Transcriptional regulation of neuronal differentiation

描述(申请人提供)：中枢神经系统的发展依赖于神经干细胞和前体细胞产生一系列不同的神经元和神经胶质细胞的能力，这些神经元和胶质细胞在成熟的神经网络中执行高度专业化的功能。这一过程中的错误可能会导致破坏性的发育异常，破坏神经系统的完整性，或导致更微妙的缺陷，影响学习、行为、沟通和运动。在我们提出的研究中，我们将研究在胚胎发育过程中调节脊髓运动神经元形成的遗传途径。我们最近发现，随着运动神经元分化的进行，FoxP转录因子家族的成员逐渐表达，从Foxp2开始分裂祖细胞，然后是Foxp4随着细胞的分化，然后Foxp1在有丝分裂后运动神经元的亚群中表达。FoxP蛋白是体内许多组织发育所必需的，其功能的改变有助于癌症的生长。FOXP在整个中枢神经系统中也广泛表达，它们的功能与与语言相关的大脑区域的发育有关。然而，在细胞和分子水平上，FoxP蛋白在神经系统中的功能仍然很大程度上是未知的。此前，我们已经证明Foxp1对于支配肢体和交感神经系统的MN亚型的形成是必不可少的，这引发了其他FoxP蛋白在神经发育中扮演什么角色(S)的问题。在拟议研究的目标1中，我们将研究Foxp2和Foxp4在调节神经上皮完整性和神经干细胞/祖细胞维持方面的作用。在目标2中，我们将测试每个FoxP蛋白对MN Fate的指定和分化的贡献。通过这些研究，我们将对发育中的胚胎如何形成运动回路，以及这一过程最终如何被重述以修复受损或患病的神经组织提供重要的新见解。此外，鉴于FOXPS在神经系统中的广泛表达及其与神经系统疾病的关系，我们预计我们的研究将进一步提供关于该转录因子家族如何参与中枢神经系统的形成和功能的更一般信息。) 公共卫生相关性：脊髓运动神经元对所有肌肉运动都是必不可少的，它们功能的丧失是几种毁灭性的神经退行性疾病以及无法从脊髓损伤中恢复的基础。目前，治疗这些疾病的方法很少，尽管人们非常希望使用干细胞来源的MNS来取代受损的神经元和恢复运动功能，并创造出可用于体外研究MN疾病发病机制的细胞。通过拟议的研究，我们将为MN形成的关键发育机制提供重要的新见解，并显著促进我们对如何从干细胞创建完整的运动神经元亚型以建立疾病模型和产生治疗有益细胞的理解。好了！

DESCRIPTION (provided by applicant): The development of the central nervous system depends upon the ability of neural stem and progenitor cells to produce an array of distinct neurons and glia that carry out highly specialized functions in mature neural networks. Errors in this process can result in devastating developmental abnormalities that disrupt the integrity of the nervous system or cause more subtle defects that affect learning, behavior, communication, and movement. In our proposed research, we will investigate the genetic pathways that regulate the formation of motor neurons in the spinal cord during embryonic development. We have recently found that members of the Foxp transcription factor family are progressively expressed as motor neuron differentiation proceeds, beginning with Foxp2 in dividing progenitors, followed by Foxp4 as the cells differentiate, and then Foxp1 in subsets of postmitotic motor neurons. Foxp proteins are required for the development of many tissues in the body and alterations in their function contributes to cancerous growth. Foxps are also broadly expressed throughout the CNS, and their function has been implicated in the development of brain regions associated with language. However, at the cellular and molecular level, the functions of Foxp proteins in the nervous system remain largely unknown. Previously, we have shown that Foxp1 is essential for the formation of the MN subtypes that innervate the limbs and sympathetic nervous system, raising the question of what role(s) do the other Foxp proteins play in neural development? In Aim 1 of the proposed research, we will investigate the actions of Foxp2 and Foxp4 in regulating neuroepithelial integrity and neural stem/progenitor cell maintenance. In Aim 2, we will test the contributions of each Foxp protein to MN fate specification and differentiation. Through these studies, we will provide important new insights into how motor circuits are formed in developing embryos, and how this process may eventually be recapitulated for the repair of injured or diseased neural tissue. In addition, given the broad expression of Foxps in the nervous system and their association with neurological disorders, we anticipate that our studies will further provide more general information on how this transcription factor family contributes to the formation and function of the CNS. ) PUBLIC HEALTH RELEVANCE: Spinal motor neurons are essential for all muscle movements, and the loss of their function underlies several devastating neurodegenerative diseases as well as a failure to recover from spinal cord injuries. Currently, few therapies exist to treat these conditions, though great hope has been placed on using stem cell-derived MNs to replace damaged neurons and restore motor functions, and create cells that could be used to study the pathogenesis of MN diseases in vitro. Through the proposed studies, we will provide important new insights into the key developmental mechanisms that underlie MN formation and significantly advance our understanding of how the full repertoire of motor neuron subtypes may be created from stem cells to build disease models and generate therapeutically beneficial cells. !