Hox-dependent mechanisms for establishment and maintenance of motor neuron terminal identity

建立和维持运动神经元末端身份的 Hox 依赖性机制

基本信息

  • 批准号:
    10558639
  • 负责人:
  • 金额:
    $ 41.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-03-15 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Defects in motor neuron (MN) function or survival result in severe human pathologies, such as amyotrophic lateral sclerosis and spinal muscular atrophy, with distinct MN subtypes differing in their susceptibility to disease. There is currently no effective treatment for these disorders, in part due to a lack of understanding of the molecular mechanisms that allow distinct MN subtypes to acquire and maintain their function-defining properties. The continuous expression, from development through adulthood, of subtype-specific terminal identity genes (e.g., genes coding for ion channels, neurotransmitter receptors, neuropeptides, signaling molecules) defines the unique, functional features of a given MN subtype throughout life. How these genes are induced and maintained is poorly understood. This proposal uses a novel approach to specifically focus on the transcriptional regulation of MN subtype-specific terminal identity genes. The goal of this proposal is to uncover conserved, gene regulatory mechanisms that establish during development, and maintain throughout life, the expression of MN subtype-specific terminal features. To this end, this proposal combines the strengths of two model organisms: the nematode Caenorhabditis elegans and mouse Mus musculus. By studying how C. elegans ventral nerve cord (VNC) MNs acquire their subtype-specific features, we discovered a gene regulatory mechanism that involves the intersectional activity of highly conserved transcription factors. We found that the transcription factor UNC-3 induces and maintains the expression of terminal identity genes in all VNC MN subtypes. However, UNC-3 does not act alone. It requires co-factors in the form of Hox proteins that act synergistically with UNC-3 to activate expression of terminal identity genes in distinct MN subtypes along the anterior-posterior axis of the VNC. We observed Hox expression in developing and adult MNs, suggesting that Hox proteins, similar to UNC-3, not only induce, but also maintain expression of terminal identity genes. The unpublished data in this application indicate that Hox proteins, in mice, also control expression of terminal identity genes in spinal MNs, suggesting evolutionary conservation of our C. elegans findings. This proposal aims to uncover the function of Hox proteins in adult C. elegans MNs (Aim 1), decipher the gene regulatory mechanisms downstream of Hox in C. elegans MNs (Aim 2), and test the hypothesis that a mouse Hox protein (Hoxc8), similar to its C. elegans orthologs, is required to induce and maintain expression of terminal identity genes in MNs of the brachial spinal cord (Aim 3). Completion of the proposed activities will advance our understanding of how distinct MN subtypes become and remain functional, which may provide new insights into the etiology, diagnosis, and treatment of MN disorders.
运动神经元(MN)功能或存活的缺陷导致严重的人类病理学,例如肌萎缩性神经营养不良。 脊髓侧索硬化症和脊髓性肌萎缩症,不同的MN亚型在其易感性上不同, 疾病目前对这些疾病没有有效的治疗方法,部分原因是缺乏了解 允许不同MN亚型获得并维持其功能定义的分子机制 特性.从发育到成年,亚型特异性终末 身份基因(例如,编码离子通道、神经递质受体、神经肽、信号传导的基因 分子)定义了整个生命中给定MN亚型的独特功能特征。这些基因如何 是如何被诱导和维持的,人们对此知之甚少。该提案采用了一种新颖的方法, MN亚型特异性末端同一性基因的转录调控。 这项提案的目标是揭示保守的,基因调控机制,建立在 发展,并保持整个生命,MN亚型特异性终端功能的表达。本 最后,该建议结合了两种模式生物的优势:线虫秀丽隐杆线虫 和小鼠Mus musculus。通过研究C.线虫腹神经索(VNC)MN获得它们的 亚型特异性特征,我们发现了一个基因调控机制,涉及交叉 高度保守的转录因子的活性。我们发现转录因子β-3诱导和 维持所有VNC MN亚型中末端同一性基因的表达。然而, 一个人它需要以Hox蛋白形式存在的辅助因子,该蛋白与β-3协同作用以激活 不同MN亚型中末端同一性基因沿VNC前后轴沿着的表达。 我们观察到Hox在发育和成年MN中的表达,表明Hox蛋白,类似于Hox-3, 不仅诱导而且维持末端同一性基因的表达。这份未公布的数据 应用表明,Hox蛋白,在小鼠中,也控制脊髓中末端同一性基因的表达, MNs,表明我们的C. elegans的发现这项提案旨在揭示 Hox蛋白在C. elegans MNs(Aim 1),破译基因调控机制 在C的Hox下游。elegans MN(Aim 2),并检验小鼠Hox蛋白(Hoxc 8), 类似于C。秀丽隐杆线虫直系同源物是诱导和维持末端同一性基因表达所必需的 在臂脊髓的MN中(目标3)。完成拟议的活动将促进我们的 了解不同的MN亚型如何变得和保持功能,这可能会提供新的见解 MN疾病的病因、诊断和治疗。

项目成果

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Paschalis Kratsios其他文献

Paschalis Kratsios的其他文献

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{{ truncateString('Paschalis Kratsios', 18)}}的其他基金

Hox-dependent mechanisms for establishment and maintenance of motor neuron terminal identity
建立和维持运动神经元末端身份的 Hox 依赖性机制
  • 批准号:
    10338148
  • 财政年份:
    2020
  • 资助金额:
    $ 41.13万
  • 项目类别:
Molecular mechanisms of motor neuron terminal identity
运动神经元末梢识别的分子机制
  • 批准号:
    10608101
  • 财政年份:
    2020
  • 资助金额:
    $ 41.13万
  • 项目类别:
Molecular mechanisms of motor neuron terminal identity
运动神经元末梢识别的分子机制
  • 批准号:
    10383153
  • 财政年份:
    2020
  • 资助金额:
    $ 41.13万
  • 项目类别:
Molecular mechanisms of motor neuron terminal identity
运动神经元末梢识别的分子机制
  • 批准号:
    10183355
  • 财政年份:
    2020
  • 资助金额:
    $ 41.13万
  • 项目类别:
Molecular mechanisms of motor neuron terminal identity
运动神经元末梢识别的分子机制
  • 批准号:
    10034226
  • 财政年份:
    2020
  • 资助金额:
    $ 41.13万
  • 项目类别:
Identification of the transcriptional targets of three conserved regulatory factors necessary for motor neuron subtype function - Resubmission 01
运动神经元亚型功能所需的三种保守调节因子的转录靶标的鉴定 - 重新提交 01
  • 批准号:
    9757517
  • 财政年份:
    2019
  • 资助金额:
    $ 41.13万
  • 项目类别:
Gene regulatory mechanisms that assign and maintain motor neuron terminal differe
分配和维持运动神经元末梢的基因调控机制不同
  • 批准号:
    8737986
  • 财政年份:
    2013
  • 资助金额:
    $ 41.13万
  • 项目类别:
Gene regulatory mechanisms that assign and maintain motor neuron terminal differe
分配和维持运动神经元末梢的基因调控机制不同
  • 批准号:
    8617342
  • 财政年份:
    2013
  • 资助金额:
    $ 41.13万
  • 项目类别:

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