title: Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions.
abstract: Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by hamartomatous neurological lesions that exhibit abnormal cell proliferation and differentiation. Hyperactivation of mTOR pathway by mutations in either the Tsc1 or Tsc2 gene underlies TSC pathogenesis, but involvement of specific neural cell populations in the formation of TSC-associated neurological lesions remains unclear. We deleted Tsc1 in Emx1-expressing embryonic telencephalic neural stem cells (NSCs) and found that mutant mice faithfully recapitulated TSC neuropathological lesions, such as cortical lamination defects and subependymal nodules (SENs). These alterations were caused by enhanced generation of SVZ neural progeny, followed by their premature differentiation and impaired maturation during both embryonic and postnatal development. Notably, mTORC1-dependent Akt inhibition and STAT3 activation were involved in the reduced self-renewal and earlier neuronal and astroglial differentiation of mutant NSCs. Thus, finely tuned mTOR activation in embryonic NSCs may be critical to prevent development of TSC-associated brain lesions.
authors: Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
authors: Laura
authors: L
authors: Magri
authors: Marco
authors: M
authors: Cambiaghi
authors: Manuela
authors: M
authors: Cominelli
authors: Clara
authors: C
authors: Alfaro-Cervello
authors: Marco
authors: M
authors: Cursi
authors: Mauro
authors: M
authors: Pala
authors: Alessandro
authors: A
authors: Bulfone
authors: Jose Manuel
authors: JM
authors: Garcìa-Verdugo
authors: Letizia
authors: L
authors: Leocani
authors: Fabio
authors: F
authors: Minicucci
authors: Pietro Luigi
authors: PL
authors: Poliani
authors: Rossella
authors: R
authors: Galli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002552:Cerebral Ventricles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D047108:Embryonic Development; D053595:Embryonic Stem Cells / Q000201:enzymology*; D004827:Epilepsy / Q000150:complications / Q000473:pathology; D020868:Gene Silencing; D018390:Gene Targeting; D058627:Megalencephaly / Q000150:complications / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D058953:Neural Stem Cells / Q000201:enzymology*; D046569:Neuroepithelial Cells / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013687:Telencephalon / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases