Journal Article

Loss of <i>Tsc2</i> in radial glia models the brain pathology of tuberous sclerosis complex in the mouse

Sharon W. Way, James McKenna, Ulrike Mietzsch, R. Michelle Reith, Henry Cheng-ju Wu and Michael J. Gambello

in Human Molecular Genetics

Volume 18, issue 7, pages 1252-1265
Published in print April 2009 | ISSN: 0964-6906
Published online January 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp025
Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse

Show Summary Details

Preview

Tuberous sclerosis complex (TSC) is an autosomal dominant, tumor predisposition disorder characterized by significant neurodevelopmental brain lesions, such as tubers and subependymal nodules. The neuropathology of TSC is often associated with seizures and intellectual disability. To learn about the developmental perturbations that lead to these brain lesions, we created a mouse model that selectively deletes the Tsc2 gene from radial glial progenitor cells in the developing cerebral cortex and hippocampus. These Tsc2 mutant mice were severely runted, developed post-natal megalencephaly and died between 3 and 4 weeks of age. Analysis of brain pathology demonstrated cortical and hippocampal lamination defects, hippocampal heterotopias, enlarged dysplastic neurons and glia, abnormal myelination and an astrocytosis. These histologic abnormalities were accompanied by activation of the mTORC1 pathway as assessed by increased phosphorylated S6 in brain lysates and tissue sections. Developmental analysis demonstrated that loss of Tsc2 increased the subventricular Tbr2-positive basal cell progenitor pool at the expense of early born Tbr1-positive post-mitotic neurons. These results establish the novel concept that loss of function of Tsc2 in radial glial progenitors is one initiating event in the development of TSC brain lesions as well as underscore the importance of Tsc2 in the regulation of neural progenitor pools. Given the similarities between the mouse and the human TSC lesions, this model will be useful in further understanding TSC brain pathophysiology, testing potential therapies and identifying other genetic pathways that are altered in TSC.

Journal Article.  7917 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.