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1.
Development ; 148(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383890

RESUMO

Neural crest cells (NCCs) within the mandibular and maxillary prominences of the first pharyngeal arch are initially competent to respond to signals from either region. However, mechanisms that are only partially understood establish developmental tissue boundaries to ensure spatially correct patterning. In the 'hinge and caps' model of facial development, signals from both ventral prominences (the caps) pattern the adjacent tissues whereas the intervening region, referred to as the maxillomandibular junction (the hinge), maintains separation of the mandibular and maxillary domains. One cap signal is GATA3, a member of the GATA family of zinc-finger transcription factors with a distinct expression pattern in the ventral-most part of the mandibular and maxillary portions of the first arch. Here, we show that disruption of Gata3 in mouse embryos leads to craniofacial microsomia and syngnathia (bony fusion of the upper and lower jaws) that results from changes in BMP4 and FGF8 gene regulatory networks within NCCs near the maxillomandibular junction. GATA3 is thus a crucial component in establishing the network of factors that functionally separate the upper and lower jaws during development.


Assuntos
Padronização Corporal , Face/embriologia , Fator de Transcrição GATA3/metabolismo , Animais , Região Branquial/citologia , Região Branquial/embriologia , Região Branquial/metabolismo , Morte Celular , Proliferação de Células , Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Embrião de Mamíferos , Fator de Transcrição GATA3/genética , Regulação da Expressão Gênica no Desenvolvimento , Mandíbula/citologia , Mandíbula/embriologia , Maxila/citologia , Maxila/embriologia , Camundongos , Morfogênese , Crista Neural/citologia , Crista Neural/embriologia , Crista Neural/metabolismo
2.
Development ; 148(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34414417

RESUMO

Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, and craniofacial and/or renal defects. Variants in the transcription factor Six1 and its co-factor Eya1, both of which are required for otic development, are linked to BOR. We previously identified Sobp as a potential Six1 co-factor, and SOBP variants in mouse and humans cause otic phenotypes; therefore, we asked whether Sobp interacts with Six1 and thereby may contribute to BOR. Co-immunoprecipitation and immunofluorescence experiments demonstrate that Sobp binds to and colocalizes with Six1 in the cell nucleus. Luciferase assays show that Sobp interferes with the transcriptional activation of Six1+Eya1 target genes. Experiments in Xenopus embryos that either knock down or increase expression of Sobp show that it is required for formation of ectodermal domains at neural plate stages. In addition, altering Sobp levels disrupts otic vesicle development and causes craniofacial cartilage defects. Expression of Xenopus Sobp containing the human variant disrupts the pre-placodal ectoderm similar to full-length Sobp, but other changes are distinct. These results indicate that Sobp modifies Six1 function and is required for vertebrate craniofacial development, and identify Sobp as a potential candidate gene for BOR.


Assuntos
Desenvolvimento Ósseo , Proteínas de Homeodomínio/metabolismo , Metaloproteínas/metabolismo , Proteínas de Xenopus/metabolismo , Animais , Síndrome Brânquio-Otorrenal/embriologia , Síndrome Brânquio-Otorrenal/genética , Núcleo Celular/metabolismo , Orelha Interna/embriologia , Orelha Interna/metabolismo , Ectoderma/embriologia , Ectoderma/metabolismo , Expressão Gênica , Proteínas de Homeodomínio/genética , Larva/crescimento & desenvolvimento , Metaloproteínas/genética , Crista Neural/embriologia , Crista Neural/metabolismo , Ligação Proteica , Proteínas Tirosina Fosfatases/metabolismo , Ativação Transcricional , Proteínas de Xenopus/genética , Xenopus laevis
3.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202161

RESUMO

The autonomic nervous system derives from the neural crest (NC) and supplies motor innervation to the smooth muscle of visceral organs, including the lower urinary tract (LUT). During fetal development, sacral NC cells colonize the urogenital sinus to form pelvic ganglia (PG) flanking the bladder neck. The coordinated activity of PG neurons is required for normal urination; however, little is known about the development of PG neuronal diversity. To discover candidate genes involved in PG neurogenesis, the transcriptome profiling of sacral NC and developing PG was performed, and we identified the enrichment of the type 3 serotonin receptor (5-HT3, encoded by Htr3a and Htr3b). We determined that Htr3a is one of the first serotonin receptor genes that is up-regulated in sacral NC progenitors and is maintained in differentiating PG neurons. In vitro cultures showed that the disruption of 5-HT3 signaling alters the differentiation outcomes of sacral NC cells, while the stimulation of 5-HT3 in explanted fetal pelvic ganglia severely diminished neurite arbor outgrowth. Overall, this study provides a valuable resource for the analysis of signaling pathways in PG development, identifies 5-HT3 as a novel regulator of NC lineage diversification and neuronal maturation in the peripheral nervous system, and indicates that the perturbation of 5-HT3 signaling in gestation has the potential to alter bladder function later in life.


Assuntos
Crista Neural/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Transdução de Sinais , Sistema Urinário/inervação , Sistema Urinário/metabolismo , Animais , Sistema Nervoso Autônomo , Diferenciação Celular , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Camundongos , Crista Neural/embriologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neuritos/metabolismo , Neurogênese , Crescimento Neuronal , Neurônios/metabolismo , Receptores de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/genética , Transcriptoma , Sistema Urinário/embriologia
4.
Commun Biol ; 4(1): 695, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099848

RESUMO

The role of a neural crest developmental transcriptional program, which critically involves Sox10 upregulation, is a key conserved aspect of melanoma initiation in both humans and zebrafish, yet transcriptional regulation of sox10 expression is incompletely understood. Here we used ATAC-Seq analysis of multiple zebrafish melanoma tumors to identify recurrently open chromatin domains as putative melanoma-specific sox10 enhancers. Screening in vivo with EGFP reporter constructs revealed 9 of 11 putative sox10 enhancers with embryonic activity in zebrafish. Focusing on the most active enhancer region in melanoma, we identified a region 23 kilobases upstream of sox10, termed peak5, that drives EGFP reporter expression in a subset of neural crest cells, Kolmer-Agduhr neurons, and early melanoma patches and tumors with high specificity. A ~200 base pair region, conserved in Cyprinidae, within peak5 is required for transgenic reporter activity in neural crest and melanoma. This region contains dimeric SoxE/Sox10 dimeric binding sites essential for peak5 neural crest and melanoma activity. We show that deletion of the endogenous peak5 conserved genomic locus decreases embryonic sox10 expression and disrupts adult stripe patterning in our melanoma model background. Our work demonstrates the power of linking developmental and cancer models to better understand neural crest identity in melanoma.


Assuntos
Melanoma/genética , Crista Neural/embriologia , Fatores de Transcrição SOXE/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Animais , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Crista Neural/metabolismo
5.
Development ; 148(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34184034

RESUMO

Signaling through the platelet-derived growth factor receptor alpha (PDGFRα) is crucial for mammalian craniofacial development, although the mechanisms by which the activity of downstream intracellular effectors is regulated to mediate gene expression changes have not been defined. We find that the RNA-binding protein Srsf3 is phosphorylated at Akt consensus sites downstream of PI3K-mediated PDGFRα signaling in mouse palatal mesenchyme cells, leading to its nuclear translocation. We further demonstrate that ablation of Srsf3 in the mouse neural crest lineage leads to facial clefting due to defective cranial neural crest cell proliferation and survival. Finally, we show that Srsf3 regulates the alternative RNA splicing of transcripts encoding protein kinases in the mouse facial process mesenchyme to regulate PDGFRα-dependent intracellular signaling. Collectively, our findings reveal that alternative RNA splicing is an important mechanism of gene expression regulation downstream of PI3K/Akt-mediated PDGFRα signaling in the facial mesenchyme and identify Srsf3 as a critical regulator of craniofacial development.


Assuntos
Processamento Alternativo , Mesoderma/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Transdução de Sinais , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Ligantes , Masculino , Camundongos , Camundongos Knockout , Crista Neural/embriologia , Crista Neural/metabolismo , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas de Ligação a RNA/metabolismo , Fatores de Processamento de Serina-Arginina/genética
6.
Dev Biol ; 477: 251-261, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34102166

RESUMO

BMP signaling plays iterative roles during vertebrate neural crest development from induction through craniofacial morphogenesis. However, far less is known about the role of BMP activity in cranial neural crest epithelial-to-mesenchymal transition and delamination. By measuring canonical BMP signaling activity as a function of time from specification through early migration of avian midbrain neural crest cells, we found elevated BMP signaling during delamination stages. Moreover, inhibition of canonical BMP activity via a dominant negative mutant Type I BMP receptor showed that BMP signaling is required for neural crest migration from the midbrain, independent from an effect on EMT and delamination. Transcriptome profiling on control compared to BMP-inhibited cranial neural crest cells identified novel BMP targets during neural crest delamination and early migration including targets of the Notch pathway that are upregulated following BMP inhibition. These results suggest potential crosstalk between the BMP and Notch pathways in early migrating cranial neural crest and provide novel insight into mechanisms regulated by BMP signaling during early craniofacial development.


Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Mesencéfalo/embriologia , Crista Neural/metabolismo , Transdução de Sinais , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Embrião de Galinha , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Mesencéfalo/metabolismo , Crista Neural/embriologia , Crânio/embriologia , Crânio/metabolismo , Técnicas de Cultura de Tecidos
7.
Development ; 148(10)2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33999995

RESUMO

The focal adhesion protein Kindlin2 is essential for integrin activation, a process that is fundamental to cell-extracellular matrix adhesion. Kindlin 2 (Fermt2) is widely expressed in mouse embryos, and its absence causes lethality at the peri-implantation stage due to the failure to trigger integrin activation. The function of kindlin2 during embryogenesis has not yet been fully elucidated as a result of this early embryonic lethality. Here, we showed that kindlin2 is essential for neural crest (NC) formation in Xenopus embryos. Loss-of-function assays performed with kindlin2-specific morpholino antisense oligos (MOs) or with CRISPR/Cas9 techniques in Xenopus embryos severely inhibit the specification of the NC. Moreover, integrin-binding-deficient mutants of Kindlin2 rescued the phenotype caused by loss of kindlin2, suggesting that the function of kindlin2 during NC specification is independent of integrins. Mechanistically, we found that Kindlin2 regulates the fibroblast growth factor (FGF) pathway, and promotes the stability of FGF receptor 1. Our study reveals a novel function of Kindlin2 in regulating the FGF signaling pathway and provides mechanistic insights into the function of Kindlin2 during NC specification.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas de Membrana/metabolismo , Crista Neural/embriologia , Proteínas de Xenopus/metabolismo , Xenopus laevis/embriologia , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Técnicas de Inativação de Genes , Células HEK293 , Células HeLa , Humanos , Integrinas/metabolismo , Proteínas de Membrana/genética , Morfolinos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/genética , Proteínas de Xenopus/genética
8.
PLoS Genet ; 17(5): e1009579, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34033651

RESUMO

We sought to understand how perturbation of signaling pathways and their targets generates variable phenotypes. In humans, GATA3 associates with highly variable defects, such as HDR syndrome, microsomia and choanal atresia. We previously characterized a zebrafish point mutation in gata3 with highly variable craniofacial defects to the posterior palate. This variability could be due to residual Gata3 function, however, we observe the same phenotypic variability in gata3 null mutants. Using hsp:GATA3-GFP transgenics, we demonstrate that Gata3 function is required between 24 and 30 hpf. At this time maxillary neural crest cells fated to generate the palate express gata3. Transplantation experiments show that neural crest cells require Gata3 function for palatal development. Via a candidate approach, we determined if Bmp signaling was upstream of gata3 and if this pathway explained the mutant's phenotypic variation. Using BRE:d2EGFP transgenics, we demonstrate that maxillary neural crest cells are Bmp responsive by 24 hpf. We find that gata3 expression in maxillary neural crest requires Bmp signaling and that blocking Bmp signaling, in hsp:DN-Bmpr1a-GFP embryos, can phenocopy gata3 mutants. Palatal defects are rescued in hsp:DN-Bmpr1a-GFP;hsp:GATA3-GFP double transgenic embryos, collectively demonstrating that gata3 is downstream of Bmp signaling. However, Bmp attenuation does not alter phenotypic variability in gata3 loss-of-function embryos, implicating a different pathway. Due to phenotypes observed in hypomorphic shha mutants, the Sonic Hedgehog (Shh) pathway was a promising candidate for this pathway. Small molecule activators and inhibitors of the Shh pathway lessen and exacerbate, respectively, the phenotypic severity of gata3 mutants. Importantly, inhibition of Shh can cause gata3 haploinsufficiency, as observed in humans. We find that gata3 mutants in a less expressive genetic background have a compensatory upregulation of Shh signaling. These results demonstrate that the level of Shh signaling can modulate the phenotypes observed in gata3 mutants.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Fator de Transcrição GATA3/genética , Proteínas Hedgehog/metabolismo , Fenótipo , Transdução de Sinais , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Embrião não Mamífero/citologia , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Fator de Transcrição GATA3/metabolismo , Haploinsuficiência , Mutação com Perda de Função , Mutação , Crista Neural/citologia , Crista Neural/embriologia , Crista Neural/metabolismo , Organogênese , Crânio/citologia , Crânio/embriologia , Peixe-Zebra/embriologia
9.
Dev Biol ; 477: 241-250, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34052210

RESUMO

A critical cell type participating in cardiac outflow tract development is a subpopulation of the neural crest cells, the cardiac neural crest cells (NCCs), whose defect causes a spectrum of cardiovascular abnormalities. Accumulating evidence indicates that mTOR, which belongs to the PI3K-related kinase family and impacts multiple signaling pathways in a variety of contexts, plays a pivotal role for NCC development. Here, we investigated functional roles of mTOR for cardiac neural crest development using several lines of mouse genetic models. We found that disruption of mTOR caused NCC defects and failure of cardiac outflow tract separation, which resulted in a spectrum of cardiac defects including persistent truncus arteriosus, ventricular septal defect and ventricular wall defect. Specifically, mutant neural crest cells showed reduced migration into the cardiac OFT and prematurely exited the cell cycle. A number of critical factors and fundamental signaling pathways, which are important for neural crest and cardiomyocyte development, were impaired. Moreover, actin dynamics was disrupted by mTOR deletion. Finally, by phenotyping the neural crest Rptor and Rictor knockout mice respectively, we demonstrate that mTOR acts principally through the mTORC1 pathway for cardiac neural crest cells. Altogether, these data established essential roles of mTOR for cardiac NCC development and imply that dysregulation of mTOR in NCCs may underline a spectrum of cardiac defects.


Assuntos
Anormalidades Cardiovasculares/genética , Coração/embriologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Miocárdio/metabolismo , Crista Neural/embriologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Células Cultivadas , Deleção de Genes , Redes e Vias Metabólicas , Camundongos , Crista Neural/metabolismo , Serina-Treonina Quinases TOR/genética
11.
Dev Biol ; 476: 200-208, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33864777

RESUMO

Nager syndrome is a rare human developmental disorder characterized by hypoplastic neural crest-derived craniofacial bones and limb defects. Mutations in SF3B4 gene, which encodes a component of the spliceosome, are a major cause for Nager. A review of the literature indicates that 45% of confirmed cases are also affected by conductive, sensorineural or mixed hearing loss. Conductive hearing loss is due to defective middle ear ossicles, which are neural crest derived, while sensorineural hearing loss typically results from defective inner ear or vestibulocochlear nerve, which are both derived from the otic placode. Animal model of Nager syndrome indicates that upon Sf3b4 knockdown cranial neural crest progenitors are depleted, which may account for the conductive hearing loss in these patients. To determine whether Sf3b4 plays a role in otic placode formation we analyzed the impact of Sf3b4 knockdown on otic development. Sf3b4-depleted Xenopus embryos exhibited reduced expression of several pan-placodal genes six1, dmrta1 and foxi4.1. We confirmed the dependence of placode genes expression on Sf3b4 function in animal cap explants expressing noggin, a BMP antagonist critical to induce placode fate in the ectoderm. Later in development, Sf3b4 morphant embryos had reduced expression of pax8, tbx2, otx2, bmp4 and wnt3a at the otic vesicle stage, and altered otic vesicle development. We propose that in addition to the neural crest, Sf3b4 is required for otic development, which may account for sensorineural hearing loss in Nager syndrome.


Assuntos
Perda Auditiva/genética , Disostose Mandibulofacial/genética , Fatores de Processamento de RNA/metabolismo , Proteínas de Xenopus/metabolismo , Animais , Surdez/genética , Modelos Animais de Doenças , Orelha Interna/metabolismo , Ectoderma/metabolismo , Desenvolvimento Embrionário/genética , Gânglios Parassimpáticos/embriologia , Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Perda Auditiva/fisiopatologia , Disostose Mandibulofacial/metabolismo , Disostose Mandibulofacial/fisiopatologia , Crista Neural/embriologia , Fatores de Processamento de RNA/genética , Proteínas de Xenopus/genética , Xenopus laevis/genética , Xenopus laevis/metabolismo
12.
Commun Biol ; 4(1): 442, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824393

RESUMO

Cranial Neural Crest Cells (CNCC) originate at the cephalic region from forebrain, midbrain and hindbrain, migrate into the developing craniofacial region, and subsequently differentiate into multiple cell types. The entire specification, delamination, migration, and differentiation process is highly regulated and abnormalities during this craniofacial development cause birth defects. To better understand the molecular networks underlying CNCC, we integrate paired gene expression & chromatin accessibility data and reconstruct the genome-wide human Regulatory network of CNCC (hReg-CNCC). Consensus optimization predicts high-quality regulations and reveals the architecture of upstream, core, and downstream transcription factors that are associated with functions of neural plate border, specification, and migration. hReg-CNCC allows us to annotate genetic variants of human facial GWAS and disease traits with associated cis-regulatory modules, transcription factors, and target genes. For example, we reveal the distal and combinatorial regulation of multiple SNPs to core TF ALX1 and associations to facial distances and cranial rare disease. In addition, hReg-CNCC connects the DNA sequence differences in evolution, such as ultra-conserved elements and human accelerated regions, with gene expression and phenotype. hReg-CNCC provides a valuable resource to interpret genetic variants as early as gastrulation during embryonic development. The network resources are available at https://github.com/AMSSwanglab/hReg-CNCC .


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Crista Neural/embriologia , Humanos
13.
PLoS Genet ; 17(3): e1009446, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33750945

RESUMO

The BAF complex plays an important role in the development of a wide range of tissues by modulating gene expression programs at the chromatin level. However, its role in neural crest development has remained unclear. To determine the role of the BAF complex, we deleted BAF155/BAF170, the core subunits required for the assembly, stability, and functions of the BAF complex in neural crest cells (NCCs). Neural crest-specific deletion of BAF155/BAF170 leads to embryonic lethality due to a wide range of developmental defects including craniofacial, pharyngeal arch artery, and OFT defects. RNAseq and transcription factor enrichment analysis revealed that the BAF complex modulates the expression of multiple signaling pathway genes including Hippo and Notch, essential for the migration, proliferation, and differentiation of the NCCs. Furthermore, we demonstrated that the BAF complex is essential for the Brg1-Yap-Tead-dependent transcription of target genes in NCCs. Together, our results demonstrate an important role of the BAF complex in modulating the gene regulatory network essential for neural crest development.


Assuntos
Montagem e Desmontagem da Cromatina , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Crista Neural/embriologia , Crista Neural/metabolismo , Neurogênese/genética , Animais , Diferenciação Celular/genética , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Desenvolvimento Embrionário/genética , Deleção de Genes , Redes Reguladoras de Genes , Genes Reporter , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética
14.
Dev Biol ; 475: 118-130, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33705737

RESUMO

The lysine methyltransferase NSD3 is required for the expression of key neural crest transcription factors and the migration of neural crest cells. Nevertheless, a complete view of the genes dependent upon NSD3 for expression and the developmental processes impacted by NSD3 in the neural crest was lacking. We used RNA sequencing (RNA-seq) to profile transcripts differentially expressed after NSD3 knockdown in chick premigratory neural crest cells, identifying 674 genes. Gene Ontology and gene set enrichment analyses further support a requirement for NSD3 during neural crest development and show that NSD3 knockdown also upregulates ribosome biogenesis. To validate our results, we selected three genes not previously associated with neural crest development, Astrotactin 1 (Astn1), Dispatched 3 (Disp3), and Tropomyosin 1 (Tpm1). Using whole mount in situ hybridization, we show that premigratory neural crest cells express these genes and that NSD3 knockdown downregulates (Astn1 and Disp3) and upregulates (Tpm1) their expression, consistent with RNA-seq results. Altogether, this study identifies novel putative regulators of neural crest development and provides insight into the transcriptional consequences of NSD3 in the neural crest, with implications for cancer.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Histona-Lisina N-Metiltransferase/metabolismo , Crista Neural/fisiologia , Animais , Embrião de Galinha , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/genética , Histona-Lisina N-Metiltransferase/genética , Hibridização In Situ/métodos , Crista Neural/embriologia , Crista Neural/metabolismo , Análise de Sequência de RNA/métodos , Fatores de Transcrição/metabolismo
15.
Sci Rep ; 11(1): 6987, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772057

RESUMO

Certain driver mutations and pathological diagnoses are associated with the anatomical site of meningioma, based on which the meninges have different embryological origins. We hypothesized that mutations and pathological diagnoses of meningiomas are associated with different embryological origins. We comprehensively evaluated associations among tumor location, pathological diagnosis (histological type), and genetic alterations including AKT1, KLF4, SMO, POLR2A, and NF2 mutations and 22q deletion in 269 meningioma cases. Based on the embryological origin of meninges, the tumor locations were as follows: neural crest, paraxial mesodermal, and dorsal mesodermal origins. Tumors originating from the dura of certain embryologic origin displayed a significantly different pathological diagnoses and genetic abnormality ratio. For instance, driver genetic mutations with AKT1, KLF4, SMO, and POLR2A, were significantly associated with the paraxial mesodermal origin (p = 1.7 × 10-10). However, meningiomas with NF2-associated mutations were significantly associated with neural crest origin (p = 3.9 × 10-12). On analysis of recurrence, no difference was observed in embryological origin. However, POLR2A mutation was a risk factor for the tumor recurrence (p = 1.7 × 10-2, Hazard Ratio 4.08, 95% Confidence Interval 1.28-13.0). Assessment of the embryological origin of the meninges may provide novel insights into the pathomechanism of meningiomas.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Neoplasias Meníngeas/genética , Meninges/embriologia , Meninges/patologia , Meningioma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Fatores de Transcrição Kruppel-Like/genética , Masculino , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/patologia , Meningioma/diagnóstico , Meningioma/patologia , Pessoa de Meia-Idade , Mutação/genética , Crista Neural/embriologia , Proteínas Proto-Oncogênicas c-akt/genética , Receptor Smoothened/genética , Adulto Jovem
16.
Development ; 148(4)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589510

RESUMO

Within the developing head, tissues undergo cell-fate transitions to shape the forming structures. This starts with the neural crest, which undergoes epithelial-to-mesenchymal transition (EMT) to form, amongst other tissues, many of the skeletal tissues of the head. In the eye and ear, these neural crest cells then transform back into an epithelium, via mesenchymal-to-epithelial transition (MET), highlighting the flexibility of this population. Elsewhere in the head, the epithelium loses its integrity and transforms into mesenchyme. Here, we review these craniofacial transitions, looking at why they happen, the factors that trigger them, and the cell and molecular changes they involve. We also discuss the consequences of aberrant EMT and MET in the head.


Assuntos
Epitélio/embriologia , Cabeça/embriologia , Mesoderma/embriologia , Animais , Diferenciação Celular , Movimento Celular , Transição Epitelial-Mesenquimal , Humanos , Crista Neural/embriologia , Especificidade de Órgãos , Vertebrados
17.
Int J Mol Sci ; 22(3)2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33573345

RESUMO

Skeletal disorders, such as osteoarthritis and bone fractures, are among the major conditions that can compromise the quality of daily life of elderly individuals. To treat them, regenerative therapies using skeletal cells have been an attractive choice for patients with unmet clinical needs. Currently, there are two major strategies to prepare the cell sources. The first is to use induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs), which can recapitulate the skeletal developmental process and differentiate into various skeletal cells. Skeletal tissues are derived from three distinct origins: the neural crest, paraxial mesoderm, and lateral plate mesoderm. Thus, various protocols have been proposed to recapitulate the sequential process of skeletal development. The second strategy is to extract stem cells from skeletal tissues. In addition to mesenchymal stem/stromal cells (MSCs), multiple cell types have been identified as alternative cell sources. These cells have distinct multipotent properties allowing them to differentiate into skeletal cells and various potential applications for skeletal regeneration. In this review, we summarize state-of-the-art research in stem cell differentiation based on the understanding of embryogenic skeletal development and stem cells existing in skeletal tissues. We then discuss the potential applications of these cell types for regenerative medicine.


Assuntos
Desenvolvimento Ósseo/fisiologia , Osso e Ossos/fisiologia , Fraturas Ósseas/terapia , Osteoartrite/terapia , Medicina Regenerativa/métodos , Animais , Osso e Ossos/embriologia , Osso e Ossos/lesões , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário/fisiologia , Células-Tronco Embrionárias/fisiologia , Fraturas Ósseas/fisiopatologia , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Células-Tronco Mesenquimais/fisiologia , Mesoderma/embriologia , Crista Neural/embriologia , Osteoartrite/fisiopatologia , Osteoblastos/fisiologia , Osteoblastos/transplante , Medicina Regenerativa/tendências , Transplante de Células-Tronco/métodos , Transplante de Células-Tronco/tendências
18.
Dev Biol ; 475: 245-255, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33548210

RESUMO

The neural crest is a migratory stem cell population that contributes to various tissues and organs during vertebrate embryonic development. These cells possess remarkable developmental plasticity and give rise to many different cell types, including chondrocytes, osteocytes, peripheral neurons, glia, melanocytes, and smooth muscle cells. Although the genetic mechanisms underlying neural crest development have been extensively studied, many facets of this process remain unexplored. One key aspect of cellular physiology that has gained prominence in the context of embryonic development is metabolic regulation. Recent discoveries in neural crest biology suggest that metabolic regulation may play a central role in the formation, migration, and differentiation of these cells. This possibility is further supported by clinical studies that have demonstrated a high prevalence of neural crest anomalies in babies with congenital metabolic disorders. Here, we examine why neural crest development is prone to metabolic disruption and discuss how carbon metabolism regulates developmental processes like epithelial-to-mesenchymal transition (EMT) and cell migration. Finally, we explore how understanding neural crest metabolism may inform upon the etiology of several congenital birth defects.


Assuntos
Desenvolvimento Embrionário/fisiologia , Crista Neural/citologia , Crista Neural/embriologia , Animais , Carbono/metabolismo , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Glicólise/fisiologia , Humanos , Crista Neural/metabolismo , Neurogênese/genética , Neurogênese/fisiologia , Vertebrados/embriologia
19.
Science ; 371(6529)2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33542111

RESUMO

During development, cells progress from a pluripotent state to a more restricted fate within a particular germ layer. However, cranial neural crest cells (CNCCs), a transient cell population that generates most of the craniofacial skeleton, have much broader differentiation potential than their ectodermal lineage of origin. Here, we identify a neuroepithelial precursor population characterized by expression of canonical pluripotency transcription factors that gives rise to CNCCs and is essential for craniofacial development. Pluripotency factor Oct4 is transiently reactivated in CNCCs and is required for the subsequent formation of ectomesenchyme. Furthermore, open chromatin landscapes of Oct4+ CNCC precursors resemble those of epiblast stem cells, with additional features suggestive of priming for mesenchymal programs. We propose that CNCCs expand their developmental potential through a transient reacquisition of molecular signatures of pluripotency.


Assuntos
Crista Neural/embriologia , Células-Tronco Pluripotentes/fisiologia , Animais , Diferenciação Celular/genética , Movimento Celular , Embrião de Mamíferos , Camadas Germinativas/citologia , Camundongos , Crista Neural/citologia , Crista Neural/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco Pluripotentes/citologia , RNA-Seq , Transcrição Genética , Transcriptoma
20.
Neurosurgery ; 88(2): 234-245, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33094349

RESUMO

In this review, we describe Schwann cell development from embryonic neural crest cells to terminally differentiated myelinated and nonmyelinated mature Schwann cells. We focus on the genetic drivers and signaling mechanisms mediating decisions to proliferate versus differentiate during Schwann cell development, highlighting pathways that overlap with Schwann cell development and are dysregulated in tumorigenesis. We conclude by considering how our knowledge of the events underlying Schwann cell development and mouse models of schwannoma, neurofibroma, and malignant peripheral nerve sheath tumor can inform novel therapeutic strategies for patients with cancers derived from Schwann cell lineages.


Assuntos
Transformação Celular Neoplásica , Crista Neural/embriologia , Neurogênese/fisiologia , Neoplasias do Sistema Nervoso Periférico , Células de Schwann , Animais , Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Humanos , Camundongos , Neoplasias do Sistema Nervoso Periférico/genética , Neoplasias do Sistema Nervoso Periférico/patologia , Transdução de Sinais/fisiologia
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