Emanuel DiCicco-Bloom Professor UMDNJ Dept. of Neuroscience & Cell Biology/Pediatrics RWJMS Research & Public Health Room 362 683 Hoes Lane Piscataway. NJ 08854 (732) 235-5381 FAX - 4990 dicicco@cabm.rutgers.edu

Regulation of developmental and adult neurogenesis. cell cycle mechanisms

While 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 Publications

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. Apr 12. [Epub ahead of print]

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)
Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E. Neurotoxicology. 27(6):970-81.

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.

Suh. J.. Lu. N.. Nicot. A.. Tatsuno. I. and DiCicco-Bloom. E. (2001) PACAP is an anti-mitogenic signal in developing cerebral cortex. Nature Neuroscience 4:123-24.

Cheng. Y.. Tao. Y.. Black. I.B.. and DiCicco-Bloom. E. (2001) A single peripheral injection of basic fibroblast growth factor (bFGF) stimulates granule cell production and increases cerebellar growth in new born rats. J Neurobiol. 46:220-229.

Nicot. A and DiCicco-Bloom. E. (2001) Regulation of neuroblast mitosis is determined by PACAP receptor isoform expression. Proc. Natl. Acad. Sci. (USA) 98:4758-4763.

Zhou. X.. Suh. J.. Cerretti. D.P.. Zhou. R.. and DiCicco-Bloom. E. (2001) Ephrins stimulate neurite outgrowth during early cortical neurogenous. (submitted).

DiCicco-Bloom. E.. Deutsch. P.J.. Maltzman. J.. Zhang. J.. Pintar. J.E.. Zheng. J.. Friedman. W.F. and Zaremba. T. (2000) Autocrine expression and ontogenetic functions of the PACAP ligand/receptor system during sympathetic development. Dev. Biol. 219:197-213.

Gao. P.-P.. Sun. C.-H.. Zhou. X.-P.. DiCicco-Bloom. E.. and Zhou. R. (2000) Ephrins stimulate or inhibit neurite outgrowth and survival as a function of neuronal cell type. J. Neurosci. Res. 60:427-436.