Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

David H. Gutmann, Allison Loehr, Yujing Zhang, Joanna Kim, Mark Henkemeyer, Amanda Cashen

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Individuals affected with neurofibromatosis 1 (NF1) harbor increased numbers of GFAP-immunoreactive cerebral astrocytes and develop astrocytomas that can lead to blindness and death. Mice heterozygous for a targeted Nf1 mutation (Nf1+/-) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neurofibromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is sufficient for abnormal astrocyte proliferation. Here, we report that Nf1+/- mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/- astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were co-cultured with C17 neuronal cells. This C17 neuronal cell-induced Nf1+/- increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-ras-dependent effect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These findings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be sufficient for the development of astrocytic growth abnormalities in patients with NF1.

Original languageEnglish (US)
Pages (from-to)4450-4459
Number of pages10
JournalOncogene
Volume18
Issue number31
DOIs
StatePublished - Aug 5 1999

Keywords

  • GTPase activating protein
  • Glioma
  • Neurofibromin
  • Tumor suppressor gene
  • p21-ras

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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