Tuberous sclerosis complex (TSC) is an autosomal dominant tumor predisposition disorder affecting approximately 1/6000 individuals. Patients have mutations in either the TSC1 or TSC2 gene, encoding the proteins hamartin and tuberin, and have similar, but not identical, phenotypes. Substantial morbidity and mortality are caused by brain lesions such as tubers, subependymal nodules, and other neuronal heterotopias. These lesions are associated with seizures, autism, and other developmental disabilities. Remarkably, little is known about the pathogenesis of these lesions or how they lead to developmental disabilities. The overall goal of this project is to model, identify and study the neurodevelopmental defects that lead to the brain lesions of TSC. We have engineered a novel mouse model of the neuropathology of TSC by selectively deleting the Tsc2 gene in radial glial progenitor cells of the developing brain. These mice die from seizures between 3 weeks and a month of age and have enlarged brains, neuronal migration defects composed of giant cells, and increased numbers of astrocytes. These brain lesions are very similar to those described in humans with TSC and provide a novel model in which to study the in vivo neurodevelopmental aspects of TSC.
The specific aims are: 1) to investigate how loss of function of Tsc2 in radial glia affects proliferation, differentiation and apoptosis in the developing and adult brain; 2) to understand the in vivo effects of loss of tuberin on neuronal morphology and migration; and, 3) to identify separate functions of the Tsc1 and Tsc2 genes in vivo by generating a similar Tsc1 based model and comparing its brain phenotype to the Tsc2 model. These studies will expand the understanding of tuberin and hamartin's role in the developing brain in TSC neuropathology, and in other TSC-associated diseases such as autism and epilepsy. Knowledge of independent in vivo functions of each gene may lead to targeted therapeutic interventions for patients with disease due to TSC1 mutations versus TSC2 mutations. The goal of this research project is to use mouse genetics to understand the developmental abnormalities that lead to the brain lesions of the genetic disease tuberous sclerosis complex. Well characterized models will establish a foundation for the testing of future targeted therapies and establish developmental neurobiologic differences between subsets of patients with TSC. ? ? ?
