Genomic control of neural crest identity by signaling systems

通过信号系统对神经嵴特性进行基因组控制

基本信息

批准号：
10673423
负责人：
Marcos Simoes-Costa
金额：
$ 41.62万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673423
关键词：
Address Affect Agonist Animal Model Back Binding Binding Sites Biological Assay Birds Bone Morphogenetic Proteins Cartilage Cells Co-Immunoprecipitations Complement Complex Congenital Abnormality Craniofacial Abnormalities Cues Development Diagnosis Disease Elements Embryo Embryonic Development Enhancers Ensure Etiology Face Fluorescence Future Gene Expression Genes Genetic Genetic Transcription Genomic Segment Genomics Goals Health Human In Vitro Ligation Logic Malignant Neoplasms Modeling Molecular Mutation Natural regeneration Neural Crest Neural Crest Cell Nuclear Output Pathway interactions Phenotype Play Positioning Attribute Process Regulatory Element Role Running Signal Pathway Signal Transduction Signaling Protein Skeleton Surveys System TFAP2A gene Testing Therapeutic Therapeutic Intervention Time Tissue Engineering Tissues WNT Signaling Pathway Work beta catenin bone cell type combinatorial craniofacial craniofacial development directed differentiation disability embryonic stem cell experimental study extracellular gene regulatory network genome-wide insight multipotent cell neural plate neuroregulation novel progenitor programs repaired stem cell differentiation stem cell population stem cells transcriptome transcriptomics

Address Affect Agonist Animal Model Back Binding Binding Sites Biological Assay Birds Bone Morphogenetic Proteins Cartilage Cells Co-Immunoprecipitations Complement Complex Congenital Abnormality Craniofacial Abnormalities Cues Development Diagnosis Disease Elements Embryo Embryonic Development Enhancers Ensure Etiology Face Fluorescence Future Gene Expression Genes Genetic Genetic Transcription Genomic Segment Genomics Goals Health Human In Vitro Ligation Logic Malignant Neoplasms Modeling Molecular Mutation Natural regeneration Neural Crest Neural Crest Cell Nuclear Output Pathway interactions Phenotype Play Positioning Attribute Process Regulatory Element Role Running Signal Pathway Signal Transduction Signaling Protein Skeleton Surveys System TFAP2A gene Testing Therapeutic Therapeutic Intervention Time Tissue Engineering Tissues WNT Signaling Pathway Work beta catenin bone cell type combinatorial craniofacial craniofacial development directed differentiation disability embryonic stem cell experimental study extracellular gene regulatory network genome-wide insight multipotent cell neural plate neuroregulation novel progenitor programs repaired stem cell differentiation stem cell population stem cells transcriptome transcriptomics

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项目摘要

PROJECT SUMMARY / ABSTRACT The neural crest is an embryonic stem cell population that gives rise to multiple derivatives, including most of the craniofacial skeleton. The formation of neural crest cells is controlled by a gene regulatory network (GRN) that endows these progenitor cells with their unique features, including multipotency and the ability to migrate. This complex molecular program is modulated by extracellular signals that ensure precise spatial control of neural crest specification. In particular, the Wingless (Wnt) signaling pathway has been shown to play a pivotal role in the establishment of craniofacial cell types. Despite the importance of this signaling pathway, only a few direct Wnt targets have been identified within the neural crest GRN. Furthermore, we also lack a mechanistic understanding of how Wnts cooperate with other signaling systems, such as the Bone Morphogenetic Protein (BMP) pathway, during early neural crest development. To identify novel targets of canonical Wnt signaling, we surveyed the genomic occupancy of Wnt nuclear effectors Lef1 and β-catenin in nascent avian neural crest cells. This analysis uncovered multiple neural crest genes that are controlled via tissue-specific Wnt- responsive enhancers. Intriguingly, we found that the genomic regions occupied by both Lef1/β-catenin also contained multiple binding motifs for Smads, the nuclear effectors of BMP signaling. Accordingly, we hypothesize that canonical Wnts cooperate with BMPs to initiate the neural crest gene GRN at the neural plate border. We will test this hypothesis by (a) identifying the direct Wnt target genes in the neural crest GRN; (b) defining how combinatorial input of Wnt and BMP signaling systems affects the output of the neural crest enhancers; and (c) determining how effectors of Wnts and BMPs interact to control gene expression. The overarching goal of this proposal is to define how environmental cues impact gene expression in a genome- wide manner to modulate cell identity. We anticipate that the findings of this proposal will provide a comprehensive model of how enhancers integrate inputs from distinct signaling systems to activate complex transcriptional programs. The mechanisms uncovered in this work will impact not only tissue engineering but also inform upon abnormal shifts in cell identity that are relevant to human health, such as cancer and congenital malformations.

项目摘要 /摘要神经rest是一种胚胎干细胞种群，产生多种衍生物，包括大多数神经rest细胞的形成由基因调节网络（GRN）控制这赋予了这些祖细胞的独特特征，包括多元性和迁移能力。这个复杂的分子程序是通过细胞外信号调节的，该信号确保了精确的空间控制神经rest规格。特别是，无翼（Wnt）信号通路已显示出扮演关键在颅面细胞类型的建立中的作用。尽管此信号通路很重要，但只有少数在神经Crest GRN中已经确定了直接的Wnt目标。此外，我们也缺乏机械了解WNT如何与其他信号系统协调，例如骨形态发生蛋白（BMP）途径，在早期神经rest发育期间。为了确定规范Wnt信号的新目标，我们调查了新生鸟类神经元中Wnt核效应LEF1和β-catenin的基因组占用细胞。该分析发现了通过组织特异性Wnt-控制的多个神经rest基因响应式增强剂。有趣的是，我们发现同时LEF1/β-catenin占据的基因组区域也包含SMAD的多个结合基序，这是BMP信号传导的核效应。根据我们的说法假设规范WNT与BMP合作以启动神经元基因GRN在神经元板上边界。我们将通过（a）识别神经Crest GRN中的直接Wnt靶基因来检验这一假设；（b）定义Wnt和BMP信号系统的组合输入如何影响神经rest的输出增强剂；（c）确定WNT和BMP的影响如何相互作用以控制基因表达。这该提案的总体目标是定义环境线索如何影响基因组中的基因表达调节细胞身份的广泛方式。我们预计该提案的发现将提供增强剂如何整合来自不同信号系统的输入以激活复合物的综合模型转录程序。这项工作中发现的机制不仅会影响组织工程，而且会影响还可以告知与人类健康有关的细胞身份异常转变，例如癌症和先天性畸形。