Hormone and Activity-Dependent Neural Gene Expression

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)在大脑发育中的基本作用机制。大脑发育严重依赖于T3，它促进轴突成熟、树突树枝形成、突触形成、髓鞘形成、细胞增殖和凋亡。新生儿/胎儿时期的甲状腺激素缺乏会导致严重的精神发育迟滞(即克汀病)。尽管甲状腺功能缺乏症影响深远，但对T3在CMS发生中作用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形成，是建立和加强突触连接所必需的。因此，荷尔蒙和电活动都是脊椎动物大脑正常发育所必需的。对由电活动和发育中的中枢神经系统中的T3诱导的即刻早期基因(腿)的分析表明，信号通路是重叠的。早期我们发现，转录因子碱性转录元件结合蛋白(BTEB1)在啮齿类动物脑内的表达在出生后发育过程中强烈上调。我们发现BTEB1受T3的直接调控，并且BTEB1在神经元形态发生、刺激轴突延伸和分支方面发挥作用。我们的发现支持这样的观点，即BTEB1在T3依赖的神经元形态发生中起关键作用。除了激素调节外，我们最近还发现BTEB1在中枢神经系统中是一个活动调节基因。为了阐明BTEB1在哺乳动物脑发育中的作用，我们建议：1)分析BTEB1在小鼠中枢神经系统中的发育和激素依赖性表达；2)分析小鼠BTEB1启动子对甲状腺的调节；3)分析小鼠BTEB1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，并将开始整合激素依赖的信号通路和电活动依赖的通路的知识。对这些通路的详细了解对于理解基本的神经发育过程是必要的，并可能为预防和/或治疗由激素信号通路中断引起的神经疾病提供策略。

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.