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: 7263418
• 负责人: Daniel S Kessler
• 金额: $ 32.19万
• 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/7263418
• 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

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的关键早期步骤。TGF β信号传导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是必不可少的。鉴于这些不同的发育功能和Nodal通过正反馈加强自身表达的能力，Nodal信号传导的精确控制对于正常发育至关重要。为了限制Nodal活性，Nodal途径的多种拮抗剂在脊椎动物胚胎中表达。该建议的一个中心目标是确定调节Nodal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福克斯家族基因在调节非洲爪蟾中胚层发育过程中的Nodal信号通路的新功能。FoxD 3在Spemann组织者中起作用，以抑制Nodal表达的负调节因子并促进中胚层形成。Fasti（FoxH 1）是Nodal信号的转录调节因子，它意外地与Groucho辅阻遏物结合以抑制Nodal中胚层的诱导和自动调节。这表明Fasti-Groucho 4在中胚层域外沉默Nodal途径中的作用。为了确定FoxD 3和Fasti如何调节Nodal途径，提出了三个目的：1）通过分析微阵列筛选候选物，并通过定义介导Nodal对FoxD 3的转录应答的因子，鉴定FoxD 3的发育重要靶点，和2）对Fasti-Groucho 4复合物进行生化、转录、和发育，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Nodal通路的转录网络，这可能揭示调节其他TGF β信号通路的一般机制。FoxD 3还维持干细胞谱系的多能性，并且所提出的机制研究可能有助于更好地理解干细胞生物学。此外，考虑到FoxD 3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，这些研究对于理解人类神经嵴疾病和癌症也具有重要意义。