Cell Cycle Regulation as Determinant of Brain Size and Histogenesis

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

Previous studies indicate a role for G1 active cyclin D2 (cD2) in the patterning and function of mammalian[unreadable] brain. Unexpected of a cell cycle protein, loss of cD2 leads to small brains and to selective loss of[unreadable] interneurons in the cerebellum. This project will examine cD2's role in the regulation of progenitor cell[unreadable] divisions and genesis of telencephalic interneurons. Pilot data indicate that, like the striking deficits in[unreadable] cerebellar granule and stellate neurons in this model, cD2-/- neocortex and hippocampus contain[unreadable] significantly fewer parvalbumin (Pv) containing interneurons while seeming to spare calretinin (CLR) and[unreadable] somatostatin (SSN) subtypes. These mice display rare spontaneous seizures and studies with Project 4[unreadable] indicate cD2 nulls have a lower seizure threshold to drugs affecting GABAergic systems. Four hypotheses[unreadable] will be pursued in four Specific Aims:[unreadable] 1. cD2 regulates the number and differentiation of selected neural precursors in cerebral cortex.[unreadable] Experiments will determine:[unreadable] a. cD2 expression mapped during histogenesis of the telencephalon.[unreadable] b. which progenitor pools are most affected in cD2 null brain.[unreadable] c. which neuronal types are dependent upon cD2 expression during histogenesis.[unreadable] 2. Reduced cell division can affect subpopulations of cortical interneurons disproportionately. The[unreadable] interneuron subtypes lost in cD2-/- will be identified and compared with projection neuron[unreadable] populations.[unreadable] 3. cD2 promotes symmetric progenitor divisions, favoring the secondary proliferative population,[unreadable] to keep precursors in cycle that would otherwise exit. Studies will use:[unreadable] a. time-lapse imaging of progenitors in slice cultures from WT, cD2-/- and cD1-/- mice (in[unreadable] collaboration with Project 3).[unreadable] b. acute over- and under-expression of cD2 protein in vivo and in vitro.[unreadable] 4. Conditional loss of cD2 can be used to probe cortical vs. subcortical contributions of cD2 to[unreadable] brain structure and behavior. A floxP cD2 mouse will be produced and used to inactivate cD2 in[unreadable] MGE or neocortex/hippocampus.[unreadable] a. structural consequences will be examined in Project 1.[unreadable] b. behavioral studies will be pursued in Project 4.