Zinc finger proteins involved in neuronal development

描述(申请人提供)：锌在发育过程中起着至关重要的作用，特别是在大脑中，锌的浓度很高。锌水平必须严格控制，因为锌稳态的破坏与各种疾病有关，从阿尔茨海默病到中风引起的缺血，再到精神分裂症。大脑中的大部分锌被发现与蛋白质结合，包括锌指转录因子。在神经元发育中起关键作用的两个锌指转录因子是神经锌指因子-1(NZF-1)和髓鞘转录因子1(MyT1)。这些蛋白质分别对神经元和少突胶质细胞的发育是必不可少的，这些蛋白质的失调与脑癌、精神分裂症和智力低下有关。尽管它们在神经元发育中很重要，但人们对这些蛋白质的结构/功能知之甚少。NZF-1和MyT1都含有多个同源的锌结合结构域，但识别和调控完全不同的基因。这一建议的目的是确定使这两种蛋白质能够调控不同基因的因素，并了解锌介导的DNA识别机制。提出了以下两个目标：1)5个锌指结构域在NZF-1中的作用是什么？2)6个锌指结构域在MyT1中的作用是什么，与NZF-1有什么不同？将采用一种系统的方法，使用生化和生物物理方法。了解这些蛋白质的基本生化和生物物理性质将是了解这些高度同源的转录因子如何调节神经元发育的第一步，并为错误调控如何导致神经疾病提供关键的见解。

DESCRIPTION (provided by applicant): Zinc plays a crucial role in development, particularly in the brain where it is found at high concentrations. Zinc levels must be tightly controlled as disruption of zinc homeostasis has been linked to a variety of disorders ranging from Alzheimer's disease to ischemia induced by cerebral stroke to schizophrenia. Most zinc in the brain is found bound to proteins, including zinc finger transcription factors. Two zinc finger transcription factors that play a crucial role in neuronal development are Neural Zinc Finger Factor-1 (NZF-1) and Myelin Transcription Factor 1 (MyT1). These proteins are essential for the development of neurons and oligodendrocytes, respectively and misregulation of these proteins has been associated brain cancer, schizophrenia, and mental retardation. Despite their importance in neuronal development, relatively little is known about the structure/function of these proteins. Both NZF-1 and MyT1 contain multiple, homologous zinc binding domains yet recognize and regulate completely different genes. This proposal is aimed at identifying the factors that enable the two proteins to regulate different genes and at understanding the mechanism of zinc mediated DNA recognition. The following two aims are proposed: 1) What are the roles of the 5 zinc finger domains in NZF-1? and 2) What are the roles of the 6 zinc finger domains in MyT1 and how do these differ from those of NZF-1? A systematic approach, using biochemical and biophysical methodologies, will be taken. Understanding the fundamental biochemical and biophysical properties of these proteins will be a first step towards understanding how these highly homologous transcription factors function to regulate neuronal development and provide key insights into how misregulation may lead to neurological disorders.