ROLE OF THE MED1 SUBUNIT OF MEDIATOR CO-ACTIVATOR COMPLEX IN NEURAL STEM CELLS

描述（由申请人提供）：介体共激活剂复合物（Mediator）是一种25-30蛋白复合物，在真核细胞中调节基因转录中起关键作用。介体在脑细胞中表达，但目前其确切功能尚未确定。特别是我们缺乏对与神经转录因子相互作用的中介子亚基的作用的理解。在这个试点项目中，我们将调查中介1的功能 亚基（Med 1）的神经干细胞中使用条件Med 1敲除小鼠。我们将确定神经干细胞是否在缺乏Med 1的情况下存活。我们还将使用体内和细胞培养分析的组合来定义由于缺乏Med 1而受到干扰的基本生物过程。这些实验将首次研究Med 1在神经干细胞中的作用，并为将来对Med 1和其他Mediator亚基的大规模研究提供框架。基因转录是神经细胞生命的一个基本方面，而Mediator可能是其中不可或缺的一部分，许多人类神经遗传性疾病都是由Mediator亚基突变引起的，因此这项工作对临床和转化神经科学具有重要意义。 公共卫生相关性：该项目研究了一种由30种蛋白质组成的复合物，这种蛋白质对人类大多数基因的转录至关重要。其中三种蛋白质发生突变，导致人类严重的发育障碍，包括神经管和大脑的严重畸形。关于神经干细胞、神经元和神经胶质中的复合物知之甚少，因此研究结果可能与理解神经疾病及其诊断和治疗有关。

DESCRIPTION (provided by applicant): The Mediator Co-activator Complex (Mediator) is a 25-30 protein complex that plays a pivotal role in regulating gene transcription in eukaryotic cells. Mediator is expressed in brain cells but currently its precise functions have not been defined. In particular we lack of understanding of the roles of Mediator subunits that interact wit neural transcription factors. In this pilot project we'll investigate the function of the Mediator1 subunit (Med1) in neural stem cells using conditional Med1 knockout mice. We will determine if neural stem cells survive in absence of Med1. We will also use a combination of in vivo and cell culture analyses to define the basic biological processes that are perturbed by lack of Med1. These experiments will give a first look at the role of Med1 in neural stem cells and provide a framework for future large-scale studies of this and other Mediator subunits. Gene transcription is a fundamental aspect of neural cell life and Mediator is likely to be an integral part of it. A number of human neural genetic disorders arise from mutation of Mediator subunits so this work is highly relevant to clinical and translational neuroscience. PUBLIC HEALTH RELEVANCE: This project investigates a complex of 30 proteins that is essential for transcription of most genes in humans. Three of the proteins are mutated to give serious developmental disorders in humans including severe malformations of the neural tube and brain. Very little is known about the complex in neural stem cells, neurons and glia so the results will likely be relevant to understanding neural diseases and in their diagnosis and treatment.