Alterations in cell cycle events that disrupt neuronal production are likely to underlie cortical malformations associated with microcephaly. This project examines the dynamics of proliferation in the embryonic telencephalon in normal and mutant mice to gain insights into mechanisms that regulate neurogenesis in health and disease. Specific subsets of neocortical neurons arise from spatially distributed proliferative zones and involve distinct molecular signals. Most cortical inhibitory interneurons originate in the subcortical telencephalon, while excitatory projection neurons arise in the cortical telencephalon. These cell types converge in the developing neocortex to form characteristic cortical circuits. The experiments outlined in this proposal will examine how patterns of neurogenesis differ between the cortical and subcortical telencephalon and within the two neurogenic niches, the ventricular (VZ) and subventricular (SVZ) zones. We will explore how neurogenesis may be modulated by intrinsic and epigenetic factors within these regions and how regional alterations in the pattern of division might contribute to microcephaly. We will use techniques of retroviral lineage analysis, optical imaging, time-lapse confocal microscopy, and electrophysiology to characterize progenitor divisions and answer the following questions: How do patterns of asymmetric and symmetric progenitor cell divisions generate neuronal diversity in the developing subcortical telencephalon? Do spatially distinct neurogenic niches determine the mode of cell division and patterns of neurogenesis? Does cleavage plane determine or predict progenitor fate? Do cell-extrinsic, fate determining signals such as GABA activate cortical VZ cells and promote symmetric progenitor divisions? Do regulators of cell cycle progression such as cyclin D2 influence cell cycle dynamics by promoting neurogenic division? Does the secreted fate-influencing factor Sonic Hedgehog regulate neurogenesis in the subcortical VZ and SVZ? The critical balance between excitation and inhibition underlies the regulation of excitability in the developing and mature cortex, and an imbalance can 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 this critical balance is maintained.
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