Opposing mitogenic regulation by PACAP in sympathetic and cerebral cortical precursors correlates with differential expression of PACAP receptor (PAC1-R) isoforms.

Neurogenesis in the peripheral and central nervous systems proceeds in region-specific fashion, although underlying mechanisms remain undefined. 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 development. We found previously that PAC1-R activation elicited opposing mitogenic effects in neurogenetic cultures, stimulating peripheral sympathetic neuroblasts while inhibiting cerebral cortical precursors. We have now defined the expression of PAC1-R mRNA isoforms and activation of second-messenger pathways in these model populations. Sympathetic neuroblasts express the "hop" receptor isoform, through which PACAP elicits increased levels of cAMP and activation of the PI signaling pathway. In contrast, cerebral cortical precursors express primarily the "short" (non-insert) receptor isoform and exhibit increased cAMP levels alone following PACAP treatment. Thus, opposing mitogenic regulation 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 populations, suggesting that the peptide is produced and acts locally to regulate precursor proliferation. These observations indicate that the PACAP ligand/receptor system is expressed in both the peripheral and central nervous system during development. More generally, these studies suggest that widely expressed extracellular factors mediate region-specific neurogenesis by activating lineage-restricted receptor isoforms and intracellular pathways.