Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse.
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.
Way
Sharon W
SW
Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center, Houston, TX 77030, USA.
McKenna
James
J
Mietzsch
Ulrike
U
Reith
R Michelle
RM
Wu
Henry Cheng-Ju
HC
Gambello
Michael J
MJ
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019426:Integrases / Q000378:metabolism; D054081:Malformations of Cortical Development, Group II / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D011506:Proteins; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000473:pathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
D005904:Glial Fibrillary Acidic Protein; D046912:Multiprotein Complexes; D011506:Proteins; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C045073:Cre recombinase; D019426:Integrases