Selective Activation of mTORC1 Signaling Recapitulates Microcephaly, Tuberous Sclerosis, and Neurodegenerative Diseases
Hidetoshi Kassai,
Yuki Sugaya,
Shoko Noda,
Kazuki Nakao,
Tatsuya Maeda,
Masanobu Kano,
Atsu Aiba
Affiliations
Hidetoshi Kassai
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Yuki Sugaya
Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Shoko Noda
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Kazuki Nakao
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Tatsuya Maeda
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan
Masanobu Kano
Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Atsu Aiba
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Mammalian target of rapamycin (mTOR) has been implicated in human neurological diseases such as tuberous sclerosis complex (TSC), neurodegeneration, and autism. However, little is known about when and how mTOR is involved in the pathogenesis of these diseases, due to a lack of animal models that directly increase mTOR activity. Here, we generated transgenic mice expressing a gain-of-function mutant of mTOR in the forebrain in a temporally controlled manner. Selective activation of mTORC1 in embryonic stages induced cortical atrophy caused by prominent apoptosis of neuronal progenitors, associated with upregulation of HIF-1α. In striking contrast, activation of the mTORC1 pathway in adulthood resulted in cortical hypertrophy with fatal epileptic seizures, recapitulating human TSC. Activated mTORC1 in the adult cortex also promoted rapid accumulation of cytoplasmic inclusions and activation of microglial cells, indicative of progressive neurodegeneration. Our findings demonstrate that mTORC1 plays different roles in developmental and adult stages and contributes to human neurological diseases.
