Regulation of precursor proliferation in the embyronic cortex: The anti-mitogenic role of pituitary adenylate cyclase-activating polypeptide (PACAP)

In the nervous system, the number of neurons and their relative abundance are fundamental determinants of neural function and behavior. Neurological analyses have revealed that several major mental disorders in humans may be related to abnormal generation of the numbers or types of neurons during development. Thus, exploration of the cellular and molecular mechanisms regulating neuronal precursor proliferation, and consequently production of neurons, may shed light on the etiologies and therapies of these disorders. Although mitogens stimulating proliferation have been identified, little is known about anti-mitogenic factors. I now report that the neuropeptide PACAP inhibits precursor proliferation by inhibiting cell cycle progression in the developing cerebral cortex.; Initially, since the PACAP receptor has splice variant isoforms activating distinctive second messenger pathways, the expression pattern of the isoforms was characterized. Throughout the neurogenic period, the isoforms are differentially expressed in the cortex, suggesting the PACAP system serves distinct functions by altering its receptors and intracellular signaling.