Abstract

Vasoactive intestinal peptide (VIP) is a potent regulator of neuroblast proliferation and survival in vitro. Administration of VIP antagonist to pregnant mice produced a pronounced microcephaly condition in offspring, providing a new model for human brain disease. VIP effects in tissue culture can also be brought about by the structurally-related neuropeptide pituitary adenylate cyclase activating peptide (PACAP). Despite the demonstrated capacity of these peptides to regulate CNS development, investigators have been unable to show that VIP or PACAP is expressed in embryonic CNS of mice at early stages. Thus, the current model contends that VIP is derived transplacentally from the mother, and thereby acts as a global regulator of embryonic CNS development. To challenge this model , sensitive in situ hybridization protocols to detect mRNA for these ligands and their receptors was developed. This combined with data obtained by Northern analyses suggest that the VIP/PACAP ligand/receptor system may be operational within the embryo at the earliest stages of neurogenesis. It is thus proposed that VIP and PACAP are derived from the embryo and act in local domains to regulate CNS development. Two novel potential target populations for VIP and PACAP were identified by this analysis, neuroepithelial cells and microglia. It is proposed that VIP and PACAP regulate the proliferation of these cells. This will be tested using dispersed cell and short-term cultures of intact embryos. In addition, the unexplained ability of these peptides to induce proliferation in some cell populations and cell cycle withdrawal in others will be examined. It is hypothesized that the differences are due to G-protein coupling of receptors to different signal transduction pathways. This will be tested using a combination of pharmacological, molecular, and biochemical approaches, including analysis of the Rs/Raf/MAP kinase pathway. The results are expected to provide important mechanistic information on how these neuropeptides play important roles in CNS development, as well as in nerve injury, neurological tumors, and degenerative diseases of the nervous system.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD034475-03
Application #
2889295
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Oster-Granite, Mary Lou
Project Start
1997-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

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

  Publications

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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