THYROID HORMONE ACTION IN BRAIN DEVELOPMENT

甲状腺激素在大脑发育中的作用

• 批准号: 2600672
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2600672
• 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） 影响神经元的成熟，轴突的生长，突触 形成和髓鞘形成。 虽然我们知道很多关于毛 中枢神经系统（CNS）和神经系统的形态学缺陷 胎儿和新生儿的临床表现 甲状腺功能减退（即，严重智力迟钝-克汀病），很少 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，发育的病因学 中枢神经系统的疾病，并开发有效的治疗方法， 紊乱 该项目的主要目标是提供一个 分子基础，了解TH行动在大脑发育， 研究激素诱导的转录调控网络。 TH的作用是通过特异性核内转录因子的作用介导的。 受体（TR），其作为配体激活的转录因子起作用。 在拟议的工作中，脊椎动物神经发育的两个模型， 大鼠和青蛙（非洲爪蟾）将被用于识别和分析 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，以确定三个类似的- 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 将研究通过该方法鉴定的两个基因。 第一个目标 重点是基本转录元件结合蛋白（BTEB），一个GC- 其mRNA水平受TH强烈调节的盒转录因子 老鼠大脑的发育 该基因的表达调控， 神经细胞将在转录和 转录后水平。 第二个目标是分析表达 HMG盒转录因子在神经发育中的作用 HBP 1已被证明与视网膜母细胞瘤的成员相互作用 一个生长抑制因子家族，可能在细胞增殖中起重要作用。 分化 第三个也是最后一个目标将利用另外三个cDNA 非洲爪蟾TH-反应基因的克隆（选择它们的激素 反应性和表达的发育模式）来识别 其他新的表达调控基因。 这两款车型 提供一个强大的，互补的系统， 表征重要的神经发育遗传途径， 使我们处于一个独特的位置， 了解正常和异常的神经发育。