC development. We highlight early roles for Hox1 genes in cNCC specification, proposing that this may be achieved, in part, by regulation of the balance between pluripotency and differentiation in precursor cells within the neuro-epithelium. We then describe what is known about the regulation of Hox gene expression in cNCCs and discuss this from the perspective of early vertebrate evolution., (Copyright © 2018 Elsevier Inc. All rights reserved.)

MicroRNAs are small noncoding RNAs that can control gene expression by base pairing to partially complementary mRNAs. Regulation by microRNAs plays essential roles in diverse biological processes such as neural crest formation during embryonic development. The neural crest is a multipotent cell population that develops from the dorsal neural fold of vertebrate embryos in order to migrate extensively and differentiate into a variety of tissues. Gene regulatory networks that coordinate neural crest cell specification and differentiation have been considerably studied so far. Although it is known that microRNAs play important roles in neural crest development, posttranscriptional regulation by microRNAs has not been deeply characterized yet. This review is focused on the microRNAs identified so far in order to regulate gene expression of neural crest cells during vertebrate development., (Copyright © 2018 Elsevier B.V. All rights reserved.)

AKT signaling is an essential intracellular pathway controlling cell homeostasis, cell proliferation and survival, as well as cell migration and differentiation in adults. Alterations impacting the AKT pathway are involved in many pathological conditions in human disease. Similarly, during development, multiple transmembrane molecules, such as FGF receptors, PDGF receptors or integrins, activate AKT to control embryonic cell proliferation, migration, differentiation, and also cell fate decisions. While many studies in mouse embryos have clearly implicated AKT signaling in the differentiation of several neural crest derivatives, information on AKT functions during the earliest steps of neural crest development had remained relatively scarce until recently. However, recent studies on known and novel regulators of AKT signaling demonstrate that this pathway plays critical roles throughout the development of neural crest progenitors. Non-mammalian models such as fish and frog embryos have been instrumental to our understanding of AKT functions in neural crest development, both in neural crest progenitors and in the neighboring tissues. This review combines current knowledge acquired from all these different vertebrate animal models to describe the various roles of AKT signaling related to neural crest development in vivo. We first describe the importance of AKT signaling in patterning the tissues involved in neural crest induction, namely the dorsal mesoderm and the ectoderm. We then focus on AKT signaling functions in neural crest migration and differentiation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The phenomenal migratory and differentiation capacity of neural crest cells has been well established across model organisms. While the earliest stages of neural crest development have been investigated in non-mammalian model systems such as Xenopus and Aves, the early specification of this cell population has not been evaluated in mammalian embryos, of which the murine model is the most prevalent. Towards a more comprehensive understanding of mammalian neural crest formation and human comparative studies, we have used the rabbit as a mammalian system for the study of early neural crest specification and development. We examine the expression profile of well-characterized neural crest markers in rabbit embryos across developmental time from early gastrula to later neurula stages, and provide a comparison to markers of migratory neural crest in the chick. Importantly, we apply explant specification assays to address the pivotal question of mammalian neural crest ontogeny, and provide the first evidence that a specified population of neural crest cells exists in the rabbit gastrula prior to the overt expression of neural crest markers. Finally, we demonstrate that FGF signaling is necessary for early rabbit neural crest formation, as SU5402 treatment strongly represses neural crest marker expression in explant assays. This study pioneers the rabbit as a model for neural crest development, and provides the first demonstration of mammalian neural crest specification and the requirement of FGF signaling in this process., (Copyright © 2018. Published by Elsevier Inc.)

The neural crest is a migratory cell population that contributes to multiple tissues and organs during vertebrate embryonic development. It is remarkable in its ability to differentiate into an array of different cell types, including melanocytes, cartilage, bone, smooth muscle, and peripheral nerves. Although neural crest cells are formed along the entire anterior-posterior axis of the developing embryo, they can be divided into distinct subpopulations based on their axial level of origin. These groups of cells, which include the cranial, vagal, trunk, and sacral neural crest, display varied migratory patterns and contribute to multiple derivatives. While these subpopulations have been shown to be mostly plastic and to differentiate according to environmental cues, differences in their intrinsic potentials have also been identified. For instance, the cranial neural crest is unique in its ability to give rise to cartilage and bone. Here, we examine the molecular features that underlie such developmental restrictions and discuss the hypothesis that distinct gene regulatory networks operate in these subpopulations. We also consider how reconstructing the phylogeny of the trunk and cranial neural crest cells impacts our understanding of vertebrate evolution., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The migration and distribution patterns of neural crest (NC) cells reflect the distinct embryonic environments of the head and trunk: cephalic NC cells migrate predominantly along the dorsolateral pathway to populate the craniofacial and pharyngeal regions, whereas trunk crest cells migrate along the ventrolateral pathways to form the dorsal root ganglia. These two patterns thus reflect the branchiomeric and somitomeric architecture, respectively, of the vertebrate body plan. The so-called vagal NC occupies a postotic, intermediate level between the head and trunk NC. This level of NC gives rise to both trunk- and cephalic-type (circumpharyngeal) NC cells. The anatomical pattern of the amphioxus, a basal chordate, suggests that somites and pharyngeal gills coexist along an extensive length of the body axis, indicating that the embryonic environment is similar to that of vertebrate vagal NC cells and may have been ancestral for vertebrates. The amniote-like condition in which the cephalic and trunk domains are distinctly separated would have been brought about, in part, by anteroposterior reduction of the pharyngeal domain., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Extensive studies have shown how bilateral symmetry of the vertebrate embryo is broken during early development, resulting in a molecular left-right bias in the mesoderm. However, how this early asymmetry drives the asymmetric morphogenesis of visceral organs remains poorly understood. The heart provides a striking model of left-right asymmetric morphogenesis, undergoing rightward looping to shape an initially linear heart tube and align cardiac chambers. Importantly, abnormal left-right patterning is associated with severe congenital heart defects, as exemplified in heterotaxy syndrome. Here, we compare the mechanisms underlying the rightward looping of the heart tube in fish, chick and mouse embryos. We propose that heart looping is not only a question of direction, but also one of fine-tuning shape. This is discussed in the context of evolutionary and clinical perspectives., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Placodes and neural crests represent defining features of vertebrates, yet their relationship remains unclear despite extensive investigation 1-3 . Here we use a combination of lineage tracing, gene disruption and single-cell RNA-sequencing assays to explore the properties of the lateral plate ectoderm of the proto-vertebrate, Ciona intestinalis. There are notable parallels between the patterning of the lateral plate in Ciona and the compartmentalization of the neural plate ectoderm in vertebrates 4 . Both systems exhibit sequential patterns of Six1/2, Pax3/7 and Msxb expression that depend on a network of interlocking regulatory interactions 4 . In Ciona, this compartmentalization network produces distinct but related types of sensory cells that share similarities with derivatives of both cranial placodes and the neural crest in vertebrates. Simple genetic disruptions result in the conversion of one sensory cell type into another. We focused on bipolar tail neurons, because they arise from the tail regions of the lateral plate and possess properties of the dorsal root ganglia, a derivative of the neural crest in vertebrates 5 . Notably, bipolar tail neurons were readily transformed into palp sensory cells, a proto-placodal sensory cell type that arises from the anterior-most regions of the lateral plate in the Ciona tadpole 6 . Proof of transformation was confirmed by whole-embryo single-cell RNA-sequencing assays. These findings suggest that compartmentalization of the lateral plate ectoderm preceded the advent of vertebrates, and served as a common source for the evolution of both cranial placodes and neural crest 3,4 .

The Pax3/7 transcription factor family is integral to developmental gene networks contributing to important innovations in vertebrate evolution, including the neural crest. The basal chordate lineage of amphioxus is ideally placed to understand the dynamics of the gene regulatory network evolution that produced these novelties. We report here the discovery that the cephalochordate lineage possesses two Pax3/7 genes, Pax3/7a and Pax3/7b. The tandem duplication is ancestral to all extant amphioxus, occurring in both Asymmetron and Branchiostoma, but originated after the split from the lineage leading to vertebrates. The two paralogues are differentially expressed during embryonic development, particularly in neural and somitic tissues, suggesting distinct regulation. Our results have implications for the study of amphioxus regeneration, neural plate and crest evolution, and differential tandem paralogue evolution.

The ductus arteriosus is typically viewed as a mammalian fetal blood vessel providing a right-to-left shunt of right ventricular outflow away from the lungs and to the systemic circuit, that must close at birth. This review provides a wider comparative examination of the ductus arteriosus in lungfish, reptiles, birds, and mammals. The ductus arteriosus evolved with the lung in the ancestors of the lungfish as a connection between the pulmonary arteries and dorsal aorta. During embryonic development, reptiles, birds, and mammals all possess either one or two paired ductus arteriosi that provide a fetal shunt of blood away from the lungs. Differences in the fetal circulatory arrangement are seen between these groups and this influences the importance of the ductus arteriosus as an embryonic shunt. The ductus arteriosus from lungfish and tetrapod vertebrates is an oxygen sensitive blood vessel, with shared conserved pathways involved in oxygen sensing. By expanding studies into more comparative models such as lungfish or developing birds a better understanding of the physiology of the ductus arteriosus can be developed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cranium of jawed vertebrates is composed of dorsal moiety that encapsulates the brain, or the neurocranium, and the is called the neurocranium, and the ventral moiety, the viscerocranium, that supports the pharynx. In modern jawed vertebrates (crown gnathostomes), the viscerocranium is predominantly of neural crest origin, and for the neurocranium, the rostral part is derived from neural crest cells, whereas the posterior part from the mesoderm. In the cyclostome cranium, the mesoderm/neural crest boundary of the neurocranium used to be enigmatic, let alone the morphological comparison of neurocranial between two cyclostome groups, lampreys and hagfishes. By examining the hagfish development it has become clear that cyclostomes share a common craniofacial embryonic pattern that is not shared by modern gnathostomes, and cyclostome cranium can be compared among the group as developmental modular units with comparable mesoderm/neural crest boundary within the neuroranium. Also, the dual origin of the jawed vertebrate neurocranium has now turned out to represent a derived condition, and ancestrally, the neurocranium would likely have been predominantly of mesodermal origin. Enlargement of the forebrain and reorganization of the oral apparatus seem to have led to the involvement of the neural crest in the rostral neurocranium., (© 2018 Wiley Periodicals, Inc.)

Patterning of craniofacial muscles overtly begins with the activation of lineage-specific markers at precise, evolutionarily conserved locations within prechordal, lateral, and both unsegmented and somitic paraxial mesoderm populations. Although these initial programming events occur without influence of neural crest cells, the subsequent movements and differentiation stages of most head muscles are neural crest-dependent. Incorporating both descriptive and experimental studies, this review examines each stage of myogenesis up through the formation of attachments to their skeletal partners. We present the similarities among developing muscle groups, including comparisons with trunk myogenesis, but emphasize the morphogenetic processes that are unique to each group and sometimes subsets of muscles within a group. These groups include branchial (pharyngeal) arches, which encompass both those with clear homologues in all vertebrate classes and those unique to one, for example, mammalian facial muscles, and also extraocular, laryngeal, tongue, and neck muscles. The presence of several distinct processes underlying neural crest:myoblast/myocyte interactions and behaviors is not surprising, given the wide range of both quantitative and qualitative variations in craniofacial muscle organization achieved during vertebrate evolution., (© 2018 Wiley Periodicals, Inc.)

TGF-β family ligands function in inducing and patterning many tissues of the early vertebrate embryonic body plan. Nodal signaling is essential for the specification of mesendodermal tissues and the concurrent cellular movements of gastrulation. Bone morphogenetic protein (BMP) signaling patterns tissues along the dorsal-ventral axis and simultaneously directs the cell movements of convergence and extension. After gastrulation, a second wave of Nodal signaling breaks the symmetry between the left and right sides of the embryo. During these processes, elaborate regulatory feedback between TGF-β ligands and their antagonists direct the proper specification and patterning of embryonic tissues. In this review, we summarize the current knowledge of the function and regulation of TGF-β family signaling in these processes. Although we cover principles that are involved in the development of all vertebrate embryos, we focus specifically on three popular model organisms: the mouse Mus musculus , the African clawed frog of the genus Xenopus , and the zebrafish Danio rerio , highlighting the similarities and differences between these species., (Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.)

Orofacial muscles are critical for life-sustaining behaviors, such as feeding and breathing. Centuries of work by neuroanatomists and surgeons resulted in the mapping of bulbar motor neurons in the brainstem and the course of the cranial nerves that carry their axons. Despite the sophisticated understanding of the anatomy of the region, the molecular mechanisms that dictate the development and maturation of facial motor neurons remain poorly understood. This fundamental problem has been recently revisited by physiologists with novel techniques of studying the rhythmic contraction of orofacial muscles in relationship to breathing. The molecular understanding of facial motor neuron development will not only lead to the comprehension of the neural basis of facial expression but may also unlock new avenues to generate stem cell-derived replacements. This review summarizes the current understanding of molecular programs involved in facial motor neuron generation, migration, and maturation, including neural circuit assembly., (Copyright © 2018 Elsevier Inc. All rights reserved.)