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Nature Communications Jul 2023The molecular mechanisms that coordinate patterning of the embryonic ectoderm into spatially distinct lineages to form the nervous system, epidermis, and neural...
The molecular mechanisms that coordinate patterning of the embryonic ectoderm into spatially distinct lineages to form the nervous system, epidermis, and neural crest-derived craniofacial structures are unclear. Here, biochemical disease-variant profiling reveals a posttranslational pathway that drives early ectodermal differentiation in the vertebrate head. The anteriorly expressed ubiquitin ligase CRL3-KLHL4 restricts signaling of the ubiquitous cytoskeletal regulator CDC42. This regulation relies on the CDC42-activating complex GIT1-βPIX, which CRL3-KLHL4 exploits as a substrate-specific co-adaptor to recognize and monoubiquitylate PAK1. Surprisingly, we find that ubiquitylation converts the canonical CDC42 effector PAK1 into a CDC42 inhibitor. Loss of CRL3-KLHL4 or a disease-associated KLHL4 variant reduce PAK1 ubiquitylation causing overactivation of CDC42 signaling and defective ectodermal patterning and neurulation. Thus, tissue-specific restriction of CDC42 signaling by a ubiquitin-based effector-to-inhibitor is essential for early face, brain, and skin formation, revealing how cell-fate and morphometric changes are coordinated to ensure faithful organ development.
Topics: Brain; Ectoderm; Neural Crest; Signal Transduction; Ubiquitin
PubMed: 37495603
DOI: 10.1038/s41467-023-40223-y -
Journal of Anatomy Nov 2014A key event in the formation of the pharyngeal arches is the outpocketing of the endodermal pharyngeal pouches and the establishment of contact with the overlying... (Comparative Study)
Comparative Study
A key event in the formation of the pharyngeal arches is the outpocketing of the endodermal pharyngeal pouches and the establishment of contact with the overlying ectoderm. However, relatively little is known about how the endoderm and ectoderm relate to each other at these points of contact and the extent to which this differs between the pouches. We have therefore detailed the interactions between the pharyngeal pouches and ectoderm in the chick embryo. Unlike the other pouches, the first pouch does not sustain direct contact with the ectoderm but separates after initial contact. Contrastingly, a perforation is formed between the second pouch and cleft that creates an external opening into the pharynx. Finally, the third and fourth pouch endoderm can be seen to bulge outwards through the ectoderm, although external openings to the pharyngeal lumen are not established. To understand whether these behaviours represent derived or ancestral features, we characterised the pharyngeal ectodermal-endodermal interfaces in the shark embryo. We found that the pouches of the posterior gill-bearing arches in this species also displayed the outward bulging of the endoderm into the ectoderm, although openings were established. We further used genetic tools to detail unambiguously the relationship between the endoderm and ectoderm in zebrafish and mouse embryos and again found that the posterior pouches break through the ectoderm. Thus different pharyngeal pouches establish different topological relationships with the overlying ectoderm and the posterior pouches initiate the developmental programme for the formation of gills, be they amniotes or anamniotes.
Topics: Animals; Branchial Region; Cell Death; Cell Lineage; Chick Embryo; Ectoderm; Endoderm; Mice; Morphogenesis; Phylogeny; Sharks; Vertebrates; Zebrafish
PubMed: 25201771
DOI: 10.1111/joa.12234 -
Developmental Biology May 2014Cranial placodes are evolutionary innovations of vertebrates. However, they most likely evolved by redeployment, rewiring and diversification of preexisting cell types... (Review)
Review
Cranial placodes are evolutionary innovations of vertebrates. However, they most likely evolved by redeployment, rewiring and diversification of preexisting cell types and patterning mechanisms. In the second part of this review we compare vertebrates with other animal groups to elucidate the evolutionary history of ectodermal patterning. We show that several transcription factors have ancient bilaterian roles in dorsoventral and anteroposterior regionalisation of the ectoderm. Evidence from amphioxus suggests that ancestral chordates then concentrated neurosecretory cells in the anteriormost non-neural ectoderm. This anterior proto-placodal domain subsequently gave rise to the oral siphon primordia in tunicates (with neurosecretory cells being lost) and anterior (adenohypophyseal, olfactory, and lens) placodes of vertebrates. Likewise, tunicate atrial siphon primordia and posterior (otic, lateral line, and epibranchial) placodes of vertebrates probably evolved from a posterior proto-placodal region in the tunicate-vertebrate ancestor. Since both siphon primordia in tunicates give rise to sparse populations of sensory cells, both proto-placodal domains probably also gave rise to some sensory receptors in the tunicate-vertebrate ancestor. However, proper cranial placodes, which give rise to high density arrays of specialised sensory receptors and neurons, evolved from these domains only in the vertebrate lineage. We propose that this may have involved rewiring of the regulatory network upstream and downstream of Six1/2 and Six4/5 transcription factors and their Eya family cofactors. These proteins, which play ancient roles in neuronal differentiation were first recruited to the dorsal non-neural ectoderm in the tunicate-vertebrate ancestor but subsequently probably acquired new target genes in the vertebrate lineage, allowing them to adopt new functions in regulating proliferation and patterning of neuronal progenitors.
Topics: Animals; Biological Evolution; Body Patterning; Cell Differentiation; Cell Proliferation; Ectoderm; Gene Expression Regulation, Developmental; Neural Plate; Vertebrates
PubMed: 24491817
DOI: 10.1016/j.ydbio.2014.01.019 -
Current Topics in Developmental Biology 2015Morphogenesis of the brain and face is intrinsically linked by a number of factors. These include: origins of tissues, adjacency allowing their physical interactions,... (Review)
Review
Morphogenesis of the brain and face is intrinsically linked by a number of factors. These include: origins of tissues, adjacency allowing their physical interactions, and molecular cross talk controlling growth. Neural crest cells that form the facial primordia originate on the dorsal neural tube. In the caudal pharyngeal arches, a Homeobox code regulates arch identity. In anterior regions, positional information is acquired locally. Second, the brain is a structural platform that influences positioning of the facial primordia, and brain growth influences the timing of primordia fusion. Third, the brain helps induce a signaling center, the frontonasal ectodermal zone, in the ectoderm, which participates in patterned growth of the upper jaw. Similarly, signals from neural crest cells regulate expression of fibroblast growth factor 8 in the anterior neural ridge, which controls growth of the anterior forebrain. Disruptions to these interactions have significant consequences for normal development of the craniofacial complex, leading to structural malformations and birth defects.
Topics: Animals; Brain; Ectoderm; Face; Gene Expression Regulation, Developmental; Humans; Models, Biological; Morphogenesis; Neural Crest; Signal Transduction
PubMed: 26589930
DOI: 10.1016/bs.ctdb.2015.09.001 -
Developmental Biology Jun 2001Endodermally derived organs of the gastrointestinal and respiratory system form at distinct anterioposterior and dorsoventral locations along the vertebrate body axis.... (Review)
Review
Endodermally derived organs of the gastrointestinal and respiratory system form at distinct anterioposterior and dorsoventral locations along the vertebrate body axis. This stereotyped program of organ formation depends on the correct patterning of the endodermal epithelium so that organ differentiation and morphogenesis occur at appropriate positions along the gut tube. Whereas some initial patterning of the endoderm is known to occur early, during germ-layer formation and gastrulation, later signaling events, originating from a number of adjacent tissue layers, are essential for the development of endodermal organs. Previous studies have shown that signals arising from the notochord are important for patterning of the ectodermally derived floor plate of the neural tube and the mesodermally derived somites. This review will discuss recent evidence indicating that signals arising from the notochord also play a role in regulating endoderm development.
Topics: Body Patterning; Ectoderm; Embryonic Induction; Endoderm; Germ Layers; Mesoderm; Notochord; Pancreas
PubMed: 11356015
DOI: 10.1006/dbio.2001.0214 -
Developmental Biology May 2014Specialized sensory organs in the vertebrate head originate from thickenings in the embryonic ectoderm called cranial sensory placodes. These placodes, as well as the... (Review)
Review
Specialized sensory organs in the vertebrate head originate from thickenings in the embryonic ectoderm called cranial sensory placodes. These placodes, as well as the neural crest, arise from a zone of ectoderm that borders the neural plate. This zone separates into a precursor field for the neural crest that lies adjacent to the neural plate, and a precursor field for the placodes, called the pre-placodal region (PPR), that lies lateral to the neural crest. The neural crest domain and the PPR are established in response to signaling events mediated by BMPs, FGFs and Wnts, which differentially activate transcription factors in these territories. In the PPR, members of the Six and Eya families, act in part to repress neural crest specific transcription factors, thus solidifying a placode developmental program. Subsequently, in response to environmental cues the PPR is further subdivided into placodal territories with distinct characteristics, each expressing a specific repertoire of transcription factors that provide the necessary information for their progression to mature sensory organs. In this review we summarize recent advances in the characterization of the signaling molecules and transcriptional effectors that regulate PPR specification and its subdivision into placodal domains with distinct identities.
Topics: Animals; Bone Morphogenetic Proteins; Ectoderm; Epidermal Growth Factor; Gene Expression Regulation, Developmental; Humans; Neural Crest; Neural Plate; Signal Transduction; Wnt Proteins
PubMed: 24576539
DOI: 10.1016/j.ydbio.2014.02.011 -
Journal of Assisted Reproduction and... Nov 2020Trophectoderm biopsy is increasingly performed for pre-implantation genetic testing of aneuploidies and considered a safe procedure on short-term clinical outcome,... (Review)
Review
Trophectoderm biopsy is increasingly performed for pre-implantation genetic testing of aneuploidies and considered a safe procedure on short-term clinical outcome, without strong assessment of long-term consequences. Poor biological information on human trophectoderm is available due to ethical restrictions. Therefore, most studies have been conducted in vitro (choriocarcinoma cell lines, embryonic and pluripotent stem cells) and on murine models that nevertheless poorly reflect the human counterpart. Polarization, compaction, and blastomere differentiation (e.g., the basis to ascertain trophectoderm origin) are poorly known in humans. In addition, the trophectoderm function is poorly known from a biological point of view, although a panoply of questionable and controversial microarray studies suggest that important genes overexpressed in trophectoderm are involved in pluripotency, metabolism, cell cycle, endocrine function, and implantation. The intercellular communication system between the trophectoderm cells and the inner cell mass, modulated by cell junctions and filopodia in the murine model, is obscure in humans. For the purpose of this paper, data mainly on primary cells from human and murine embryos has been reviewed. This review suggests that the trophectoderm origin and functions have been insufficiently ascertained in humans so far. Therefore, trophectoderm biopsy should be considered an experimental procedure to be undertaken only under approved rigorous experimental protocols in academic contexts.
Topics: Animals; Biopsy; Blastocyst; Cell Differentiation; Ectoderm; Embryo Implantation; Female; Humans; Mice; Pregnancy; Preimplantation Diagnosis; Trophoblasts
PubMed: 32892265
DOI: 10.1007/s10815-020-01925-0 -
Experimental Cell Research Jul 2014The vertebrate ectoderm gives rise to organs that produce mineralized or keratinized substances, including teeth, hair, and claws. Most of these ectodermal derivatives... (Review)
Review
The vertebrate ectoderm gives rise to organs that produce mineralized or keratinized substances, including teeth, hair, and claws. Most of these ectodermal derivatives grow continuously throughout the animal׳s life and have active pools of adult stem cells that generate all the necessary cell types. These organs provide powerful systems for understanding the mechanisms that enable stem cells to regenerate or renew ectodermally derived tissues, and remarkable progress in our understanding of these systems has been made in recent years using mouse models. We briefly compare what is known about stem cells and their niches in incisors, hair follicles, and claws, and we examine expression of Gli1 as a potential example of a shared stem cell marker. We summarize some of the features, structures, and functions of the stem cell niches in these ectodermal derivatives; definition of the basic elements of the stem cell niches in these organs will provide guiding principles for identification and characterization of the niche in similar systems.
Topics: Animals; Ectoderm; Epithelial Cells; Hair; Hoof and Claw; Humans; Stem Cell Niche; Tooth
PubMed: 24530577
DOI: 10.1016/j.yexcr.2014.02.003 -
Role of YAP in early ectodermal specification and a Huntington's Disease model of human neurulation.ELife Apr 2022The Hippo pathway, a highly conserved signaling cascade that functions as an integrator of molecular signals and biophysical states, ultimately impinges upon the...
The Hippo pathway, a highly conserved signaling cascade that functions as an integrator of molecular signals and biophysical states, ultimately impinges upon the transcription coactivator Yes-associated protein 1 (YAP). Hippo-YAP signaling has been shown to play key roles both at the early embryonic stages of implantation and gastrulation, and later during neurogenesis. To explore YAP's potential role in neurulation, we used self-organizing neuruloids grown from human embryonic stem cells on micropatterned substrates. We identified YAP activation as a key lineage determinant, first between neuronal ectoderm and nonneuronal ectoderm, and later between epidermis and neural crest, indicating that YAP activity can enhance the effect of BMP4 stimulation and therefore affect ectodermal specification at this developmental stage. Because aberrant Hippo-YAP signaling has been implicated in the pathology of Huntington's Disease (HD), we used isogenic mutant neuruloids to explore the relationship between signaling and the disease. We found that HD neuruloids demonstrate ectopic activation of gene targets of YAP and that pharmacological reduction of YAP's transcriptional activity can partially rescue the HD phenotype.
Topics: Cell Cycle Proteins; Ectoderm; Humans; Huntington Disease; Neurogenesis; Neurulation; Signal Transduction; YAP-Signaling Proteins
PubMed: 35451959
DOI: 10.7554/eLife.73075 -
Stem Cell Reports Jul 2018The molecular mechanism underpinning the specification of the ectoderm, a transient germ-layer tissue, during mouse gastrulation was examined here in a stem cell-based...
The molecular mechanism underpinning the specification of the ectoderm, a transient germ-layer tissue, during mouse gastrulation was examined here in a stem cell-based model. We captured a self-renewing cell population with enhanced ectoderm potency from mouse epiblast stem cells (EpiSCs) by suppressing Nodal signaling activity. The transcriptome of the Nodal-inhibited EpiSCs resembles that of the anterior epiblast of embryonic day (E)7.0 and E7.5 mouse embryo, which is accompanied by chromatin modifications that reflect the priming of ectoderm lineage-related genes for expression. Nodal-inhibited EpiSCs show enhanced ectoderm differentiation in vitro and contribute to the neuroectoderm and the surface ectoderm in postimplantation chimeras but lose the propensity for mesendoderm differentiation in vitro and in chimeras. Our findings show that specification of the ectoderm progenitors is enhanced by the repression of Nodal signaling activity, and the ectoderm-like stem cells provide an experimental model to investigate the molecular characters of the epiblast-derived ectoderm.
Topics: Animals; Biomarkers; Cell Differentiation; Cell Lineage; Cells, Cultured; Ectoderm; Embryonic Development; Epigenesis, Genetic; Fluorescent Antibody Technique; Gene Expression Profiling; Gene Expression Regulation, Developmental; Germ Layers; Mice; Nodal Protein; Signal Transduction; Wnt Signaling Pathway
PubMed: 30008328
DOI: 10.1016/j.stemcr.2018.05.019