Roles of Homeodomain Factors in Neural Development

描述（由申请人提供）：发展中的一个中心问题 神经生物学是了解控制神经元的分子调控网络， 神经元的特化、分化和维持。一些 同源结构域转录因子已被证明是关键的分子参与者 神经发生的控制。我们已经证明POU同源结构域 转录因子Brn 3a和Brn 3b在感觉神经元性神经元损伤中起重要作用 发展Barhl 1同源结构域因子选择性表达于 内耳感觉神经上皮以及中枢神经系统 (CNS)这表明它也可能在感觉神经性 发展和CNS发展。该提案旨在解决基本的 脊椎动物神经发育的机制， 同源结构域的转录因子作为我们的分析模型。 本提案中概述的研究旨在提供综合的 了解分子和细胞机制的方法， 同源域转录因子调控感觉神经发育和中枢神经系统 发展将追求三个具体目标。第一，各种发展 缺陷将被分析在螺旋，前庭和膝状神经节， 单一和复合Brn 3a和Brn 3b敲除小鼠。我们的目标是了解 Brn 3a和/或Brn 3b调节的体内发育和细胞过程 在面听神经节的发育过程中。第二，识别 Brn 3a结合蛋白可调节Brn 3a的选择和激活， 感觉神经发育过程中的靶基因，新的Brn 3a蛋白伴侣 将使用酵母双杂交筛选方法分离。其功能 将通过研究它们对DNA结合的影响来研究相关性， Brn 3a的转录特性和亚细胞定位， 研究它们的发育表达模式三、了解体内 Barhl 1在脊椎动物内耳和中枢神经系统发育中的作用，我们 将产生和表征Barhl 1敲除小鼠，并分析其生物学特性。 Barhl 1在鸡小脑中强制表达的后果。在一起， 这些拟议的研究将提供重要的见解， Brn 3和Barhl 1转录因子的生物活性以及 对控制哺乳动物的分子机制的一般见解 神经发生和神经系统疾病。

DESCRIPTION (provided by applicant): A central issue in developmental neurobiology is understanding the molecular regulatory networks that control neuronal specification, differentiation and maintenance. A number of homeodomain transcription factors have been shown to be key molecular players in the control of neurogenesis. We have demonstrated that the POU homeodomain transcription factors Brn3a and Brn3b play essential roles during sensorineural development. The Barhl1 homeodomain factor is selectively expressed in the inner ear sensorineural epithelium as well as in the central nervous system (CNS), suggesting that it may also play an important role in sensorineural development and CNS development. This proposal aims to address the fundamental mechanisms governing vertebrate neural development, using homeodomain-containing transcription factors as models for our analyses. The studies outlined in this proposal are designed to provide integrated approaches for understanding the molecular and cellular mechanisms by which homeodomain transcription factors control sensonneural development and CNS development. Three specific aims will be pursued. First, various developmental defects will be analyzed in the spiral, vestibular and geniculate ganglia of single and compound Brn3a and Brn3b knockout mice. The goal is to understand in vivo the developmental and cellular processes that Brn3a and/or Brn3b regulate during development of the facial-stato-acoustic ganglion. Second, to identify Brn3a binding proteins that may modulate Brn3a selection and activation of target genes during sensorineural development, novel Brn3a protein partners will be isolated using a yeast two-hybrid screening approach. Their functional relevance will be investigated by studying their effects on DNA-binding, transcriptional property and subcellular localization of Brn3a, and by examining their developmental expression patterns. Third, to understand in vivo the roles that Barhl1 plays during vertebrate inner ear and CNS development, we will generate and characterize Barhl1 knockout mice and analyze the biological consequences of forced expression of Barhl1 in the chick cerebellum. Together, these proposed studies will provide important insights into the in vivo biological activities of Brn3 and Barhl1 transcription factors as well as general insights into the molecular mechanisms that govern mammalian neurogenesis and neurological disorders.