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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD034475-05A1
Application #
6544010
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Oster-Granite, Mary Lou
Project Start
1997-09-01
Project End
2007-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$274,500
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Niewiadomski, Pawel; Zhujiang, Annie; Youssef, Mary et al. (2013) Interaction of PACAP with Sonic hedgehog reveals complex regulation of the hedgehog pathway by PKA. Cell Signal 25:2222-30
Yan, Yan; Zhou, Xiaofeng; Pan, Zui et al. (2013) Pro- and anti-mitogenic actions of pituitary adenylate cyclase-activating polypeptide in developing cerebral cortex: potential mediation by developmental switch of PAC1 receptor mRNA isoforms. J Neurosci 33:3865-78
Hirose, Megumi; Niewiadomski, Pawel; Tse, Gary et al. (2011) Pituitary adenylyl cyclase-activating peptide counteracts hedgehog-dependent motor neuron production in mouse embryonic stem cell cultures. J Neurosci Res 89:1363-74
Alexandre, David; Alonzeau, Jessy; Bill, Brent R et al. (2011) Expression analysis of PAC1-R and PACAP genes in zebrafish embryos. J Mol Neurosci 43:94-100
Marquez, Paul; Bebawy, David; Lelievre, Vincent et al. (2009) The role of endogenous PACAP in motor stimulation and conditioned place preference induced by morphine in mice. Psychopharmacology (Berl) 204:457-63
Nemetz, Nicole; Abad, Catalina; Lawson, Greg et al. (2008) Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP. Int J Cancer 122:1803-9
Niewiadomski, Pawel; Coute-Monvoisin, Anne-Claire; Abad, Catalina et al. (2008) Mice deficient in both pituitary adenylyl cyclase-activating polypeptide and vasoactive intestinal peptide survive, but display growth retardation and sex-dependent early death. J Mol Neurosci 36:200-7
Nakano, Ichiro; Masterman-Smith, Michael; Saigusa, Kuniyasu et al. (2008) Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J Neurosci Res 86:48-60
Lelievre, Vincent; Seksenyan, Akop; Nobuta, Hiroko et al. (2008) Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Dev Biol 313:359-70
Lelievre, V; Favrais, G; Abad, C et al. (2007) Gastrointestinal dysfunction in mice with a targeted mutation in the gene encoding vasoactive intestinal polypeptide: a model for the study of intestinal ileus and Hirschsprung's disease. Peptides 28:1688-99

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