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

基本信息

  • 批准号:
    7414374
  • 负责人:
  • 金额:
    $ 33.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(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。转化生长因子家族的节点成员对于中胚层的形成和各种其他发育过程是必不可少的。考虑到这些不同的发育功能和Nodal通过正反馈增强自身表达的能力,对Nodal信号的精确控制对于正常发育是必不可少的。为了限制结节的活性,在脊椎动物胚胎中表达了多种结节途径的拮抗剂。这项建议的一个中心目标是确定调节结节通路功能的机制,以建立胚胎中胚层的空间组织。我们已经确定了两个Fox家族基因在非洲爪哇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表达的负调控,促进中胚层的形成。Fasti(FoxH1)是Nodal信号的转录调节因子,它出人意料地与Groucho核心抑制物结合,抑制Nodal中胚层的诱导和自身调节。这表明Fasti-Groucho4在沉默中胚层结构域外的结节通路中发挥了作用。为了确定FoxD3和FastI是如何调控结节途径的,我们提出了三个目标:1)通过对候选基因芯片的分析,确定FoxD3在发育上具有重要意义的靶点;2)对Fasti-Groucho4复合体进行生化、转录和发育分析,以确定其在中胚层形成和结节途径调控中的作用。这些研究将阐明脊椎动物胚胎发生的保守机制,并定义Nodal途径的转录网络,可能揭示调节其他转化生长因子信号通路的一般机制。FoxD3还维持干细胞谱系的多能性,拟议的机制研究可能有助于更好地理解干细胞生物学。此外,鉴于FoxD3在神经脊发育和疾病中的作用,以及Fasti-Groucho在通过转化生长因子信号调节增殖控制方面的潜在作用,这些研究对于理解人类的神经脊疾病和癌症也具有重要意义。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Daniel S Kessler其他文献

FoxD3 regulation of mesoderm induction in the zebrafish embryo
  • DOI:
    10.1016/j.ydbio.2008.05.404
  • 发表时间:
    2008-07-15
  • 期刊:
  • 影响因子:
  • 作者:
    Lisa L. Chang;Daniel S Kessler
  • 通讯作者:
    Daniel S Kessler

Daniel S Kessler的其他文献

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{{ truncateString('Daniel S Kessler', 18)}}的其他基金

Mesoderm Formation and the Role of Repression by FoxD3
中胚层形成和 FoxD3 的抑制作用
  • 批准号:
    6430114
  • 财政年份:
    2002
  • 资助金额:
    $ 33.19万
  • 项目类别:
Mesoderm Formation and the Role of Repression by FoxD3
中胚层形成和 FoxD3 的抑制作用
  • 批准号:
    6621029
  • 财政年份:
    2002
  • 资助金额:
    $ 33.19万
  • 项目类别:
Mesoderm Formation and the Role of Repression by FoxD3
中胚层形成和 FoxD3 的抑制作用
  • 批准号:
    6827812
  • 财政年份:
    2002
  • 资助金额:
    $ 33.19万
  • 项目类别:
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
  • 财政年份:
    2002
  • 资助金额:
    $ 33.19万
  • 项目类别:
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
  • 财政年份:
    2002
  • 资助金额:
    $ 33.19万
  • 项目类别:
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
  • 财政年份:
    2002
  • 资助金额:
    $ 33.19万
  • 项目类别:
Mesoderm Formation and the Role of Repression by FoxD3
中胚层形成和 FoxD3 的抑制作用
  • 批准号:
    6691718
  • 财政年份:
    2002
  • 资助金额:
    $ 33.19万
  • 项目类别:
GENETIC BASIS OF MESENCEPHALIC/METENCEPHALIC PATTERNING
中脑/后脑模式的遗传基础
  • 批准号:
    6627704
  • 财政年份:
    2001
  • 资助金额:
    $ 33.19万
  • 项目类别:
GENETIC BASIS OF MESENCEPHALIC/METENCEPHALIC PATTERNING
中脑/后脑模式的遗传基础
  • 批准号:
    6710053
  • 财政年份:
    2001
  • 资助金额:
    $ 33.19万
  • 项目类别:
GENETIC BASIS OF MESENCEPHALIC/METENCEPHALIC PATTERNING
中脑/后脑模式的遗传基础
  • 批准号:
    6490981
  • 财政年份:
    2001
  • 资助金额:
    $ 33.19万
  • 项目类别:

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