Pituitary adenylyl cyclase activating peptide (PACAP) is a neuropeptide in the secretin family with potential significance in a range of brain afflictions, including mental retardation, autism, neurodegenerative diseases, CNS injury, and brain tumors. Because PACAP and PACAP receptor gene expression is widespread at very early stages of neurogenesis, several hypotheses regarding specific developmental actions of this peptide have been proposed. For example, in vitro and in vivo studies indicate that PACAP acts as an autocrine or paracrine factor to control neural cell proliferation, survival and phenotype in several regions of the developing nervous system. It is propose here that PACAP acts to control processes in the developing hindbrain and cerebellum by antagonizing the action of the mitogen/patterning factor sonic hedgehog (Shh) via protein kinase A activation.In this proposal, genetic models will be used to identify and investigate the essential developmental roles of PACAP and the specific mechanisms involved. These models include 1) mice in which the PACAP gene have been disrupted by homologous recombination, 2) transgenic mice that express an overactive Shh signaling system due to a mutation in the Shh receptor/tumor suppressor gene ptc-1, 3) a Xenopus embryo mRNA injection system which overexpresses PACAP, and 4) PACAP-responsive embryonic hindbrain and postnatal cerebellar granule cell precursor cultures. The action of PACAP will be investigated in these models using morphologic and phenotypic markers, gene expression, and indicators of cell proliferation and apoptosis. The results are expected to reveal critical developmental functions of PACAP and provide information on the relevant signaling pathways. The work may lead to new strategies for the diagnosis and treatment of diseases of brain development, degenerative diseases and brain tumors.
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