Sustained Activation of mTOR Pathway in Embryonic Neural Stem Cells Leads to Development of Tuberous Sclerosis Complex-Associated Lesions

SummaryTuberous 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.

Graphical AbstractFigure optionsDownload high-quality image (200 K)Download as PowerPoint slideHighlights
► Tsc1 deletion in eNSCs deregulates their self-renewal and differentiation
► mTOR hyperactivation in eNSCs disarranges postnatal neurogenesis in the SVZ and SGZ
► mTOR-dependent Akt inhibition impairs eNSC self-renewal in vitro
► Premature differentiation of eNSCs in vitro requires mTOR-dependent STAT3 activation