Editors' ChoiceStem Cells

Regional Variations

Science Signaling  26 Oct 2010:
Vol. 3, Issue 145, pp. ec327
DOI: 10.1126/scisignal.3145ec327

Neurofibromatosis type 1 is an inherited cancer syndrome caused by inactivation of NF1 and characterized by astrocytomas in the brain stem (BS) and optic nerve, with patients only rarely developing tumors in the cerebral cortex (CTX). Lee et al. report that BS and CTX neural stem cells (NSCs) respond differently to loss of neurofibromin, the tumor suppressor encoded by NF1. NSCs cultured from the BS, but not those cultured from the CTX, of Nf1 knockout neonatal mice showed increased proliferation and gliogenesis compared with wild-type (WT) BS and CTX NSCs, respectively. Proliferation was also differentially affected in vivo, because brains from Nf1 mutants showed increased numbers of stem cells and glial progenitor cells in the BS, but not the CTX, relative to WT mice. Phosphorylation of Akt was only increased relative to WT in NSCs cultured from the BS; however, expression of a constitutively active form of Akt in NSCs in vivo increased the number of glia in both BS and CTX, suggesting that differences in Akt activity may underlie the differing effects of Nf1 deficiency in these two regions. The mammalian target of rapamycin complex 2 (mTORC2) component rictor was more abundant in BS compared to CTX both in vivo and in cultured NSCs, and knocking down rictor (but not the mTORC1 component raptor) by RNA interference inhibited proliferation and Akt activation in BS NSCs but had no effect on CTX NSCs. Rapamycin inhibited proliferation of BS NSCs, but not CTX NSCs, cultured from Nf1 mutants, and it inhibited Akt-dependent Thr198 phosphorylation of the cyclin-dependent kinase inhibitor p27 in BS NSCs but not in CTX NSCs. Together, these results suggest that the differential abundance of rictor leads to enhanced Akt and p27 activation in BS NSCs, making this population of NSCs particularly susceptible to unregulated growth upon loss of neurofibromin.

D. Y. Lee, T.-H. Yeh, R. J. Emnett, C. R. White, D. H. Gutmann, Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev. 24, 2317–2329 (2010). [Abstract] [Full Text]