Transcriptional regulation of neuronal differentiation

描述（由申请人提供）：中枢神经系统的发展依赖于神经干细胞和祖细胞产生一系列不同的神经元和胶质细胞的能力，这些神经元和胶质细胞在成熟的神经网络中执行高度特化的功能。这个过程中的错误会导致毁灭性的发育异常，破坏神经系统的完整性，或者导致影响学习、行为、交流和运动的更细微的缺陷。在我们提出的研究中，我们将研究在胚胎发育期间调节脊髓运动神经元形成的遗传途径。我们最近发现Foxp转录因子家族的成员随着运动神经元分化的进行而逐渐表达，从分裂祖细胞中的Foxp2开始，接着是细胞分化中的Foxp4，然后是有丝分裂后运动神经元亚群中的Foxp1。Foxp蛋白是人体许多组织发育所必需的，其功能的改变会导致癌症的生长。Foxps也在整个中枢神经系统中广泛表达，它们的功能与大脑中与语言相关区域的发育有关。然而，在细胞和分子水平上，Foxp蛋白在神经系统中的功能在很大程度上仍然未知。先前，我们已经证明Foxp1对于支配四肢和交感神经系统的MN亚型的形成是必不可少的，这就提出了其他Foxp1蛋白在神经发育中起什么作用的问题。在本研究的目的1中，我们将研究Foxp2和Foxp4在调节神经上皮完整性和神经干/祖细胞维持中的作用。在目标2中，我们将测试每种Foxp蛋白对MN命运规范和分化的贡献。通过这些研究，我们将提供重要的新见解，了解运动回路是如何在发育中的胚胎中形成的，以及这一过程最终如何重现以修复受伤或患病的神经组织。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联，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促进中枢神经系统的形成和功能的更一般的信息。

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. !