Transcriptional regulation of morphogenetic behavior and invasive cell fate specification in C. elegans

秀丽隐杆线虫形态发生行为和侵袭细胞命运规范的转录调控

基本信息

  • 批准号:
    9980182
  • 负责人:
  • 金额:
    $ 3.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-07-20 至 2022-07-19
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY / ABSTRACT The ability of cells to traverse basement membranes (BMs) is a key part of fertility, development, immunity, and disease. BM invasion is facilitated through expression of extracellular matrix proteins, upregulation of matrix metalloproteinases, polarization of the F-actin cytoskeleton, and cell cycle arrest. Precise coordination of these pro-invasive programs is largely achieved through transcriptional regulation; however, our understanding of the gene regulatory networks (GRNs) involved is limited due to the lack of model systems in which cell invasion can be visualized live. Here, I propose to fill this gap in knowledge by utilizing morphogenesis of the Caenorhabditis elegans uterine-vulval connection as a tractable and visually amenable model to examine cell invasion in vivo. During development of the hermaphroditic somatic gonad, a specialized uterine cell called the anchor cell (AC) invades through the underlying BM to connect the uterus to the vulval epithelium. The AC itself is specified in a cell fate decision event earlier in development, in which two initially equipotent cells diverge via stochastic Notch asymmetry, giving rise to the presumptive AC and a proliferative ventral uterine (VU) cell. Prior research by our lab and others has identified six transcription factors (TFs) that regulate AC invasion. These include the basic leucine zipper TF fos-1 (Fos), the basic helix-loop-helix TF hlh-2 (E/Daughterless), two nuclear hormone receptors, nhr-67 (NR2E1/Tailless/TLX) and sex-1 (RARB/NR1B2), as well as two zinc-finger TFs, egl-43 (EVI1/MEL1) and mep-1. These TFs appear to be functioning in at least three distinct GRN sub-circuits to regulate AC invasion, one of which involves NHR-67, which functions upstream of CKI-1 (p21/p27) to induce G1 cell cycle arrest. Remarkably, five of the six pro-invasive TFs function reiteratively during the AC/VU cell fate decision. These include the three TFs comprising the NHR-67/cell cycle-dependent pro-invasive pathway (EGL- 43S, MEP-1, and NHR-67), as well as HLH-2 and SEX-1, which have predicted binding sites within the nhr-67 promoter. Thus, based on the literature and my preliminary studies, my central hypothesis is that the AC invasive program is dependent on the function of multiple GRN sub-circuits, one of which modulates cell cycle arrest and is reiteratively used in AC fate specification. In Aim 1 of this project, I will dissect the cis- and trans-regulation of AC invasion, focusing on the cell cycle-dependent GRN sub-circuit involving the pro-invasive TF nhr-67/TLX. In Aim 2, I will examine the roles of pro-invasive TFs that reiteratively function in AC specification and investigate if cell cycle control is the common denominator underlying these two processes. Cutting-edge functional tools, including an endogenous protein depletion system and a novel cell cycle state sensor, paired with the ability to perform high-resolution subcellular visual analyses, will allow for thorough and rigorous testing of this hypothesis.
项目总结/摘要 细胞穿过基底膜(BM)的能力是生育力、发育、免疫和免疫系统的关键部分。 疾病通过细胞外基质蛋白的表达,基质蛋白的上调, 金属蛋白酶、F-肌动蛋白细胞骨架极化和细胞周期阻滞。精确协调这些 亲侵入程序主要是通过转录调控实现的;然而,我们对转录调控的理解是, 由于缺乏细胞侵袭的模型系统,所涉及的基因调控网络(GRNs)是有限的, 活的可视化。在这里,我建议填补这方面的知识空白,利用形态发生的小杆线虫 线虫子宫-外阴连接作为一个易处理的和视觉上顺从的模型来检查体内细胞侵袭。 在两性体细胞性腺发育过程中,一种称为锚细胞(AC)的特化子宫细胞 通过下面的BM侵入以连接子宫和外阴上皮。AC本身在 细胞命运决定事件,发生在发育早期,其中两个最初等能的细胞通过随机Notch分化 不对称,产生推定的AC和增殖的腹侧子宫(VU)细胞。我们之前的研究 实验室和其他人已经确定了六种调节AC入侵的转录因子(TF)。其中包括基本的 亮氨酸拉链TF fos-1(Fos),碱性螺旋-环-螺旋TF hlh-2(E/Daughterless),两种核激素 受体nhr-67(NR 2 E1/Tailless/TLX)和sex-1(RARB/NR 1B 2),以及两个锌指转录因子egl-43 (EVI1/MEL 1)和mep-1。这些TF似乎在至少三个不同的GRN子回路中起作用, 调节AC侵入,其中之一涉及NHR-67,其在CKI-1(p21/p27)上游起作用以诱导G1期 细胞周期停滞值得注意的是,在AC/VU细胞的命运中,六种促侵袭TF中的五种粘附地起作用。 决定这些包括三种TF,其包含NHR-67/细胞周期依赖性促侵袭途径(EGL-67)。 43 S、MEP-1和NHR-67),以及HLH-2和SEX-1,它们在nhr-67内具有预测的结合位点。 启动子因此,基于文献和我的初步研究,我的中心假设是AC侵袭性 程序依赖于多个GRN子电路的功能,其中一个调节细胞周期停滞, 在AC命运规范中被粘附地使用。在本项目的目标1中,我将剖析 AC侵袭,关注涉及促侵袭TF nhr-67/TLX的细胞周期依赖性GRN子回路。在 目的2,我将研究在AC特化中粘附性起作用的促侵袭性TF的作用,并研究 如果细胞周期控制是这两个过程的共同点。尖端的功能工具, 包括内源性蛋白质消耗系统和新型细胞周期状态传感器, 进行高分辨率的亚细胞视觉分析,将允许彻底和严格的测试这一假设。

项目成果

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Taylor Kinney其他文献

Taylor Kinney的其他文献

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{{ truncateString('Taylor Kinney', 18)}}的其他基金

Transcriptional regulation of morphogenetic behavior and invasive cell fate specification in C. elegans
秀丽隐杆线虫形态发生行为和侵袭细胞命运规范的转录调控
  • 批准号:
    10212437
  • 财政年份:
    2019
  • 资助金额:
    $ 3.9万
  • 项目类别:

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