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

• 批准号: 10017179
• 负责人: Marcos Simoes-Costa
• 金额: $ 35.83万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017179
• 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; Regulator Genes; 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; disability; embryonic stem cell; experimental study; extracellular; genome-wide; insight; multipotent cell; neural plate; neuroregulation; novel; progenitor; programs; repaired; stem cell differentiation; stem cell population; stem cells; transcriptome; transcriptomics

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.

项目概要/摘要 神经嵴是胚胎干细胞群，可产生多种衍生物，包括大多数 颅面骨骼。神经嵴细胞的形成由基因调控网络（GRN）控制 赋予这些祖细胞独特的特征，包括多能性和迁移能力。 这种复杂的分子程序由细胞外信号调节，确保精确的空间控制 神经嵴规格。特别是，Wingless (Wnt) 信号通路已被证明发挥着关键作用。 在颅面细胞类型建立中的作用。尽管该信号通路很重要，但只有少数 直接 Wnt 靶标已在神经嵴 GRN 内确定。此外，我们还缺乏一个机制。 了解 Wnt 如何与其他信号系统（例如骨形态发生蛋白）合作 （BMP）途径，在早期神经嵴发育过程中。为了确定经典 Wnt 信号传导的新靶标，我们 调查了新生禽类神经嵴中 Wnt 核效应子 Lef1 和 β-catenin 的基因组占据情况 细胞。该分析发现了通过组织特异性 Wnt- 控制的多个神经嵴基因 响应增强剂。有趣的是，我们发现 Lef1/β-catenin 占据的基因组区域也 包含 Smads 的多个结合基序，Smads 是 BMP 信号传导的核效应子。据此，我们 假设典型的 Wnt 与 BMP 合作启动神经板的神经嵴基因 GRN 边界。我们将通过 (a) 识别神经嵴 GRN 中的直接 Wnt 靶基因来检验这一假设； (二) 定义 Wnt 和 BMP 信号系统的组合输入如何影响神经嵴的输出 增强剂； (c) 确定 Wnt 和 BMP 的效应子如何相互作用来控制基因表达。这 该提案的总体目标是定义环境因素如何影响基因组中的基因表达—— 调节细胞身份的广泛方式。我们预计该提案的调查结果将提供 增强子如何整合来自不同信号系统的输入以激活复杂的综合模型 转录程序。这项工作中揭示的机制不仅会影响组织工程，还会影响 还报告与人类健康相关的细胞身份的异常变化，例如癌症和 先天性畸形。