Architecture of a Genetic Network Governing Morphogenesis

控制形态发生的遗传网络的架构

基本信息

  • 批准号:
    8728952
  • 负责人:
  • 金额:
    $ 29.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-30 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

Cellular morphogenesis is an essential part of animal development and growth. During this process, cells coordinately change shape, migrate, and may fuse. These processes are executed by molecules called "effectors". Such effectors have been identified in several model systems and include the cytoskeleton and determinants of cell polarity. The sex-, tissue-, position-, and time-specificity of morphogenesis is determined by "regulators", such as transcription factors. How transcriptional regulators are linked to the effectors in a gene network (GN) for morphogenesis is not well understood in nearly any system, but such knowledge is required to predict how perturbations could lead to morphogenetic changes during development, cancer, and the evolution of form. Elucidating this GN would also impact our understanding of wound healing and regeneration. Our long-term goal is to completely delineate the GN architecture governing the morphogenesis of a novel, simple and sexually dimorphic model structure, the tail tip of Caenorhabditis elegans. The tail tip is composed of four cells which-in males only-radically alter their shape and position at the end of larval development. Previous studies identified a "master regulator" for tail tip morphogenesis (TTM), the transcription factor DMD-3 (homologous to DMRT1 in humans, which specifies male fates). Without DMD-3, TTM completely fails. Also, DMD-3 is sufficient to cause TTM when ectopically expressed in hermaphrodites. Here, we will test how DMD-3 is linked to the effectors of TTM. Specific Aim 1 will test this hypothesis by a series of pairwise molecular epistasis experiments with DMD-3 and a set of key effectors of TTM which the Fitch lab previously identified in a postembryonic-RNAi screen. In these experiments, a gene X (e.g. DMD-3) will be knocked down and the effect on the transcription, translation or subcellular localization of a gene product Y will be analyzed. Network analysis will be used to identify auto-regulatory, feedback, feed-forward, or other system controls important for the GN. Specific Aim 2 addresses the question of which other genes are downstream of DMD-3 and what contributes to the sufficiency of DMD-3 for TTM. Tail-tip-specific transcriptome analyses will be performed on samples from wild-type males and hermaphrodites, males deficient for DMD-3, and hermaphrodites misexpressing DMD-3. The expected outcome is a framework for the GN architecture downstream of DMD-3 and an understanding of how it governs the localization or expression of key effectors of cell shape change. This GN will lay the requisite foundation for future studies on the molecular mechanisms underlying these interactions and how they affect cell-biological modules. These results are expected to have a positive impact on medicine, as they could identify key conserved genes that control morphogenesis, thus providing new targets for drugs to mitigate the effects of morphogenetic defects or cancer, or to aid wound healing.
细胞形态发生是动物发育和生长的重要组成部分。在这个过程中,细胞 协调地改变形状,迁移,并可能融合。这些过程是由一种叫做 “效应器”。已经在几种模型系统中鉴定了这样的效应物,并且包括细胞骨架和 细胞极性的决定因素。形态发生的性别、组织、位置和时间特异性是确定的 由“调节因子”,如转录因子。转录调控因子如何与效应子连接, 形态发生的基因网络(GN)在几乎所有系统中都没有得到很好的理解,但这种知识是 需要预测扰动如何导致发育过程中的形态发生变化,癌症, 形式的演变。阐明这种GN也会影响我们对伤口愈合的理解, 再生我们的长期目标是完全描绘控制形态发生的GN结构 的一种新的,简单的和性的二态模型结构,尾尖的秀丽隐杆线虫。尾尖是 由四个细胞组成,在幼虫末期, 发展先前的研究确定了尾尖形态发生(TTM)的“主调节因子”, 转录因子DMD-3(与人类中的DMRT 1同源,其指定男性命运)。没有DMD-3, TTM完全失败。此外,DMD-3在雌雄同体异位表达时足以引起TTM。 在这里,我们将测试DMD-3是如何与TTM的效应器相关联的。具体目标1将通过以下方式检验这一假设: 用DMD-3和一组TTM的关键效应物进行了一系列成对分子上位性实验, 惠誉实验室此前在一项胚胎后RNAi筛选中发现。在这些实验中,基因X(例如DMD-3) 基因的转录、翻译或亚细胞定位 将分析产品Y。网络分析将用于识别自动调节、反馈、前馈或 其他对GN重要的系统控制。具体目标2解决了哪些其他基因是 DMD-3的下游以及什么有助于DMD-3对TTM的充分性。尾尖特异性 转录组分析将在来自野生型雄性和雌雄同体、雄性 DMD-3缺陷和DMD-3错误表达的雌雄同体。预期的成果是为 DMD-3下游的GN结构以及对其如何控制DMD-3的定位或表达的理解。 细胞形状变化的关键效应器。这一指南将为今后的研究奠定必要的基础, 这些相互作用的分子机制以及它们如何影响细胞生物模块。这些结果 有望对医学产生积极影响,因为它们可以识别控制癌症的关键保守基因。 形态发生,从而为药物提供新的靶点,以减轻形态发生缺陷或 癌症或帮助伤口愈合。

项目成果

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David H. A. Fitch其他文献

David H. A. Fitch的其他文献

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{{ truncateString('David H. A. Fitch', 18)}}的其他基金

Control and Implementation of a Morphogenetic Program
形态发生程序的控制和实施
  • 批准号:
    10582981
  • 财政年份:
    2021
  • 资助金额:
    $ 29.64万
  • 项目类别:
Control and Implementation of a Morphogenetic Program
形态发生程序的控制和实施
  • 批准号:
    10725035
  • 财政年份:
    2021
  • 资助金额:
    $ 29.64万
  • 项目类别:
Control and Implementation of a Morphogenetic Program
形态发生程序的控制和实施
  • 批准号:
    10592885
  • 财政年份:
    2021
  • 资助金额:
    $ 29.64万
  • 项目类别:
Control and Implementation of a Morphogenetic Program
形态发生程序的控制和实施
  • 批准号:
    10593185
  • 财政年份:
    2021
  • 资助金额:
    $ 29.64万
  • 项目类别:
Control and Implementation of a Morphogenetic Program
形态发生程序的控制和实施
  • 批准号:
    10592207
  • 财政年份:
    2021
  • 资助金额:
    $ 29.64万
  • 项目类别:
Control and Implementation of a Morphogenetic Program
形态发生程序的控制和实施
  • 批准号:
    10399531
  • 财政年份:
    2021
  • 资助金额:
    $ 29.64万
  • 项目类别:
Control and Implementation of a Morphogenetic Program
形态发生程序的控制和实施
  • 批准号:
    10184787
  • 财政年份:
    2021
  • 资助金额:
    $ 29.64万
  • 项目类别:
Architecture of a Genetic Network Governing Morphogenesis
控制形态发生的遗传网络的架构
  • 批准号:
    8554367
  • 财政年份:
    2012
  • 资助金额:
    $ 29.64万
  • 项目类别:
Architecture of a Genetic Network Governing Morphogenesis
控制形态发生的遗传网络的架构
  • 批准号:
    8439867
  • 财政年份:
    2012
  • 资助金额:
    $ 29.64万
  • 项目类别:
COMPARATIVE GENETIC ANALYSIS OF NEMATODE DEVELOPMENT
线虫发育的比较遗传分析
  • 批准号:
    3044873
  • 财政年份:
    1992
  • 资助金额:
    $ 29.64万
  • 项目类别:

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