Role of Mammalian Hairless Gene in Neural Development

描述(申请人提供)：这项工作的长期目标是 了解哺乳动物中枢神经系统发育的分子机制 神经系统(CNS)。这个实验室正在研究哺乳动物的角色 无毛(Hr)基因在神经发育中的作用，因为hr的表达受 发育中的大鼠脑中的甲状腺激素。甲状腺激素对人体健康至关重要 哺乳动物中枢神经系统发育正常；甲状腺激素水平不足 会导致严重的认知和运动功能缺陷 包括智力低下和共济失调。甲状腺激素通过 调节特定靶点表达的核受体蛋白 基因。目前发现的靶基因很少，因此人们对该基因知之甚少。 甲状腺激素影响中枢神经系统发育的机制。我们已经展示了 HR的表达是由甲状腺激素高度诱导的，此外， HR编码的蛋白质与甲状腺激素受体相互作用。 功能研究表明，HR是一种转录辅助抑制因子， 提示HR在体内的作用是影响其基因表达。 其他甲状腺激素反应基因。作为一个因素，既受 甲状腺激素并与甲状腺激素受体相互作用，HR可能是关键 大脑中甲状腺激素作用的中介物。这项拟议的研究审查了 HR在大脑中的表达和功能。以帮助阐明人力资源在 哺乳动物脑发育，HR的时空表达模式 MRNA和蛋白质将在发育中的大鼠大脑中得到表征。它的重要性 用于调节大脑发育的人力资源将通过检查 在体内的HR功能，这应该会导致大脑结构的改变， 功能或两者兼而有之。为了测试这一点，hr的空等位基因将由 有针对性地删除hr基因，hr的体内功能将是 通过检测hr突变小鼠潜在的神经改变进行评估。 此分析将包括测试人力资源影响 通过检测下游甲状腺激素反应基因在体内的表达 Hr突变小鼠甲状腺激素反应基因的表达。这个机制是通过 体外实验将确定哪些HR介导转录抑制 化验。了解甲状腺激素反应基因的功能，如 HR将有助于了解甲状腺激素在大脑中的作用机制 发展。这些信息对于了解甲状腺是如何 激素缺乏会导致神经异常，并可能提示 预防和/或治疗由以下原因引起的神经系统疾病的策略 其他因素。

DESCRIPTION (provided by applicant): The long term goal of this work is to understand molecular mechanisms underlying development of the mammalian central nervous system (CNS). This laboratory is examining the role of the mammalian hairless (hr)gene in neural development, as hr expression is regulated by thyroid hormone in developing rat brain. Thyroid hormone is essential for proper development of the mammalian CNS; inadequate levels of thyroid hormone during development leads to severe deficits in cognitive and motor functions that include mental retardation and ataxia. Thyroid hormone acts through nuclear receptor proteins that regulate the expression of specific target genes. Few target genes have been identified, thus little is known about the mechanism by which thyroid hormone influences CNS development. We have shown that hr expression is highly induced by thyroid hormone, and in addition, that the protein encoded by hr (Hr) interacts with thyroid hormone receptor. Functional studies indicate that Hr is a transcriptional corepressor, suggesting that the in vivo function of Hr is to influence the expression of other thyroid hormone-responsive genes. As a factor that is both regulated by thyroid hormone and interacts with thyroid hormone receptor, Hr is likely a key mediator of thyroid hormone action in the brain. The proposed research examines hr expression and function in the brain. To help elucidate the role of hr in mammalian brain development, the spatial and temporal expression pattern of hr mRNA and protein will be characterized in developing rat brain. The importance of hr for regulating brain development will be determined by examining loss of hr function in vivo, which should result in alteration of brain structure, function or both. To test this, a null allele of hr will be generated by targeted deletion of the hr locus, and the in vivo function of hr will be assessed by examining potential neurological alterations in hr mutant mice. This analysis will include testing the proposal that Hr influences the expression of downstream thyroid hormone-responsive genes in vivo, by examining thyroid hormone-responsive gene expression in hr mutant mice. The mechanism by which Hr mediates transcriptional repression will be determined using in vitro assays. Understanding the function of a thyroid hormone-responsive gene such as hr will help discern the mechanism of thyroid hormone action in brain development. Such information is necessary for understanding how thyroid hormone deficiency causes neurological abnormalities, and may suggest strategies for prevention and/or treatment of neurological disorders caused by other factors.