 | 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
diciccem@umdnj.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.
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