Abstract
Tuberous Sclerosis Complex (TSC) is a disease caused by autosomal dominant mutations in the TSC1 or TSC2 genes, and is characterized by tumor susceptibility, brain lesions, seizures and behavioral impairments. The TSC1 and TSC2 genes encode proteins forming a complex (TSC), which is a major regulator and suppressor of mammalian target of rapamycin complex 1 (mTORC1), a signaling complex that promotes cell growth and proliferation. TSC1/2 loss of heterozygosity (LOH) and the subsequent complete loss of TSC regulatory activity in null cells causes mTORC1 dysregulation and TSC-associated brain lesions or other tissue tumors. However, it is not clear whether TSC1/2 heterozygous brain cells are abnormal and contribute to TSC neuropathology. To investigate this issue, we generated induced pluripotent stem cells (iPSCs) from TSC patients and unaffected controls, and utilized these to obtain neural progenitor cells (NPCs) and differentiated neurons in vitro. These patient-derived TSC2 heterozygous NPCs were delayed in their ability to differentiate into neurons. Patient-derived progenitor cells also exhibited a modest activation of mTORC1 signaling downstream of TSC, and a marked attenuation of upstream PI3K/AKT signaling. We further s...Continue Reading
Citations
Aug 10, 2019·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Guang Yang, Alex Shcheglovitov
May 10, 2019·Developmental Dynamics : an Official Publication of the American Association of Anatomists·John D Blair, Helen S Bateup
Apr 13, 2019·Acta Neuropathologica·Jennifer A Cotter
Feb 23, 2020·Molecular Autism·Wardiya Afshar Saber, Mustafa Sahin
Sep 4, 2020·Journal of Neurochemistry·Thomas J TurnerGabriele Lignani
Jun 27, 2019·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Wei Niu, Jack M Parent
Jan 17, 2020·International Journal of Molecular Sciences·Bruno SterliniAnna Corradi
Apr 9, 2020·Molecular Autism·Karina A KruthAislinn J Williams
Jan 16, 2021·Cells·Stephanie DoovesVivi M Heine
Mar 7, 2021·Pharmaceutics·Chiara VillaMarialuisa Lavitrano
Apr 26, 2021·The FEBS Journal·Santiago Camblor-Perujo, Natalia L Kononenko
Sep 2, 2021·Cerebral Cortex·Iva SalamonMegerditch Kiledjian
Jan 1, 2022·Nature Methods·Zhisong HeBarbara Treutlein