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: 7618473
• 负责人: Daniel S Kessler
• 金额: $ 32.18万
• 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/7618473
• 关键词: Adult; Binding; Body Patterning; Cell Lineage; Complex; Development; Developmental Process; Disease; Dorsal; Elements; Embryo; Embryonic Development; Endoderm; Family; Feedback; Foxes; Gene Expression; Gene Expression Regulation; Gene Family; Gene Targeting; Genes; Genetic Transcription; Germ Layers; Goals; Homeostasis; Left; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Mesoderm; Molecular; Mutate; Neural Crest; Nodal; Pathway interactions; Protein Binding; Proteins; Regulation; Regulatory Pathway; Response Elements; Role; Signal Pathway; Signal Transduction; Smad Proteins; Smad protein; Spemann' s Organizer; Stem cells; Testing; Transcription Repressor/Corepressor; Transcriptional Regulation; Validation; Xenopus; base; chromatin immunoprecipitation; extracellular; gene repression; human disease; inhibitor/antagonist; member; novel; pluripotency; promoter; research study; response; stem cell biology; transcription factor; xenopus development

DESCRIPTION (provided by applicant): Formation of embryonic mesoderm is a critical early step in vertebrate embryogenesis. Nodal members of the TGF¿ 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. FoxD3 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 FoxD3 will be identified by analysis of microarray screen candidates, and by defining factors that mediate the Nodal transcriptional response to FoxD3 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 TGF¿ signaling pathways. FoxD3 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 FoxD3 in neural crest development and disease, and the potential role of Fasti-Groucho in modulating proliferative control by TGF¿ signals, these studies also have significance for understanding human diseases of the neural crest and cancer.

描述（由申请人提供）：胚胎中胚层的形成是脊椎动物胚胎发生中关键的早期步骤。 TGF 信号因子家族的节点成员对于中胚层形成和各种其他发育过程至关重要。鉴于这些不同的发育功能以及 Nodal 通过正反馈增强自身表达的能力，精确控制 Nodal 信号传导对于正常发育至关重要。为了限制 Nodal 活性，脊椎动物胚胎中表达了 Nodal 途径的多种拮抗剂。该提案的中心目标是定义调节节点通路功能的机制，以建立胚胎中胚层的空间组织。我们已经确定了两个 Fox 家族基因在非洲爪蟾中胚层发育过程中调节 Nodal 信号通路的新功能。 FoxD3 在 Spemann 组织器中发挥作用，抑制 Nodal 表达的负调节因子并促进中胚层形成。 Fasti (FoxH1) 是 Nodal 信号的转录介质，出人意料地与 Groucho 辅阻遏物结合，抑制 Nodal 中胚层诱导和自动调节。这表明 Fasti-Groucho4 在沉默中胚层域外的 Nodal 通路中发挥着作用。为了确定 FoxD3 和 Fasti 如何调节 Nodal 途径，提出了三个目标：1) 通过分析微阵列筛选候选物，并通过定义介导对 FoxD3 的 Nodal 转录反应的因子来鉴定 FoxD3 的发育重要靶标；2) 对 Fasti-Groucho4 复合物进行生化、转录和发育分析，以确定其在中胚层形成和 Nodal 途径中的作用 规定。这些研究将阐明脊椎动物胚胎发生的保守机制，并定义 Nodal 途径的转录网络，该网络可能揭示调节其他 TGF¿ 信号传导途径的一般机制。 FoxD3还维持干细胞谱系的多能性，所提出的机制研究可能有助于更好地了解干细胞生物学。此外，考虑到 FoxD3 在神经嵴发育和疾病中的作用，以及 Fasti-Groucho 在通过 TGF 信号调节增殖控制中的潜在作用，这些研究对于了解人类神经嵴疾病和癌症也具有重要意义。