Regulation of cell cycle dynamics is a contributing mechanism for generating cortical diversity and regulating the balance between excitatory and inhibitory neurons. In early telencephalic development, symmetrical cell divisions expand the pool of neuronal progenitor cells. With the onset of neurogenesis in the cortex, the progenitors of the excitatory cells undergo asymmetric divisions within the ventricular zone (VZ) to generate neurons. The key feature of asymmetric divisions is the unequal inheritance of intrinsic determinants. However, both cell-intrinsic and cell-extrinsic factors influence neuronal production. In this proposal, we will use techniques of retroviral lineage analysis, optical imaging, time-lapse confocal microscopy, and electrophysiology to characterize progenitor cell divisions and to answer the following questions: How do patterns of asymmetric and symmetric progenitor cell divisions in the cortical proliferative zone in vivo generate neuronal diversity in the developing neocortex? Do spatially distinct neurogenic niches determine the mode of cell division and patterns of neurogenesis? Does cleavage plane determine or predict progenitor fate? Does segregation of the cell-intrinsic factor Numb determine symmetry/asymmetry of division and how does this differ at different stages of corticogenesis? Do cell-extrinsic fate-determining signals such as GABA activate cortical VZ cells and promote symmetric progenitor divisions to expand the precursor pool? Do GABAergic interneurons originating in the striatum promote the generation of excitatory pyramidal cells in the developing cortex? These related yet independent questions are the subject of the current proposal. The critical balance between excitation and inhibition underlies the regulation of excitability in the developing and mature cortex and an imbalance is known to have significant pathological effects ranging from subtle disorders associated with seizures, to devastating cortical malformations with intractable epilepsy. The data from these experiments will help us to understand how the critical balance of excitatory and inhibitory cells is regulated and how this affects brain development.
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