PAX GENE REGULATION IN EMBRYOGENESIS

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In vertebrates, the nervous system develops from a simple psuedostratified epithelium, the neuroectoderm. Regionalisation of the early neuroectoderm results in the position-specific generation of different classes of neurons within the nervous system. The genetic events that regulate the postional regulation of cell fate are not understood. Differential transcriptional activity within the early nervous system is to believed to be an important factor. A family of paired box (Pax) genes that encode transcription factors are expressed in discrete regions of the early nervous system. We have recently isolated a paired box gene, Pax-3 that is expressed in the early spinal cord in dorso-ventrally restricted populations of neural progenitor cells. We have also isolated the chicken Pax-6 and Pax-7 genes which are also dorso-ventrally restricted in the spinal cord neuroepithelium. It is known that dorso-ventral polarity plays an decisive role in determining neuronal cell fate in the spinal cord, leading us to believe that the expression of Pax-3, Pax-6 and Pax-7 in neural precursors is an important regulatory step in spinal cord patterning. The experiments outlined in this grant are aimed at elucidating the regulatory interactions that establish the dorso-ventral expression of Pax-3 in the spinal cord, by identifying cis-acting sequences and tissues that control expression. The effect that loss of Pax-3 function has on the development of neural precursors cells, in particular those that give rise to the neural crest will also be examined in splotch mice, with the aim of defining those steps in neural crest development that are regulated by Pax-3. The involvement, of Pax-3 in the human hereditary disease Waardenburg Syndrome and the observation that a number of neural tube defects are present in the mouse model of Waardenburg Syndrome, splotch, are an indication of the important insights into these hereditary defects that will be gained from these studies. The long term goal of this project is to define the role of Pax-3 in neural development and begin to identify the signals that regulate its expression pattern in the vertebrate nervous system.