Alterations in cell cycle events that disrupt neuronal production are likely to underlie cortical malformationsassociated with microcephaly. This project examines the dynamics of proliferation in the embryonictelencephalon in normal and mutant mice to gain insights into mechanisms that regulate neurogenesis inhealth and disease. Specific subsets of neocortical neurons arise from spatially distributed proliferativezones and involve distinct molecular signals. Most cortical inhibitory interneurons originate in the subcorticaltelencephalon, while excitatory projection neurons arise in the cortical telencephalon. These cell typesconverge in the developing neocortex to form characteristic cortical circuits. The experiments outlined in thisproposal will examine how patterns of neurogenesis differ between the cortical and subcortical telencephalonand within the two neurogenic niches, the ventricular (VZ) and subventricular (SVZ) zones. We will explorehow neurogenesis may be modulated by intrinsic and epigenetic factors within these regions and howregional alterations in the pattern of division might contribute to microcephaly.We will use techniques of retroviral lineage analysis, optical imaging, time-lapse confocal microscopy, andelectrophysiology to characterize progenitor divisions and answer the following questions: How do patternsof asymmetric and symmetric progenitor cell divisions generate neuronal diversity in the developingsubcortical telencephalon? Do spatially distinct neurogenic niches determine the mode of cell division andpatterns of neurogenesis? Does cleavage plane determine or predict progenitor fate? Do cell-extrinsic, fatedetermining signals such as GABA activate cortical VZ cells and promote symmetric progenitor divisions? Doregulators of cell cycle progression such as cyclin D2 influence cell cycle dynamics by promoting neurogenicdivision? Does the secreted fate-influencing factor Sonic Hedgehog regulate neurogenesis in the subcorticalVZ and SVZ? The critical balance between excitation and inhibition underlies the regulation of excitability inthe developing and mature cortex, and an imbalance can have significant pathological effects ranging fromsubtle 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.
| 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 |
| Tyson, Jennifer A; Anderson, Stewart A (2014) GABAergic interneuron transplants to study development and treat disease. Trends Neurosci 37:169-77 |
| Gilani, Ahmed I; Chohan, Muhammad O; Inan, Melis et al. (2014) Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition. Proc Natl Acad Sci U S A 111:7450-5 |
| Sultan, Khadeejah T; Shi, Wei; Shi, Song-Hai (2014) Clonal origins of neocortical interneurons. Curr Opin Neurobiol 26:125-31 |
Showing the most recent 10 out of 36 publications
