Sox transcription factor function and redundancy in the central nervous system

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During the early development of complex multicellular organisms such as humans, cells must adopt particular fates in order to generate the variety of tissues and organs necessary to build the embryo. Early in development, specific sets of cells gain the ability to subsequently develop the various cell types of the nervous system. Once specified, this cell population will divide in an undifferentiated state, known as neural stem cells, to generate sufficient cells that can subsequently be directed to make neurons and other cell types necessary to build a nervous system. Not only are these neural stem cells important for normal development, they may also be isolated or generated from other cell types and grown in the laboratory. It is hoped that neural stem cells will in the future provide a route for the treatment of human neurological disorders that are currently intractable. Underpinning the developmental choices cells make and their maintenance of the stem cell state are sets of proteins known as transcription factors (TFs) that act in the cell nucleus to control the specific sets of genes that define the neural state. One such class of TFs important in neural stem cells are known as Sox proteins. While there has been considerable work aimed at addressing how Sox proteins act to control the stem cell state in mammals, this work is complicated by the fact that three closely related proteins are present in neural cells at the same time and compensate for each other when mutations are made. This makes it difficult to understand how these proteins function and this is an important issue since they play such a crucial role in stem cell biology.The fruit fly, Drosophila melanogaster, is a model system widely used in the laboratory to study basic aspects of the genetics and development of complex multicellular animals. In general, the fly offers a much simpler system for studying basic biological processes since it is easy to maintain, easy to manipulate genetically and does not raise concerns about excessive animal use in experimental work. Over the years it has been established that many of the cell fate choices fly cells make are governed by sets of regulatory proteins that are very closely related to mammalian proteins performing similar roles. In the case of Sox proteins acting in the nervous system, we have shown the fly offers a simpler experimental system that still shares some of the complexity shown by mammalian proteins. Instead of three Sox proteins, the fly has only two, and we have shown that mouse and human Sox proteins are able to efficiently function in the fly.Sox proteins function by controlling sets of genes that define the phenotype of a cell and our recent work has shown that Sox proteins in fly and mouse neural stem cells control many of the same genes. However, despite a considerable amount of work on both mammalian and fly Sox proteins we still have a very poor mechanistic understanding of how they act to regulate their target genes. If we are to generate and manipulate neural stem cells in that lab for therapeutic uses, it is important we fully understand the roles Sox proteins play, particularly since they are now often used to produce and maintain stem cells. We will perform a detailed analysis of both fly and mammalian Sox proteins in the Drosophila model to understand more fully how they recognize the specific genes they control in the nucleus, how related Sox proteins act together and are able to compensate for each others loss and explore exactly why important cells types such as neural stem cells need to express closely related Sox proteins. Although our work is performed in the fly, the fact that Sox function is so similar in fly and mouse means that what we learn will be relevant to human biology.