Developmental stage-specific activation of mTOR signaling in mouse cerebral cortex

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  • Kassai Hidetoshi
    Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
  • Aiba Atsu
    Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo

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  • 恒常的活性化型 mTOR による精神神経疾患モデルマウスの作製と解析
  • コウジョウテキ カッセイカガタ mTOR ニ ヨル セイシン シンケイ シッカン モデルマウス ノ サクセイ ト カイセキ

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Abstract

Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase and plays a central role in regulation of cell growth and proliferation in response to nutrients and environmental stimuli. mTOR is found in two functionally distinct complexes, mTORC1 and mTORC2. mTORC1 is hyperactivated in many human diseases such as cancer and diabetes. In central nervous system, hyperactivation of mTORC1 is implicated in tuberous sclerosis, autism and neurodegenerative disease. In this study, we generated transgenic mice carrying mTOR kinase with gain - of - function mutations that direct selective activation of mTORC1 pathway in a spatially and temporally controlled manner. Active mTOR expression in embryonic cortex induced progressive apoptotic cell death of cortical neuronal progenitors, thereby resulting in cortical atrophy. In contrast, mTORC1 activation in postmitotic neuron led cortical hypertrophy and severe epileptic seizures. In addition, cytoplasmic inclusions were rapidly accumulated in the cortical neurons after chronic activation of mTORC1, indicative of neurodegeneration. These data demonstrate that neuronal functions of mTORC1 are different between embryonic and adult brains, and involved in human neurological diseases such as microcephaly, tuberous sclerosis and neurodegeneration.

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