Autocrine expression and ontogenetic functions of the PACAP ligand/receptor system during sympathetic development

The superior cervical ganglion (SCG) is a well-characterized model of neura l development, in which several regulatory signals have been identified. Va soactive intestinal peptide (VIP) has been found to regulate diverse ontoge netic processes in sympathetics, though functional requirements for high pe ptide concentrations suggest that other ligands are involved. We now descri be expression and functions of pituitary adenylate cyclase-activating polyp eptide (PACAP) during SCG ontogeny, suggesting that the peptide plays criti cal roles in neurogenesis. PACAP and PACAP receptor (PAC(1)) mRNA's were de tected at embryonic days 14.5 (E14.5) through E17.5 in vivo and virtually a ll precursors exhibited ligand and receptor, indicating that the system is expressed as neuroblasts proliferate. Exposure of cultured precursors to PA CAP peptides, containing 27 or 38 residues, increased mitogenic activity 4- fold. Significantly, PACAP was 1000-fold more potent than VIP and a highly potent and selective antagonist entirely blocked effects of micromolar VIP, consistent with both peptides acting via PAC(1) receptors. Moreover, PACAP potently enhanced precursor survival more than 2-fold, suggesting that pre viously defined VIP effects were mediated via PAC(1) receptors and that PAC AP is the more significant developmental signal. In addition to neurogenesi s, PACAP promoted neuronal differentiation, increasing neurite outgrowth 4- fold and enhancing expression of neurotrophin receptors trkC and trkA. Sinc e PACAP potently activated cAMP and PI pathways and increased intracellular Ca2+, the peptide may interact with other developmental signals. PACAP sti mulation of precursor mitosis, survival, and trk receptor expression sugges ts that the signaling system plays a critical autocrine role during sympath etic neurogenesis. (C) 2000 Academic Press.