Cells of the neuroectoderm choose to become neurons after receiving proper environmental cues, both stimulatory and inhibitory. Much is known about factors that induce neurogenesis, but inhibitory regulation of neurogenesis is poorly understood. Experiments in invertebrates reveal that signals transmitted through the Notch/lin 12/glp1 family of transmembrane proteins determine the fate of individual cells by inhibiting differentiation of certain cell fates. Preliminary experiments by the applicants and others indicate that signaling via vertebrate Notch and Delta homologous is central to the choice of a neural fate in higher animals. However, the details of how Notch-Delta signaling guides mammalian neurogenesis have so far remained elusive. The applicants propose to evaluate Notch signaling in mammalian neurogenesis in the P19 cell line where neurogenesis and myogenesis respond to Notch signals. Using the tools developed and tested in vitro, the applicants plan to study the role of Notch signals on developing cerebral cortex neurons and in olfactory neurons in vivo. They then propose to determine the intracellular mechanisms of Notch-ligand signal transduction using these model systems as biological assays.
