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

Oncogene. 1999 Aug 5;18(31):4450-9. doi: 10.1038/sj.onc.1202829.


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 Nf17+/- 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 cocultured 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Astrocytes / cytology*
  • Astrocytes / physiology
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Cell Division / drug effects
  • Cell Line
  • Coculture Techniques
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Genes, Neurofibromatosis 1*
  • Glial Fibrillary Acidic Protein / analysis
  • Heterozygote
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurofibromatosis 1 / genetics
  • Neurofibromatosis 1 / pathology
  • Neurofibromin 1
  • Neurons / cytology*
  • Neurons / physiology
  • Proteins / genetics*
  • Proteins / metabolism*


  • Enzyme Inhibitors
  • Flavonoids
  • Glial Fibrillary Acidic Protein
  • Nerve Tissue Proteins
  • Neurofibromin 1
  • Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one