Hormone and Activity-Dependent Neural Gene Expression

激素和活动依赖性神经基因表达

• 批准号: 7062471
• 负责人: ROBERT J DENVER
• 金额: $ 20.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7062471
• 关键词: confocal scanning microscopy; developmental neurobiology; gene expression; genetic promoter element; genetic regulation; genetically modified animals; hormone regulation /control mechanism; immunocytochemistry; laboratory mouse; neurogenesis; sectioning; thyroid hormones; transcription factor

DESCRIPTION (provided by applicant): The overall goal of the proposed studies is to understand basic mechanisms of thyroid hormone (T3) action in brain development. Brain development is critically dependent on T3, which promotes axonal maturation, dendritic arborization, synapse formation, myelination, cell proliferation and apoptosis. Thyroid hormone deficiency during neonatal/fetal life results in severe mental retardation (i.e., cretinism). Despite the profound effects of thyroid deficiency, relatively little is known about the molecular mechanisms of T3 action in CMS development. Electrical activity in the CNS promotes the elaboration of axons and dendrites, and is required for the establishment and strengthening of synaptic connections. Thus, both hormones and electrical activity are necessary for normal development of the vertebrate brain. Analysis of the immediate early genes (lEGs) induced by electrical activity and by T3 in the developing CNS suggests overlapping signaling pathways. Earlier we discovered that the transcription factor basic transcription element binding protein (BTEB1) is strongly upregulated during postnatal development in rodent brain. We showed that BTEB1 is directly regulated by T3 and that BTEB1 plays a role in neuronal morphogenesis, stimulating neurite extension and branching. Our findings support the view that BTEB1 is a critical player in T3-dependent neuronal morphogenesis. In addition to hormonal regulation, we recently found that BTEB1 is an activity-regulated gene in the CNS. To elucidate the role that BTEB1 plays in mammalian brain development, we propose to: 1) analyze developmental and hormone-dependent BTEB1 expression in mouse CNS, 2) analyze thyroid regulation of the mouse BTEB1 promoter, and 3) analyze activity-dependent regulation of the mouse BTEB1 gene. This research will provide an important foundation for understanding the molecular basis of T3 action on brain development, and will begin to integrate knowledge of hormone-dependent signaling pathways with electrical activity-dependent pathways. A detailed knowledge of these pathways is necessary for understanding basic neurodevelopmental processes, and may suggest strategies for prevention and/or treatment of neurological disorders caused by disruption of hormone signaling pathways.

描述（由申请人提供）：拟议研究的总体目标是了解甲状腺激素（T3）在大脑发育中的作用的基本机制。脑发育严重依赖于T3，它促进轴突成熟、树突树突形成、突触形成、髓鞘形成、细胞增殖和凋亡。新生儿/胎儿期甲状腺激素缺乏会导致严重的智力迟钝（即克汀症）。尽管甲状腺缺乏具有深远的影响，但对T3在CMS发展中的分子机制知之甚少。中枢神经系统的电活动促进轴突和树突的发育，是建立和加强突触连接所必需的。因此，激素和脑电活动对于脊椎动物大脑的正常发育都是必需的。电活动和T3在发育中的中枢神经系统中诱导的即时早期基因（lEGs）的分析表明信号通路重叠。早期我们发现转录因子基本转录元件结合蛋白（BTEB1）在啮齿动物出生后的大脑发育过程中强烈上调。我们发现BTEB1直接受T3的调控，并且BTEB1在神经元形态发生中起作用，刺激神经突的伸展和分支。我们的研究结果支持BTEB1在t3依赖性神经元形态发生中起关键作用的观点。除了激素调节外，我们最近发现BTEB1是中枢神经系统中一个活动调节基因。为了阐明BTEB1在哺乳动物脑发育中的作用，我们建议：1)分析小鼠中枢神经系统中发育和激素依赖性的BTEB1表达，2)分析小鼠BTEB1启动子对甲状腺的调控，3)分析小鼠BTEB1基因的活性依赖性调控。本研究将为理解T3对脑发育作用的分子基础提供重要基础，并将开始整合激素依赖性信号通路和电活动依赖性信号通路的知识。这些通路的详细知识对于理解基本的神经发育过程是必要的，并且可能为预防和/或治疗由激素信号通路中断引起的神经系统疾病提供策略。