Pathogenesis of Tuberous Sclerosis Cortical Lesions

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DESCRIPTION (provided by applicant): During corticogenesis, radial glial cells and their progeny undergo stereotyped patterns of division and migration that coordinate neuronal production and placement, creating the layered cerebral cortex. In contrast, epileptogenic cortical lesions in the brains of individuals heterozygous for a tuberous sclerosis gene, TSC1 orTSC2, are hypercellular and display disrupted lamination and distorted gray-white matter boundaries. These malformations are thought to consist of clones derived from precursors in which a secondary mutation eliminates expression of either gene product. However, the pathogenesis of these cortical lesions in relation to normal patterns of cortical proliferation and migration has not been investigated, and the role of TSC gene products in corticogenesis remains unknown. Experiments outlined below propose to address these questions by mimicking the genetic deficiency of tuberous sclerosis in vivo. RNAi vectors targeting TSC2 transcript will be introduced into cortical progenitors through intrauterine injections into lateral ventricles of rat embryos. By observing the proliferation and migration of these labeled cells in comparison to controls, the influence of the gene defect on corticogenesis will be examined.