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

Da Yong Lee, Tu Hsueh Yeh, Ryan J. Emnett, Crystal R. White, David H. Gutmann

Research output: Contribution to journalArticle

77 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2317-2329
Number of pages13
JournalGenes and Development
Volume24
Issue number20
DOIs
Publication statusPublished - Oct 15 2010
Externally publishedYes

Fingerprint

Neurofibromatosis 1
Neuroglia
Stem Cells
Brain
Brain Stem
Cell Proliferation
Sirolimus
Phosphorylation

Keywords

  • Akt
  • Gliogenesis
  • mTOR
  • Neural stem cell
  • Neurofibromin
  • Regional heterogeneity

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. / Lee, Da Yong; Yeh, Tu Hsueh; Emnett, Ryan J.; White, Crystal R.; Gutmann, David H.

In: Genes and Development, Vol. 24, No. 20, 15.10.2010, p. 2317-2329.

Research output: Contribution to journalArticle

Lee, Da Yong ; Yeh, Tu Hsueh ; Emnett, Ryan J. ; White, Crystal R. ; Gutmann, David H. / Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. In: Genes and Development. 2010 ; Vol. 24, No. 20. pp. 2317-2329.
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