Granule cells of the cerebellum arise from a secondary germinal zone, the external granule layer (EGL), where granule cell progenitors (GCPs) proliferate in response to stimulation with Sonic hedgehog (Shh). Deregulation of Shh signaling in the cerebellum results in medulloblastoma (MB) in both mice and humans. Pituitary adenylate cyclase-activating polypeptide (PACAP), a ubiquitous and multifunctional polypeptide, is produced by the Purkinje cells of the cerebellum and by GCPs during development and binds to specifi c PAC1 receptors on GCPs. It has been shown that (1) PACAP signaling prevents apoptosis of GCPs exposed to mutiple insults, (2) it is capable of counteracting the proliferative effect of Shh on these cells and (3) its deletion in ptc1+/- mice signifi cantly increases MB incidence. In the current study we present evidence suggesting that PACAP antagonizes Shh signaling in GCPs through activation of protein kinase A. Our results also imply that PKA activation is regulated by Shh- and PACAP-activated signaling pathways independently of each other. We also show through microarray analysis of cultured GCPs that PACAP and Shh activate distinct sets of genes in these cells and that virtually all Shh-induced changes in gene expression can be effi ciently inhibited by 10 nM PACAP.
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