Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse

• Type of Material: Article
• Authors: Sharon W. Way, University of Texas Health Science Center; James McKenna, University of Texas Health Science Center; Ulrike Mietzsch, University of Texas Health Science Center; R. Michelle Reith, University of Texas Health Science Center; Henry Cheng-ju Wu, University of Texas Health Science Center; Michael J. Gambello, Emory University
• Language: English
• Date: 2009-04-01
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
• Publication Version: Final Published Version
• Copyright Statement: © 2009 The Author(s).
• License: Creative Commons Attribution NonCommercial License 2.0 Germany
• Final Published Version (URL): http://dx.doi.org/10.1093/hmg/ddp025
• Title of Journal or Parent Work: Human Molecular Genetics
• ISSN: 0964-6906
• Volume: 18
• Issue: 7
• Start Page: 1252
• End Page: 1265
• Grant/Funding Information: Funding to Pay the Open Access Charge was provided by the National Institutes of Health.; This work is supported by NIH grant to M.J.G. (RO1NS060804) and the Tuberous Sclerosis Alliance.
• Keywords: DEVELOPING NEOCORTEX; Biochemistry & Molecular Biology; MICE; EKER RAT MODEL; PROGENITOR CELLS; NEURONS ARISE; Science & Technology; Genetics & Heredity; PRODUCT TUBERIN; CELL-GROWTH; EMBRYONIC LETHALITY; TUMOR-SUPPRESSOR PROTEINS; RAPAMYCIN; Life Sciences & Biomedicine
• Research Categories: Biology, Genetics; Health Sciences, Human Development

Abstract

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.