Although progress has been made in identifying factors that regulate the proliferation and differentiation of granule cell precursors (GCPs), how these factors exert their effects on the cell cycle and differentiation have not been fully elucidated. In this proposal, the possibility that meningeal signals modulate Sonic hedgehog (Shh)-induced GCP proliferation and pituitary adenylate cyclase activating peptide (PACAP)-mediated differentiation will be examined. Building on work that suggests that Myc and CDK 2 may participate in Shh-induced proliferation, dominant negative forms of these proteins or their co-factors will be used to investigate their role in Shh-induced proliferation. The transcription factors Gli1, Zic1, and Zipro1 are known to influence granule cell proliferation. Overexpression of these transcription factors will be coupled with microarray analysis in order to identify pathways important to GCP proliferation. Taken together, these experiments will contribute to our understanding of neural proliferation and differentiation, and will aid in understanding clinical disorders such as medulloblastoma, an aggressive form of pediatric brain cancer, that may arise from the dysregulated proliferation of GCPs.
