Transcriptional mechanisms of neural stem cell maintenance and neurogenesis

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The purpose of this project is to better understand how stem cells decide whether to multiply or to generate nerve cells. Stem cells are the crucial progenitor cells that generate all the specialized cells that form the organs in the embryo. They are also present in adult organs where they are required for maintenance and repair. Each organ has its own stem cells that generate the particular cell types of that organ. In medicine, stem cells can be used to replace cells that are damaged in diseases; for example blood stem cells are used to treat leukemias. In order to extend their usage to the treatment of other diseases, we must learn much more about how stem cells work. In particular we need to better understand the process by which a stem cell becomes specialised to generate one kind of cell rather than another. In this project, we will study how stem cells of the nervous system (called neural stem cells) become specialized in the generation of nerve cells (neurons). This process involves a profound change in the set of genes that are active: genes that present in stem cells are shut down, while genes characteristic of neurons become active. Gene activity is controlled by proteins called transcription factors. One of the main transcription factors that controls the generation of the neurons of our brains is called Ascl1. The primary purpose of this project is to understand how Ascl1 changes the set of active genes in neural stem cells so that these cells generate new neurons.Transcription factors work by binding to DNA near the genes they activate. They bring with them a multitude of other factors (called cofactors). Some of these cofactors modify the proteins that coat the DNA, others increase the contact of transcription factors with the DNA, and together they are directly involved in activating or inactivating genes. In this project, we will identify the cofactors that help the transcription factor Ascl1 activate the genes required to generate neurons. We will also identify the cofactors that prevent the inappropriate activation of genes that promote the generation of other kinds of cells. Our adult brains contain very few stem cells, which means they are limited in their ability to recover from brain damage and disease. Understanding the machinery that makes neural stem cells produce neurons can help us develop ways to replace lost brain cells. This can be done either by activating the resident stem cells, or transforming non-brain cells (e.g. skin cells) into neurons. In either case, these can then be transplanted or used to test drugs for their ability to treat neurological diseases, and hence have the potential to offer therapeutic solutions to a variety of currently untreatable conditions. This project will help in this endeavour by identifying ways to help stem cells of the brain generate more neurons.