The cellular and molecular mechanisms leading to the birth of mammalian neurons is unknown. In contrast, genetic studies of neurogenesis in Drosophila have identified a group of genes which directs the fate of cells in the neurogenic region, the neurogenic genes. The neurogenic genes Notch and Delta cooperately direct cellular interactions between the rising neuroblasts and adjacent cells. This process is termed lateral inhibition and is responsible for determining the fate of the undifferentiated ectoderm. Do mammalian neurons arise by the same mechanism? We propose to study mammalian neurogenesis using the mouse embryonal carcinoma cell line P19 as a model system. During neurogenesis in the P19 line, cells choose either the neuronal or fibroblast lineages, similar to Drosophila. We will seek molecules homologous to Notch and Delta from mouse, and observe their expression in differentiating P19 cells. If Notch and Delta homologues direct the cellular interactions in P19 development, then altering their expression by genetic manipulations will affect the course of neurogenesis in vitro. To find out if mammalian Notch and Delta have roles during neurogenesis in vivo, transgenic mice with either constitutive or disrupted Notch and Delta genes will be created. Mutations in these genes may produce mice with defective nervous systems, indicating a major role in mammalian neurogenesis. Defects in neurogenic genes may account for the phenotypes observed in human chromosomal abnormalities and less severe congenital neurological abnormalities.
