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 神经生物学正在了解控制 神经元的规范、分化和维护。一批 同源结构域转录因子已被证明是关键的分子角色 在神经发生的控制方面。我们已经证明了POU同源结构域 转录因子Brn3a和Brn3b在感觉神经过程中发挥重要作用 发展。Barhl1同源结构域因子选择性地在 内耳感觉神经上皮和中枢神经系统 (CNS)，提示它在感觉神经中也可能起重要作用。 发展和中枢神经系统的发展。这项提议旨在解决根本问题 脊椎动物神经发育的机制，使用 包含同源结构域的转录因子作为我们分析的模型。 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 同源结构域转录因子控制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，多种发展 将对螺旋、前庭和膝状神经节的缺陷进行分析。 单一和复合Brn3a和Brn3b基因敲除小鼠。我们的目标是了解 Brn3a和/或Brn3b调节的发育和细胞过程 在面听神经节的发育过程中。第二，找出 可能调节Brn3a选择和激活的Brn3a结合蛋白 感觉神经发育中的靶基因，新的Brn3a蛋白伙伴 将使用酵母双杂交筛选方法分离。它们的功能 相关性将通过研究它们对DNA结合的影响来进行调查， Brn3a的转录特性和亚细胞定位 研究它们的发育表达模式。第三，了解活体内 Barhl1在脊椎动物内耳和中枢神经系统发育中所起的作用 将产生并鉴定Barhl1基因敲除小鼠并分析其生物学特性 Barhl1在雏鸡小脑中强制表达的后果。一起， 这些拟议的研究将为体内研究提供重要的见解 Brn3和Barhl1转录因子的生物学活性以及 对支配哺乳动物的分子机制的一般见解 神经发生和神经紊乱。

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.