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Regulation of developmental and adult neurogenesis. cell cycle mechanismsWhile disorders of brain ontogeny underlie the majority of cognitive and behavioral disturbances of childhood. little is known about regulating early nervous system development. Further. the recent discovery of ongoing adult neurogenesis raises the possibility that newly generated cells contribute to learning and memory. representing an as yet unrealized resource to repair the disordered brain. Our studies focus on defining molecular signaling systems and mechanisms that control normal production and survival of neurons in brain region-specific manner. and determining whether factors active during development also play roles in adulthood. The strategy involves characterizing distinct neuronal precursor populations. defining lineage-specific signals. and analyzing mediating cell cycle machinery. Mechanisms defined in vitro are subsequently tested for relevance in the developing and adult animal. Three major directions under current study include: 1. The role of environmental levels of bFGF in regulating neurogenesis in neonatal cerebellum and hippocampal dentate gyrus is being defined. A single. peripheral injection of bFGF results in long term increases in cerebellar and hippocampal cell numbers. and granule neurons specifically. whereas bFGF deletion mutants exhibit diminished neuronal populations. As these changes are life long. behavioral consequences are under investigation. 2. The 38 amino acid neuropeptide. PACAP. and its G-protein coupled receptor are expressed throughout the CNS and PNS proliferative zones in the embryo. and PACAP stimulates or inhibits precursor mitosis in distinct lineages according to receptor isoform expression. Studies in embryonic cerebral cortex. using transuterine. intraventricular injection (ICV) in embryos. or after ICV in adults. demonstrates that PACAP serves as an anti-mitogenic signal to neural precursors. Hence. abnormalities in PACAP ligand/receptor signaling may yield abnormal neuron numbers. whereas blocking inhibition may allow new cells to be generated to replete neuronal loss. In contrast. PACAP stimulates new neuron production in sympathetic and cerebellar granule precursors. demonstrating population-specific effects whose receptor dependency and intracellular signaling is being defined. 3. The role of cell cycle machinery in mediating pro-mitogenic and anti-mitogenic factors in culture and in vivo is under study. PACAP anti-mitogenic functions in the embryo depend on select increases in the cyclin-dependent kinase (CDK) inhibitors. which associate with CDKs to block the G1-S phase transition in primary neuronal precursors. Cell cycle deletion mutants. and normal as well as transfected primary neurons are being used to examine mediating molecular mechanisms. Selected PublicationsHalladay AK, Amaral D, Aschner M, Bolivar VJ, Bowman A, DiCicco-Bloom E, Hyman SL, Keller F, Lein P, Pessah I, Restifo L, Threadgill DW. (2009) Animal models of autism spectrum disorders: information for neurotoxicologists. Neurotoxicology. 30(5):811-21. Mairet-Coello G, Tury A, DiCicco-Bloom E. (2009) Insulin-like growth factor-1 promotes G(1)/S cell cycle progression through bidirectional regulation of cyclins and cyclin-dependent kinase inhibitors via the phosphatidylinositol 3-kinase/Akt pathway in developing rat cerebral cortex. J Neurosci. 29(3):775-88. Ye W, Mairet-Coello G, Pasoreck E, Dicicco-Bloom E. (2008) Patterns of p57Kip2 expression in embryonic rat brain suggest roles in progenitor cell cycle exit and neuronal differentiation. Dev Neurobiol. 69(1):1-21. Falluel-Morel A, Tascau LI, Sokolowski K, Brabet P, Dicicco-Bloom E. (2008) Granule cell survival is deficient in PAC1(-/-) mutant cerebellum. J Mol Neurosci. 36(1-3):38-44. Falluel-Morel A, Sokolowski K, Sisti HM, Zhou X, Shors TJ, Dicicco-Bloom E. (2007) Developmental mercury exposure elicits acute hippocampal cell death, reductions in neurogenesis, and severe learning deficits during puberty. J Neurochem. 103(5):1968-81. Burke K, Cheng Y, Li B, Petrov A, Joshi P, Berman RF, Reuhl KR, DiCicco-Bloom E. (2006) DiCicco-Bloom. E.. Lelièvre. V.. Zhou. X.. Rodriguez. W.. Tam. J.. and Waschek. JA. (2004) Embryonic expression and multi-functional actions of the natriuretic peptides and receptors in the developing nervous system. Dev Biol. 271:161-75. Nicot. A. Otto. T. Brabet. P. and DiCicco-Bloom. E.. (2004) Altered social behavior in pituitary adenylate cyclase-activating polypeptide (PACAP) type I receptor deficient mice. J Neurosci. 24:8786-8795. Nicot. A. Lelièvre. V. Tam. J. Waschek. J.A. and DiCicco-Bloom. E. (2002) Pituitary adenylate Cyclase-Activating Polypeptide (PACAP) and Sonic Hedgehog (Shh) interact to control Cerebellar Granule Precursor Cell Proliferation. J Neurosci 22:9244-54. Cheng. T.. Black. I.B. and DiCicco-Bloom. E. (2002) Hippocampal granule neuron production and population size are regulated by levels of bFGF. Eur. J. Neurosci. 15:3-12. Carey. R.G.. Li. B. and DiCicco-Bloom. E. (2002) Pituitary adenylate cyclase activating polypeptide anti-mitogenic signaling in cerebral cortical progenitors is regulated by p57Kip2-dependent CDK2 activity. J. Neurosci. 22:1583-1591. |
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