THYROID HORMONE ACTION IN BRAIN DEVELOPMENT

甲状腺激素在大脑发育中的作用

• 批准号: 2889505
• 负责人: ROBERT J DENVER
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889505
• 关键词: Xenopus; animal genetic material tag; developmental genetics; developmental neurobiology; embryo /fetus tissue /cell culture; embryogenesis; gene induction /repression; hormone regulation /control mechanism; laboratory rat; mammalian embryology; neurogenesis; neurogenetics; protein structure function; thyroid hormones; transcription factor

Normal brain development is critically dependent on thyroid hormone (TH) which influences neuronal maturation, neurite outgrowth, synapse formation and myelination. While we know much about the gross morphological defects of the central nervous system (CNS) and the clinical manifestations that result from fetal and neonatal hypothyroidism (i.e., severe mental retardation--cretinism), very little is known about the molecular mechanisms of TH action in neural development. This lack of information hinders our ability to fully understand normal development of the CNS, the etiology of developmental disorders of the CNS and to develop effective treatments for such disorders. The primary objective of this project is to provide a molecular basis for understanding TH action in brain development by studying the transcriptional regulatory networks induced by the hormone. The effects of TH are mediated by the action of specific nuclear receptors (TRs) that function as ligand-activated transcription factors. In the proposed work, two models for vertebrate neural development, the rat and the frog (Xenopus laevis) will be used to identify and analyze the function of novel TH target genes in the developing brain. We previously isolated cDNAs for 34 TH-response genes from tadpole brain and conducted cross-species hybridizations to identify three similarly- regulated genes in embryonic rat brain. In the proposed work, the regulation of gene expression and the function in neural development of two genes identified by this approach will be studied. The first aim focuses on the basic transcription element binding protein (BTEB), a GC- box transcription factor whose mRNA levels are strongly regulated by TH in developing rat brain. The regulation of expression of this gene in neural cells will be analyzed at both the transcriptional and posttranscriptional levels. The second aim will analyze the expression and function in neural development of the HMG-box transcription factor HBP1 which has been shown to interact with members of the retinoblastoma family of growth suppressors and likely plays an important role in cell differentiation. The third and final aim will utilize three other cDNA clones for Xenopus TH-response genes (chosen for their hormonal responsiveness and developmental pattern of expression) to identify other novel hormone-regulated genes in rat brain. These two models provide a powerful, complementary system for identifying and characterizing important neurodevelopmental genetic pathways and thus place us in a unique position to provide a molecular basis for understanding both normal and abnormal neurological development.

正常的大脑发育严重依赖于甲状腺激素(TH) 影响神经元成熟、轴突生长、突触 形成和髓鞘形成。虽然我们知道很多关于粗俗的 中枢神经系统(CNS)的形态缺陷和 胎儿和新生儿的临床表现 甲状腺功能减退(即严重精神发育迟滞--克汀病)，很少 已知TH在神经细胞中作用的分子机制 发展。这种信息的缺乏阻碍了我们充分 了解中枢神经系统的正常发育，发育迟缓的病因 中枢神经系统疾病并开发有效的治疗方法 精神错乱。该项目的主要目标是提供一个 TH在脑发育中作用的分子基础 研究荷尔蒙诱导的转录调控网络。 TH的作用是通过特定的核的作用来调节的。 受体作为配体激活的转录因子发挥作用。 在拟议的工作中，脊椎动物神经发育的两个模型， 老鼠和青蛙(非洲爪哇)将被用来鉴定和分析 新的TH靶基因在发育中的大脑中的功能。我们 先前从蝌蚪脑中分离的34个TH反应基因的cDNA 并进行了跨物种杂交，以确定三个相似的- 胚胎大鼠脑中的调控基因。在拟议的工作中， 基因表达调控及其在神经发育中的作用 通过这种方法确定的两个基因将被研究。第一个目标 重点是碱性转录元件结合蛋白(BTEB)，一种GC- 框转录因子，其mRNA水平受TH强烈调控 在发育中的老鼠大脑中。该基因在植物体内的表达调控 神经细胞将在转录和 转录后水平。第二个目的是分析表达 HMG-box转录因子在神经发育中的作用 已被证明与视网膜母细胞瘤成员相互作用的HBP1 生长抑制因子家族，可能在细胞中发挥重要作用 差异化。第三个也是最终目标将利用另外三个cdna 非洲爪哇TH反应基因的克隆(选择它们的荷尔蒙 表达的反应性和发育模式)以识别 大鼠大脑中其他新的激素调节基因。这两种型号 提供一个强大的补充系统，用于识别和 表征重要的神经发育遗传途径，因此 将我们置于一个独特的位置，为 了解正常和异常的神经发育。