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

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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.