CHD3 regulates BMP signalling response during cranial neural crest cell specification
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE288669 | GEO | 2025/02/05
REPOSITORIES: GEO
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Project description:The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. BAF subunit mutations cause Coffin-Siris Syndrome (CSS), a congenital disorder characterized by distinct craniofacial features and intellectual disability. Approximately 50% of CSS patients carry mutations in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a deletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS patient-derived ARID1A+/- iPSCs to model CNCC specification, we discovered that ARID1A-haploinsufficency impairs epithelial to mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes, while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos at pre-migratory neural crest stages elicits abnormal cell delamination from the neural tube. These findings reveal a novel ARID1A-ZIC2 axis essential for EMT and CNCC delamination.
2024-07-23 | GSE261846 | GEO
Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.
2021-10-12 | PXD028557 | Pride
Project description:Developmental potential is progressively restricted after germ layer specification during gastrulation. However, cranial neural crest cells challenge this paradigm, as they develop from anterior ectoderm yet give rise to both mesodermal derivatives of the craniofacial skeleton and ectodermal derivatives of the peripheral nervous system. How cranial neural crest cells differentiate into multiple lineages is poorly understood. Here, we demonstrate that cranial neural crest cells possess a transient state of increased chromatin accessibility; and that the earliest premigratory neural crest are biased towards either a neuronal or ectomesenchymal fate, with each lineage expressing distinct factors from the pluripotent state. We profile the spatiotemporal emergence of each neural crest population and demonstrate that the ectomesenchymal lineage forms prior to the neuronal progenitors. Expression of the pluripotency microRNA family miR-302 is maintained in cranial neural crest cells and genetic deletion leads to precocious specification of the ectomesenchymal lineage. We find that miR-302 directly targets Sox9 to slow the timing of ectomesenchyme induction and regulates multiple genes involved in chromatin condensation to maintain accessibility for neuronal differentiation. Loss of mir-302 results in reduced chromatin accessibility in the neuronal progenitor lineage of neural crest and a reduction in peripheral neuron differentiation. Our findings reveal a post-transcriptional mechanism governed by miRNAs from pluripotency as an important mechanism to expand developmental potential of cranial neural crest.
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Project description:Developmental potential is progressively restricted after germ layer specification during gastrulation. However, cranial neural crest cells challenge this paradigm, as they develop from anterior ectoderm yet give rise to both mesodermal derivatives of the craniofacial skeleton and ectodermal derivatives of the peripheral nervous system. How cranial neural crest cells differentiate into multiple lineages is poorly understood. Here, we demonstrate that cranial neural crest cells possess a transient state of increased chromatin accessibility; and that the earliest premigratory neural crest are biased towards either a neuronal or ectomesenchymal fate, with each lineage expressing distinct factors from the pluripotent state. We profile the spatiotemporal emergence of each neural crest population and demonstrate that the ectomesenchymal lineage forms prior to the neuronal progenitors. Expression of the pluripotency microRNA family miR-302 is maintained in cranial neural crest cells and genetic deletion leads to precocious specification of the ectomesenchymal lineage. We find that miR-302 directly targets Sox9 to slow the timing of ectomesenchyme induction and regulates multiple genes involved in chromatin condensation to maintain accessibility for neuronal differentiation. Loss of mir-302 results in reduced chromatin accessibility in the neuronal progenitor lineage of neural crest and a reduction in peripheral neuron differentiation. Our findings reveal a post-transcriptional mechanism governed by miRNAs from pluripotency as an important mechanism to expand developmental potential of cranial neural crest.
2022-10-25 | GSE215977 | GEO
Project description:The overall goal of this project is to investigate the role of TGF-beta signaling in tissue-tissue interactions between myogenic precursors of craniofacial muscles and cranial neural crest cells (CNCCs). Here, we conducted gene expression profiling of the tongue bud from mice at embryonic day E13.5 with a CNCC-specific conditional inactivation of the TGF-beta receptor type 1 gene Alk5. These mice provide a model of microglossia as well as disrupted extraocular and masticatory muscle development, which are congenital birth defects commonly observed in several syndromic conditions. To investigate the adverse effects of dysfunctional TGF-beta signaling on tissue-tissue interactions between CNCCs and myogenic precursors of craniofacial muscles, we analyzed tongue bud tissue of mice with a CNCC-specific conditional inactivation of Alk5 (Wnt1-Cre; Alk5 fl/fl). We performed microarray analyses of the tongue bud of Alk5 fl/fl control mice and Wnt1-Cre; Alk5 fl/fl mutant mice, collected at embryonic day E13.5 (n=4 per group).
2014-06-18 | E-GEOD-52358 | biostudies-arrayexpress
Project description:The overall goal of this project is to investigate the role of TGF-beta signaling in tissue-tissue interactions between myogenic precursors of craniofacial muscles and cranial neural crest cells (CNCCs). Here, we conducted gene expression profiling of the mandibular arch from mice at embryonic day E11.5 with a CNCC-specific conditional inactivation of the TGF-beta receptor type 1 gene Alk5. These mice provide a model of microglossia as well as disrupted extraocular and masticatory muscle development, which are congenital birth defects commonly observed in several syndromic conditions. To investigate the adverse effects of dysfunctional TGF-beta signaling on tissue-tissue interactions between CNCCs and myogenic precursors of craniofacial muscles, we analyzed mandibular arch tissue of mice with a CNCC-specific conditional inactivation of Alk5 (Wnt1-Cre; Alk5 fl/fl). We performed microarray analyses of the mandibular arch of Alk5 fl/fl control mice and Wnt1-Cre; Alk5 fl/fl mutant mice, collected at embryonic day E11.5 (n=4 per group).
2014-06-18 | E-GEOD-52357 | biostudies-arrayexpress
Project description:The neural crest is a highly plastic stem cell population that represents a notable exception to the germ layer theory. Despite being of ectodermal origin, these cells can differentiate into skeletal derivatives like cartilage and bone, tissues that are typically formed by mesoderm. The inductive program that endows the neural crest with these unique properties is still poorly understood. Here, we report that Smad2/3-mediated TGFβ signaling endows cranial neural crest cells with enhanced developmental potential. Our results show that TGFβ signaling modulates neural crest axial identity and directly activates the gene circuits that support skeletal differentiation. Cooperation between TGFβ and low levels of WNT-signaling in the embryonic head activates cranial-specific cis-regulatory elements of anterior genes. Activation of the TGFβ pathway allowed reprogramming of trunk neural crest cells to adopt an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGFβ signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton.
2025-01-19 | GSE175808 | GEO
Project description:The neural crest is a highly plastic stem cell population that represents a notable exception to the germ layer theory. Despite being of ectodermal origin, these cells can differentiate into skeletal derivatives like cartilage and bone, tissues that are typically formed by mesoderm. The inductive program that endows the neural crest with these unique properties is still poorly understood. Here, we report that Smad2/3-mediated TGFβ signaling endows cranial neural crest cells with enhanced developmental potential. Our results show that TGFβ signaling modulates neural crest axial identity and directly activates the gene circuits that support skeletal differentiation. Cooperation between TGFβ and low levels of WNT-signaling in the embryonic head activates cranial-specific cis-regulatory elements of anterior genes. Activation of the TGFβ pathway allowed reprogramming of trunk neural crest cells to adopt an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGFβ signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton.
2025-01-19 | GSE175809 | GEO
Project description:The neural crest is a highly plastic stem cell population that represents a notable exception to the germ layer theory. Despite being of ectodermal origin, these cells can differentiate into skeletal derivatives like cartilage and bone, tissues that are typically formed by mesoderm. The inductive program that endows the neural crest with these unique properties is still poorly understood. Here, we report that Smad2/3-mediated TGFβ signaling endows cranial neural crest cells with enhanced developmental potential. Our results show that TGFβ signaling modulates neural crest axial identity and directly activates the gene circuits that support skeletal differentiation. Cooperation between TGFβ and low levels of WNT-signaling in the embryonic head activates cranial-specific cis-regulatory elements of anterior genes. Activation of the TGFβ pathway allowed reprogramming of trunk neural crest cells to adopt an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGFβ signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton.
2025-01-19 | GSE278072 | GEO
Project description:The neural crest is a highly plastic stem cell population that represents a notable exception to the germ layer theory. Despite being of ectodermal origin, these cells can differentiate into skeletal derivatives like cartilage and bone, tissues that are typically formed by mesoderm. The inductive program that endows the neural crest with these unique properties is still poorly understood. Here, we report that Smad2/3-mediated TGFβ signaling endows cranial neural crest cells with enhanced developmental potential. Our results show that TGFβ signaling modulates neural crest axial identity and directly activates the gene circuits that support skeletal differentiation. Cooperation between TGFβ and low levels of WNT-signaling in the embryonic head activates cranial-specific cis-regulatory elements of anterior genes. Activation of the TGFβ pathway allowed reprogramming of trunk neural crest cells to adopt an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGFβ signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton.
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