OPPOSING MITOGENIC REGULATION BY PACAP IN SYMPATHETIC AND CEREBRAL CORTICAL PRECURSORS CORRELATES WITH DIFFERENTIAL EXPRESSION OF PACAP RECEPTOR (PAC(1)-R) ISOFORMS

Neurogenesis in the peripheral and central nervous systems proceeds in region-specific fashion, although underlying mechanisms remain undefi ned. Emerging evidence indicates that the neuropeptide PACAP and its G -protein-coupled receptor are expressed widely in the embryonic brain, suggesting that the ligand/receptor system plays a role in developmen t. We found previously that PAC(1)-R activation elicited opposing mito genic effects in neurogenetic cultures, stimulating peripheral sympath etic neuroblasts while inhibiting cerebral cortical precursors, We hav e now defined the expression of PAC(1)-R mRNA isoforms and activation of second-messenger pathways in these model populations, Sympathetic n euroblasts express the ''hop'' receptor isoform, through which PACAP e licits increased levels of cAMP and activation of the PI signaling pat hway. In contrast, cerebral cortical precursors express primarily the ''short'' (non-insert) receptor isoform and exhibit increased cAMP lev els alone following PACAP treatment. Thus, opposing mitogenic regulati on in sympathetic and cortical precursors correlates with differential receptor isoform expression and distinct second-messenger signaling. In addition to receptor, PACAP ligand mRNA was expressed by both popul ations, suggesting that the peptide is produced and acts locally to re gulate precursor proliferation, These observations indicate that the P ACAP ligand/receptor system is expressed in both the peripheral and ce ntral nervous system during development. More generally, these studies suggest that widely expressed extracellular factors mediate region-sp ecific neurogenesis by activating lineage-restricted receptor isoforms and intracellular pathways, (C) 1998 Wiley-Liss, Inc.