Fox Gene Regulation of Nodal Signaling in Mesoderm Development

Fox 基因对中胚层发育中节点信号的调控

• 批准号: 7465938
• 负责人: Daniel S Kessler
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7465938
• 关键词: Binding; Blood; Body Patterning; Cell Lineage; Cellular biology; Complex; Development; Developmental Process; Disease; Dorsal; Elements; Embryo; Embryonic Development; Embryonic Induction; Endoderm; Family; Feedback; Foxes; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic Transcription; Germ Layers; Goals; Homeostasis; Kidney; Left; Malignant Neoplasms; Mediating; Mediator of activation protein; Mesoderm; Microarray Analysis; Molecular; Movement; Mutate; Myocardium; Neural Crest; Neuraxis; Nodal; Pathway interactions; Protein Binding; Proteins; Regulation; Regulatory Pathway; Research Personnel; Role; Signal Pathway; Signal Transduction; Smad Proteins; Smad protein; Spemann' s Organizer; Stem cells; Testing; Transcriptional Regulation; Validation; Xenopus; bone; chromatin immunoprecipitation; human disease; inhibitor/antagonist; member; novel; pluripotency; programs; promoter; research study; response

Formation of embryonic mesoderm is a critical early step in vertebrate embryogenesis. Nodal members of the TGFfi family of signaling factors are essential for mesoderm formation and a variety of other developmental processes. Given these diverse developmental functions and the ability of Nodal to reinforce its own expression by positive feedback, precise control of Nodal signaling is essential for normal development. To restrict Nodal activity, multiple antagonists of the Nodal pathway are expressed in the vertebrate embryo. A central goal of this proposal is to define the mechanisms that modulate Nodal pathway function to establish the spatial organization of the embryonic mesoderm. We have identified novel functions for two Fox family genes in regulating the Nodal signaling pathway during Xenopus mesodermal development. FoxDS functions in the Spemann organizer to repress negative regulators of Nodal expression and promote mesoderm formation. Fasti (FoxH1), a transcriptional mediator of Nodal signals, unexpectedly binds to Groucho corepressors to inhibit Nodal mesoderm induction and autoregulation. This suggests a role for Fasti-Groucho4 in silencing the Nodal pathway outside of the mesodermal domain. To determine how FoxD3 and Fasti modulate the Nodal pathway three Aims are proposed: 1) developmentally important targets of FoxDS will be identified by analysis of microarray screen candidates, and by defining factors that mediate the Nodal transcriptional response to FoxDS and 2) the Fasti-Groucho4 complex will be analyzed biochemically, transcriptionally, and developmentally to determine its role in mesoderm formation and Nodal pathway regulation. These studies will elucidate conserved mechanisms of vertebrate embryogenesis, and define a transcriptional network for the Nodal pathway that may reveal general mechanisms for regulating other TGFfi signaling pathways. FoxDS also maintains pluripotency of stem cell lineages, and the proposed mechanistic studies may contribute to a better understanding of stem cell biology. Furthermore, given the role of FoxDS in neural crest development and disease, and the potential role of Fasti-Groucho in modulating proliferative control by TGFIi signals, these studies also have significance for understanding human diseases of the neural crest and cancer.

胚胎中胚层的形成是脊椎动物胚胎发生的关键早期步骤。节点成员 TGF β 1家族的信号传导因子是中胚层形成所必需的，并且多种其他信号传导因子也是必需的。 发展过程。鉴于这些不同的发展功能和能力的节点，以加强 其自身的表达通过正反馈，精确控制Nodal信号传导对于正常的 发展为了限制Nodal活性，Nodal途径的多种拮抗剂在细胞中表达。 脊椎动物胚胎该提案的一个中心目标是定义调节节点的机制， 通路功能，以建立胚胎中胚层的空间组织。 我们已经确定了两个Fox家族基因在调节Nodal信号通路中的新功能 在非洲爪蟾中胚层发育过程中。FoxDS在Spemann组织者中起抑制负性的作用 调节Nodal表达并促进中胚层形成。Fasti（FoxH 1），一种转录因子， Nodal信号的介导物，意外地结合到Groucho辅阻遏物以抑制Nodal中胚层 诱导和自动调节。这表明Fasti-Groucho 4在沉默Nodal途径中的作用 在中胚层区域之外。为了确定FoxD 3和Fasti如何调节Nodal通路， 目的是：1）通过对FoxDS的分析， 微阵列筛选候选人，并通过定义介导Nodal转录反应的因子， FoxDS和2）Fasti-Groucho 4复合物将进行生化分析，转录， 以确定其在中胚层形成和Nodal途径调节中的作用。 这些研究将阐明脊椎动物胚胎发生的保守机制，并定义一个新的胚胎发生机制。 Nodal通路的转录网络，可能揭示调节其他神经元的一般机制。 TGF β 1信号通路。FoxDS还保持了干细胞谱系的多能性， 机制研究可能有助于更好地理解干细胞生物学。此外，鉴于 FoxDS在神经嵴发育和疾病中的作用，以及Fasti-Groucho在 通过TGFIi信号调节增殖控制，这些研究对于理解 人类的神经嵴疾病和癌症。