Hormone and Activity-Dependent Neural Gene Expression

描述（由申请方提供）：拟定研究的总体目标是了解甲状腺激素（T3）在大脑发育中作用的基本机制。大脑发育严重依赖于T3，T3促进轴突成熟、树枝状分支、突触形成、髓鞘形成、细胞增殖和细胞凋亡。新生儿/胎儿期甲状腺激素缺乏会导致严重的智力迟钝（即，克汀病）。尽管甲状腺缺乏的影响深远，相对知之甚少的T3行动CMS发展的分子机制。CNS中的电活动促进轴突和树突的加工，并且是建立和加强突触连接所需的。因此，激素和电活动对于脊椎动物大脑的正常发育都是必要的。在发育中的CNS中由电活动和T3诱导的立即早期基因（IEGs）的分析表明重叠的信号传导途径。早期我们发现转录因子基本转录元件结合蛋白（BTEB 1）在啮齿动物脑的出生后发育过程中强烈上调。我们发现BTEB 1直接受T3调节，并且BTEB 1在神经元形态发生、刺激神经突延伸和分支中起作用。我们的研究结果支持了BTEB 1在T3依赖的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BTEB 1是CNS中的活性调节基因。为了阐明BTEB 1在哺乳动物脑发育中的作用，我们建议：1）分析发育和发育依赖性BTEB 1在小鼠CNS中的表达，2）分析小鼠BTEB 1启动子的甲状腺调节，3）分析小鼠BTEB 1基因的活性依赖性调节。这项研究将为理解T3对脑发育作用的分子基础提供重要的基础，并将开始整合脑电活动依赖的信号通路与脑电活动依赖的通路的知识。这些途径的详细知识是必要的了解基本的神经发育过程，并可能建议策略，预防和/或治疗激素信号通路中断引起的神经系统疾病。

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.