Neurofibromin regulates neural stem cell proliferation, survival, and astroglial differentiation in vitro and in vivo

Biplab Dasgupta, David H. Gutmann

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

Neurofibromatosis 1 (NF1) is a common inherited disease in which affected children exhibit abnormalities in astrocyte growth regulation and are prone to the development of brain tumors (astrocytoma). Previous studies from our laboratory demonstrated that Nf1 mutant mouse astrocytomas contains populations of proliferating nestin+ progenitor cells, suggesting that immature astroglial progenitors may serve as a reservoir of proliferating tumor cells. Here, we directly examined the consequences of Nf1 inactivation on neural stem cell (NSC) proliferation in vitro and in vivo. We found dose-dependent effects of neurofibromin expression on NSC proliferation and survival in vitro, which reflected increased RAS pathway activation and increased bcl2 expression. In addition, unlike wild-type NSCs, Nf1-/-SCs and, to a lesser extent, Nf1+/- NSCs survive as xenografts in naive recipient brains in vivo. Although Nf1-/- NSCs are multipotent, Nf1-/- and Nf1+/-, but not wild-type, NSCs generated increased numbers of morphologically abnormal, immature astroglial cells in vitro. Moreover, the Nf1-/- NSC growth and survival advantage as well as the astroglial cell differentiation defect were completely rescued by expression of the GAP (RAS-GTPase activating protein) domain of neurofibromin. Finally, the increase in astroglial progenitors and proliferating cells seen in vitro was also observed in Nf1-/- and Nf1+/- embryonic as well as Nf1+/- adult brains in vivo. Collectively, these findings support the hypothesis that alterations in neurofibromin expression in the developing brain have significant consequences for astrocyte growth and differentiation relevant to normal brain development and astrocytoma formation in children.

Original languageEnglish
Pages (from-to)5584-5594
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number23
DOIs
StatePublished - Jun 8 2005

Keywords

  • GTPase activating protein
  • Glia
  • Neurofibromatosis 1
  • Neurosphere
  • RAS
  • Stem cell

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