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