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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Special Emphasis Panel (ZNS1)
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Weill Medical College of Cornell University
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Sultan, Khadeejah T; Shi, Song-Hai (2018) Generation of diverse cortical inhibitory interneurons. Wiley Interdiscip Rev Dev Biol 7:
Sudarov, Anamaria; Zhang, Xin-Jun; Braunstein, Leighton et al. (2018) Mature Hippocampal Neurons Require LIS1 for Synaptic Integrity: Implications for Cognition. Biol Psychiatry 83:518-529
Chohan, Muhammad O; Moore, Holly (2016) Interneuron Progenitor Transplantation to Treat CNS Dysfunction. Front Neural Circuits 10:64
Sultan, Khadeejah T; Han, Zhi; Zhang, Xin-Jun et al. (2016) Clonally Related GABAergic Interneurons Do Not Randomly Disperse but Frequently Form Local Clusters in the Forebrain. Neuron 92:31-44
Tan, Xin; Liu, Wenying Angela; Zhang, Xin-Jun et al. (2016) Vascular Influence on Ventral Telencephalic Progenitors and Neocortical Interneuron Production. Dev Cell 36:624-38
Marcucci, Florencia; Murcia-Belmonte, Veronica; Wang, Qing et al. (2016) The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells. Cell Rep 17:3153-3164
Petros, Timothy J; Bultje, Ronald S; Ross, M Elizabeth et al. (2015) Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate. Cell Rep 13:1090-1095
Sultan, Khadeejah T; Shi, Wei; Shi, Song-Hai (2014) Clonal origins of neocortical interneurons. Curr Opin Neurobiol 26:125-31
Xu, Hua-Tai; Han, Zhi; Gao, Peng et al. (2014) Distinct lineage-dependent structural and functional organization of the hippocampus. Cell 157:1552-64
Mirzaa, Ghayda; Parry, David A; Fry, Andrew E et al. (2014) De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nat Genet 46:510-515

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