Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner

Da Yong Lee¹, Tu-Hsueh Yeh^1,2, Ryan J. Emnett¹, Crystal R. White¹,, and David H. Gutmann^1,3

¹ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
² Department of Neurology, Chang Gung Memorial Hospital and University, Taipei 10591, Taiwan

Abstract: Recent studies have shown that neuroglial progenitor/stem cells (NSCs) from different brain regions exhibit varying capacities for self-renewal and differentiation. In this study, we used neurofibromatosis-1 (NF1) as a model system to elucidate a novel molecular mechanism underlying brain region-specific NSC functional heterogeneity. We demonstrate that Nf1 loss leads to increased NSC proliferation and gliogenesis in the brainstem, but not in the cortex. Using Nf1 genetically engineered mice and derivative NSC neurosphere cultures, we show that this brain region-specific increase in NSC proliferation and gliogenesis results from selective Akt hyperactivation. The molecular basis for the increased brainstem-specific Akt activation in brainstem NSCs is the consequence of differential rictor expression, leading to region-specific mammalian target of rapamycin (mTOR)/rictor-mediated Akt phosphorylation and Akt-regulated p27 phosphorylation. Collectively, these findings establish mTOR/rictor-mediated Akt activation as a key driver of NSC proliferation and gliogenesis, and identify a unique mechanism for conferring brain region-specific responses to cancer-causing genetic changes.

Key Words: Neurofibromin • neural stem cell • regional heterogeneity • gliogenesis • Akt • mTOR

Received for publication June 7, 2010. Accepted for publication August 25, 2010.

E-MAIL gutmannd{at}neuro.wustl.edu; FAX (314) 362-2388.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1957110.

Supplemental material is available at http://www.genesdev.org.

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