Transcriptional regulation of neuronal differentiation

神经元分化的转录调控

• 批准号: 8322159
• 负责人: BENNETT G NOVITCH
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322159
• 关键词: Address; Adherens Junction; Affect; Axon; Biological Neural Networks; Brain region; Cancerous; Cell Cycle; Cell Maintenance; Cell physiology; Cells; Congenital Abnormality; Defect; Development; Disease; Disease model; Embryo; Embryonic Development; Failure; Family; Family member; Gene Silencing; Genes; Genetic; Goals; Growth; In Vitro; Language; Lead; Learning; Limb structure; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Movement; Mus; Muscle; Mutant Strains Mice; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuroepithelial; Neuroglia; Neurologic; Neuronal Differentiation; Neurons; Pathogenesis; Pathway interactions; Pattern; Play; Process; Proteins; Research; Role; Signal Transduction; Spinal; Spinal Cord; Spinal cord injury; Stem cells; Sympathetic Nervous System; Synapses; Testing; Time; Tissues; Transcriptional Regulation; Transgenic Organisms; communication behavior; injured; insight; loss of function; member; motor neuron development; nerve stem cell; nervous system disorder; neural circuit; neurodevelopment; neuroepithelium; neurogenesis; neuroregulation; novel; progenitor; public health relevance; relating to nervous system; repaired; research study; stem; transcription factor

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. !

描述（由申请人提供）：中枢神经系统的发展取决于神经茎和祖细胞产生一系列不同神经元和神经胶质的能力，这些神经元和神经胶质在成熟的神经网络中发挥了高度专业化的功能。在此过程中的错误可能导致破坏性的异常，从而破坏神经系统的完整性或导致影响学习，行为，沟通和运动的更微妙的缺陷。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中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被逐渐表达为运动神经元分化的过程，从FOXP2开始，从foxp2开始，然后将FOXP4作为细胞分化，然后在蒙脱病后运动神经元子集中进行FOXP1。 FOXP蛋白是体内许多组织的发展所必需的，其功能改变会导致癌性生长。 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展有关。但是，在细胞和分子水平上，神经系统中FOXP蛋白的功能在很大程度上未知。以前，我们已经表明，FOXP1对于支配四肢和交感神经系统的Mn亚型的形成至关重要，提出了其他FOXP蛋白在神经发育中起什么作用的问题？在拟议的研究的目标1中，我们将研究FOXP2和FOXP4在调节神经上皮完整性和神经茎/祖细胞维护方面的作用。在AIM 2中，我们将测试每个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，以了解如何在开发胚胎中形成运动电路，以及如何最终概括该过程以修复受伤或患病的神经组织。此外，鉴于FOXP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有关该转录因子家族如何促进CNS的形成和功能的更多一般信息。 ） 公共卫生相关性：脊柱运动神经元对于所有肌肉运动至关重要，其功能的丧失是几种破坏性的神经退行性疾病以及未能从脊髓损伤中恢复的疾病。当前，尽管对使用干细胞衍生的MN来替代受损神经元并恢复运动功能的巨大希望，但几乎没有疗法治疗这些疾病，并创建可用于研究体外MN疾病的发病机理的细胞。通过拟议的研究，我们将提供重要的新见解，以了解基于MN形成的关键发育机制，并显着提高我们对运动神经元亚型的全部曲目的理解，从干细胞中可以创建出疾病模型并产生治疗益处的细胞。呢