Role of Mammalian Hairless Gene in Neural Development

哺乳动物无毛基因在神经发育中的作用

• 批准号: 6540402
• 负责人: CATHERINE C THOMPSON
• 金额: $ 32万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540402
• 关键词: brain; central nervous system; developmental genetics; developmental neurobiology; gene expression; gene induction /repression; genetically modified animals; hormone regulation /control mechanism; immunocytochemistry; immunofluorescence technique; immunoprecipitation; in situ hybridization; laboratory mouse; laboratory rat; messenger RNA; northern blottings; polymerase chain reaction; protein structure function; regulatory gene; thyroid hormones; western blottings; yeast two hybrid system

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.

描述（由申请人提供）：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 无毛（hr）基因在神经发育中的作用，因为hr的表达受 甲状腺激素在发育中的大鼠大脑。甲状腺激素是必不可少的 哺乳动物中枢神经系统的正常发育;甲状腺激素水平不足 导致认知和运动功能的严重缺陷 包括智力迟钝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.很少有靶基因被鉴定出来，因此对这些基因的功能知之甚少。 甲状腺激素影响中枢神经系统发育的机制。我们已经表明 HR表达受甲状腺激素高度诱导，此外， hr（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是一个转录辅阻遏物， 这表明Hr的体内功能是影响 其他甲状腺激素反应基因。作为一个既受 与甲状腺激素受体相互作用，Hr可能是一个关键 甲状腺激素在大脑中作用的介质。拟议的研究审查 HR在大脑中的表达和功能。帮助阐明人力资源在 哺乳动物大脑发育、hr的空间和时间表达模式 mRNA和蛋白质将在发育中的大鼠脑中表征。的重要性 调节大脑发育的hr的损失将通过检查 在体内HR功能，这将导致脑结构的改变， 功能或两者。为了测试这一点，hr的无效等位基因将通过以下方法产生： HR基因座的靶向缺失，并且HR的体内功能将是 通过检查HR突变小鼠中潜在的神经学改变来评估。 该分析将包括测试Hr影响 下游甲状腺激素应答基因在体内的表达，通过检查 hr突变小鼠中甲状腺激素应答基因的表达。的机制 将使用体外方法确定哪种Hr介导转录抑制 测定。了解甲状腺激素反应基因的功能， hr有助于了解甲状腺激素在脑内的作用机制 发展这些信息对于了解甲状腺如何 激素缺乏会导致神经系统异常， 用于预防和/或治疗由以下引起的神经障碍的策略 其他因素