Tuberous sclerosis complex–associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt
Paola Zordan, … , Pietro L. Poliani, Rossella Galli
Paola Zordan, … , Pietro L. Poliani, Rossella Galli
Published April 2, 2018; First published February 1, 2018
Citation Information: J Clin Invest. 2018;128(4):1688-1706. https://doi.org/10.1172/JCI96342.
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Research Article Neuroscience Stem cells

Tuberous sclerosis complex–associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt

Abstract

Tuberous sclerosis complex (TSC) is a dominantly inherited disease caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, including in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these 2 lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by codeletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Notably, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs, and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC.

Authors

Paola Zordan, Manuela Cominelli, Federica Cascino, Elisa Tratta, Pietro L. Poliani, Rossella Galli

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Figure 1

Targeted inactivation of Tsc1 and Pten in early-postnatal SVZ NSCs promotes the development of SVZ aberrant structures, reminiscent of SENs.

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Targeted inactivation of Tsc1 and Pten in early-postnatal SVZ NSCs promo...
(A) Intraventricular nodular lesions were retrieved in the brains of TPN mice activated at P10 (H&E; original magnification ×40 and ×400) and were never found in controls (H&E, ×40). The lesions comprised small cells that lay within a gliofibrillary matrix (H&E, ×400) and were pS6-IR, GFAP-IR, NeuN-IR, and DCX-IR (IHC, ×100 and ×400; controls, ×40, ×100, ×400 for inset and DCX/GFAP staining). GFAP-IR and NeuN-IR cells were often colabeled for pS6 (IHC and immunofluorescence [IF], ×400). GFAP and DCX expression was never retrieved in the same cells (×400). (B) The stem cell markers Pax6 and Sox2 were expressed only in the small cells of the lesions at low levels (original magnifcation, mutant, ×40, ×100, and ×400; controls, ×40 and ×100), whereas the early neuronal marker Tuj1 was found in the majority of the cells (×40, ×200, and ×400). The late oligodendroglial marker MBP was never expressed in the lesions (×40, ×100, and ×400). (C) S100β immunoreactivity was restricted to ependymal cells and was never found in the nodular lesions (×40 and ×100; controls, ×40 and ×100). Few Iba1-IR microglial cells and vimentin-IR reactive glial cells were retrieved in the nodular lesions (×40 and ×200; controls, ×40 and ×100). The mitotic index of the lesions as measured by Ki67 was very low (×40 and ×200).