Control of neural crest multipotency by Wnt signaling and the Lin28/let-7 axis

A crucial step in cell differentiation is the silencing of developmental programs underlying multipotency. While much is known about how lineage-specific genes are activated to generate distinct cell types, the mechanisms driving suppression of stemness are far less understood. To address this, we examined the regulation of the transcriptional network that maintains progenitor identity in avian neural crest cells. Our results show that a regulatory circuit formed by Wnt, Lin28a and let-7 miRNAs controls the deployment and the subsequent silencing of the multipotency program in a position-dependent manner. Transition from multipotency to differentiation is determined by the topological relationship between the migratory cells and the dorsal neural tube, which acts as a Wnt-producing stem cell niche. Our findings highlight a mechanism that rapidly silences complex regulatory programs, and elucidate how transcriptional networks respond to positional information during cell differentiation.

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Human axial progenitors generate trunk neural crest cells in vitro

eLife ◽

10.7554/elife.35786 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 19

Author(s):

Thomas JR Frith ◽

Ilaria Granata ◽

Matthew Wind ◽

Erin Stout ◽

Oliver Thompson ◽

...

Keyword(s):

Neural Crest ◽

Cell Types ◽

Embryonic Cell ◽

Axial Position ◽

Dependent Manner ◽

In Vitro Differentiation ◽

Distinct Cell ◽

Axis Elongation ◽

Trunk Neural Crest

The neural crest (NC) is a multipotent embryonic cell population that generates distinct cell types in an axial position-dependent manner. The production of NC cells from human pluripotent stem cells (hPSCs) is a valuable approach to study human NC biology. However, the origin of human trunk NC remains undefined and current in vitro differentiation strategies induce only a modest yield of trunk NC cells. Here we show that hPSC-derived axial progenitors, the posteriorly-located drivers of embryonic axis elongation, give rise to trunk NC cells and their derivatives. Moreover, we define the molecular signatures associated with the emergence of human NC cells of distinct axial identities in vitro. Collectively, our findings indicate that there are two routes toward a human post-cranial NC state: the birth of cardiac and vagal NC is facilitated by retinoic acid-induced posteriorisation of an anterior precursor whereas trunk NC arises within a pool of posterior axial progenitors.

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Human axial progenitors generate trunk neural crest cells

10.1101/272591 ◽

2018 ◽

Author(s):

Thomas J. R. Frith ◽

Ilaria Granata ◽

Erin Stout ◽

Matthew Wind ◽

Oliver Thompson ◽

...

Keyword(s):

Neural Crest ◽

Cell Types ◽

Embryonic Cell ◽

Axial Position ◽

Dependent Manner ◽

In Vitro Differentiation ◽

Distinct Cell ◽

Axis Elongation ◽

Trunk Neural Crest

AbstractThe neural crest (NC) is a multipotent embryonic cell population generating distinct cell types in an axial position-dependent manner. The production of NC cells from human pluripotent stem cells (hPSCs) is a valuable approach to study human NC biology. However, the origin of human trunk NC remains undefined and therefore current in vitro differentiation strategies induce only a modest yield of trunk NC cells. Here we show that hPSC-derived axial progenitors, the posteriorly-located drivers of embryonic axis elongation, give rise to trunk NC cells and their derivatives. Moreover, we define the molecular signatures associated with the emergence of human NC cells of distinct axial identities in vitro. Collectively, our findings indicate that there are two routes toward a human post-cranial NC state: the birth of cardiac and vagal NC is facilitated by retinoic acid-induced posteriorisation of an anterior precursor whereas trunk NC arises within a pool of posterior axial progenitors.

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LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

Science Advances ◽

10.1126/sciadv.aau5106 ◽

2019 ◽

Vol 5 (7) ◽

pp. eaau5106 ◽

Cited By ~ 2

Author(s):

Anca G. Radu ◽

Sakina Torch ◽

Florence Fauvelle ◽

Karin Pernet-Gallay ◽

Anthony Lucas ◽

...

Keyword(s):

Neural Crest ◽

Cell Fate ◽

Neural Crest Cell ◽

Dependent Manner ◽

Cell Fates ◽

Neural Crest Stem Cells ◽

Metabolomic Profiling ◽

Intestinal Pseudo Obstruction ◽

Migratory Cells ◽

Hind Limb Paralysis

Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the Lkb1 tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of Lkb1. Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of Lkb1 mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases.

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Patterning of the angiosperm female gametophyte through the prism of theoretical paradigms

Biochemical Society Transactions ◽

10.1042/bst20140036 ◽

2014 ◽

Vol 42 (2) ◽

pp. 332-339 ◽

Cited By ~ 3

Author(s):

Dmytro S. Lituiev ◽

Ueli Grossniklaus

Keyword(s):

Cell Fate ◽

Female Gametophyte ◽

Positional Information ◽

Cell Types ◽

Theoretical Frameworks ◽

Cell Specification ◽

Distinct Cell ◽

Dynamical Nature ◽

Theoretical Paradigms ◽

Lines Of Evidence

The FG (female gametophyte) of flowering plants (angiosperms) is a simple highly polar structure composed of only a few cell types. The FG develops from a single cell through mitotic divisions to generate, depending on the species, four to 16 nuclei in a syncytium. These nuclei are then partitioned into three or four distinct cell types. The mechanisms underlying the specification of the nuclei in the FG has been a focus of research over the last decade. Nevertheless, we are far from understanding the patterning mechanisms that govern cell specification. Although some results were previously interpreted in terms of static positional information, several lines of evidence now show that local interactions are important. In the present article, we revisit the available data on developmental mutants and cell fate markers in the light of theoretical frameworks for biological patterning. We argue that a further dissection of the mechanisms may be impeded by the combinatorial and dynamical nature of developmental cues. However, accounting for these properties of developing systems is necessary to disentangle the diversity of the phenotypic manifestations of the underlying molecular interactions.

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MiR-23~27~24–mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation

Science Advances ◽

10.1126/sciadv.aaw1715 ◽

2019 ◽

Vol 5 (12) ◽

pp. eaaw1715 ◽

Cited By ~ 1

Author(s):

Cheng-Jang Wu ◽

Sunglim Cho ◽

Hsi-Yuan Huang ◽

Chun-Hao Lu ◽

Jasmin Russ ◽

...

Keyword(s):

Cell Differentiation ◽

Humoral Immunity ◽

Cell Biology ◽

Dependent Manner ◽

Cell Responses ◽

Follicular Helper ◽

Regulatory Circuit ◽

Follicular Helper T Cell ◽

Immune Challenges ◽

And Function

Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection–associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.

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Kakapo, a Novel Cytoskeletal-associated Protein Is Essential for the Restricted Localization of the Neuregulin-like Factor, Vein, at the Muscle–Tendon Junction Site

The Journal of Cell Biology ◽

10.1083/jcb.143.5.1259 ◽

1998 ◽

Vol 143 (5) ◽

pp. 1259-1270 ◽

Cited By ~ 72

Author(s):

Dan Strumpf ◽

Talila Volk

Keyword(s):

Cell Differentiation ◽

Egf Receptor ◽

Cell Types ◽

Drosophila Embryo ◽

Tendon Cell ◽

Distinct Cell ◽

Tendon Cells ◽

Junction Site ◽

Receptor Signaling Pathway ◽

Correct Association

In the Drosophila embryo, the correct association of muscles with their specific tendon cells is achieved through reciprocal interactions between these two distinct cell types. Tendon cell differentiation is initiated by activation of the EGF-receptor signaling pathway within these cells by Vein, a neuregulin-like factor secreted by the approaching myotube. Here, we describe the cloning and the molecular and genetic analyses of kakapo, a Drosophila gene, expressed in the tendons, that is essential for muscle-dependent tendon cell differentiation. Kakapo is a large intracellular protein and contains structural domains also found in cytoskeletal-related vertebrate proteins (including plakin, dystrophin, and Gas2 family members). kakapo mutant embryos exhibit abnormal muscle-dependent tendon cell differentiation. A major defect in the kakapo mutant tendon cells is the failure of Vein to be localized at the muscle–tendon junctional site; instead, Vein is dispersed and its levels are reduced. This may lead to aberrant differentiation of tendon cells and consequently to the kakapo mutant deranged somatic muscle phenotype.

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Identification of bipotent progenitors that give rise to myogenic and connective tissues in mouse

10.1101/2021.05.26.445757 ◽

2021 ◽

Author(s):

Alexandre Grimaldi ◽

Glenda Evangelina Comai ◽

Sebastien Mella ◽

Shahragim Tajbakhsh

Keyword(s):

Connective Tissue ◽

Neural Crest ◽

Neural Crest Cells ◽

Cell Types ◽

Spatial Proximity ◽

Connective Tissues ◽

Distinct Cell ◽

Dorsal Portion ◽

Tissue Cells ◽

Identity Shifts

How distinct cell fates are manifested by direct lineage ancestry from bipotent progenitors, or by specification of individual cell types within a field of cells is a key question for understanding the emergence of tissues. The interplay between skeletal muscle progenitors and associated connective tissues cells provides a model for examining how muscle functional units are established. Most craniofacial structures originate from the vertebrate-specific neural crest cells except in the dorsal portion of the head, where they arise from cranial mesoderm. Here, using multiple lineage-traced single cell RNAseq, advanced computational methods and in situ analyses, we identify Myf5+ bipotent progenitors that give rise to both muscle and juxtaposed connective tissue. Following this bifurcation, muscle and connective tissue cells retain complementary signalling features and maintain spatial proximity. Interruption of upstream myogenic identity shifts muscle progenitors to a connective tissue fate. Interestingly, Myf5-derived connective tissue cells, which adopt a novel regulatory signature, were not observed in ventral craniofacial structures that are colonised by neural crest cells. Therefore, we propose that an ancestral program gives rise to bifated muscle and connective tissue cells in skeletal muscles that are deprived of neural crest.

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Tissue Interactions in Neural Crest Cell Development and Disease

Science ◽

10.1126/science.1230717 ◽

2013 ◽

Vol 341 (6148) ◽

pp. 860-863 ◽

Cited By ~ 71

Author(s):

Yoshiko Takahashi ◽

Douglas Sipp ◽

Hideki Enomoto

Keyword(s):

Neural Crest ◽

Vascular System ◽

Neural Crest Cell ◽

Hirschsprung Disease ◽

Cell Types ◽

Microbial Pathogens ◽

Environmental Signals ◽

Tissue Interactions ◽

Migratory Cells ◽

Different Cell Types

The neural crest is a transient population of migratory cells in the embryo that gives rise to a wide variety of different cell types, including those of the peripheral nervous system. Dysfunction of neural crest cells (NCCs) is associated with multiple diseases, such as neuroblastoma and Hirschsprung disease. Recent studies have identified NCC behaviors during their migration and differentiation, with implications for their contributions to development and disease. Here, we describe how interactions between cells of the neural crest and lineages such as the vascular system, as well as those involving environmental signals and microbial pathogens, are critically important in determining the roles played by these cells.

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Hoxb3 Regulates Jag1 Expression in Pharyngeal Epithelium and Affects Interaction With Neural Crest Cells

Frontiers in Physiology ◽

10.3389/fphys.2020.612230 ◽

2021 ◽

Vol 11 ◽

Author(s):

Haoran Zhang ◽

Junjie Xie ◽

Karl Kam Hei So ◽

Ka Kui Tong ◽

Jearn Jang Sae-Pang ◽

...

Keyword(s):

Neural Crest ◽

Neural Crest Cells ◽

Positional Information ◽

Cell Types ◽

Cellular Interaction ◽

Pharyngeal Arch ◽

Surface Ectoderm ◽

Pharyngeal Arches ◽

Elevated Expression ◽

Pharyngeal Epithelium

Craniofacial morphogenesis depends on proper migration of neural crest cells and their interactions with placodes and other cell types. Hox genes provide positional information and are important in patterning the neural crest and pharyngeal arches (PAs) for coordinated formation of craniofacial structures. Hox genes are expressed in the surface ectoderm and epibranchial placodes, their roles in the pharyngeal epithelium and their downstream targets in regulating PA morphogenesis have not been established. We altered the Hox code in the pharyngeal region of the Hoxb3Tg/+ mutant, in which Hoxb3 is driven to ectopically expressed in Hoxb2 domain in the second pharyngeal arch (PA2). In the transgenic mutant, ectopic Hoxb3 expression was restricted to the surface ectoderm, including the proximal epibranchial placodal region and the distal pharyngeal epithelium. The Hoxb3Tg/+ mutants displayed hypoplasia of PA2, multiple neural crest-derived facial skeletal and nerve defects. Interestingly, we found that in the Hoxb3Tg/+ mutant, expression of the Notch ligand Jag1 was specifically up-regulated in the ectodermal pharyngeal epithelial cells of PA2. By molecular experiments, we demonstrated that Hoxb3 could bind to an upstream genomic site S2 and directly regulate Jag1 expression. In the Hoxb3Tg/+ mutant, elevated expression of Jag1 in the pharyngeal epithelium led to abnormal cellular interaction and deficiency of neural crest cells migrating into PA2. In summary, we showed that Hoxb3 regulates Jag1 expression and proposed a model of pharyngeal epithelium and neural crest interaction during pharyngeal arch development.

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The Ocular Neural Crest: Specification, Migration, and Then What?

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.595896 ◽

2020 ◽

Vol 8 ◽

Author(s):

Antionette L. Williams ◽

Brenda L. Bohnsack

Keyword(s):

Neural Crest ◽

Cell Biology ◽

Current Knowledge ◽

Anterior Segment ◽

Clinical Manifestations ◽

Positional Information ◽

Cell Types ◽

Congenital Glaucoma ◽

Ocular Development ◽

Regenerative Therapies

During vertebrate embryonic development, a population of dorsal neural tube-derived stem cells, termed the neural crest (NC), undergo a series of morphogenetic changes and extensive migration to become a diverse array of cell types. Around the developing eye, this multipotent ocular NC cell population, called the periocular mesenchyme (POM), comprises migratory mesenchymal cells that eventually give rise to many of the elements in the anterior of the eye, such as the cornea, sclera, trabecular meshwork, and iris. Molecular cell biology and genetic analyses of congenital eye diseases have provided important information on the regulation of NC contributions to this area of the eye. Nevertheless, a complete understanding of the NC as a contributor to ocular development remains elusive. In addition, positional information during ocular NC migration and the molecular pathways that regulate end tissue differentiation have yet to be fully elucidated. Further, the clinical challenges of ocular diseases, such as Axenfeld-Rieger syndrome (ARS), Peters anomaly (PA) and primary congenital glaucoma (PCG), strongly suggest the need for better treatments. While several aspects of NC evolution have recently been reviewed, this discussion will consolidate the most recent current knowledge on the specification, migration, and contributions of the NC to ocular development, highlighting the anterior segment and the knowledge obtained from the clinical manifestations of its associated diseases. Ultimately, this knowledge can inform translational discoveries with potential for sorely needed regenerative therapies.

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