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

运动神经元(MN)功能或存活缺陷会导致严重的人类病理，如肌营养不良 侧索硬化症和脊髓性肌萎缩症，不同的MN亚型对 疾病。目前还没有有效的治疗这些疾病的方法，部分原因是缺乏了解 允许不同的MN亚型获得和维持其功能定义的分子机制 属性。从发育到成年期，亚型特定末端的持续表达 识别基因(例如，编码离子通道、神经递质受体、神经肽、信号的基因 分子)定义了特定MN亚型在整个生命过程中的独特功能特征。这些基因是如何 是如何诱导和维持的，人们对此知之甚少。这项提案使用了一种新的方法来特别关注 关于MN亚型特异性末端识别基因的转录调控。 这项提案的目标是揭示保守的、基因调控机制，这些机制在 在一生中发展和保持MN亚型特定终端特征的表达。对这件事 最后，这项提议结合了两种模式生物的优点：线虫秀丽线虫 和小鼠肌肉。通过研究线虫腹神经索(VNC)MN是如何获得它们的 亚型特有的特征，我们发现了一种涉及交叉性的基因调控机制 高度保守的转录因子的活性。我们发现转录因子UNC-3诱导和 在所有VNC MN亚型中维持末端标识基因的表达。然而，UNC-3不起作用 独自一人。它需要与UNC-3协同作用的HOX蛋白形式的辅因子才能激活 终末识别基因在不同MN亚型中沿VNC前后轴的表达 我们观察到HOX在发育中和成年MN中的表达，表明HOX蛋白类似于UNC-3， 不仅诱导并维持末端同源基因的表达。这篇文章中未发布的数据 应用表明，在小鼠体内，Hox蛋白也控制着脊髓中末端识别基因的表达 MNS，这表明我们的线虫发现在进化上是保守的。这项提案旨在揭示 HOX蛋白在线虫成虫MNS中的功能(目标1)，破译基因调控机制 在线虫MNS中的Hox下游(Aim 2)，并检验这样的假设：小鼠Hox蛋白(Hoxc8)， 与其线虫同源基因类似，需要诱导和维持末端标识基因的表达 在臂丛脊髓的MNS(目标3)。拟议活动的完成将推进我们的 了解MN亚型的不同功能，这可能会提供新的见解 探讨MN疾病的病因、诊断和治疗。

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.