Neurofibromatosis 1 (NF1) heterozygosity results in a cell-autonomous growth advantage for astrocytes

Michaela Livia Bajenaru, Jessica Donahoe, Teresa Corral, Karlyne M. Reilly, Sean Brophy, Angel Pellicer, David H. Gutmann

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Individuals with neurofibromatosis 1 (NF1) develop low-grade astrocytomas at an increased frequency. To gain insight into the function of the Nf1 gene product as a growth regulator for astrocytes, we examined mice heterozygous for a targeted Nf1 mutation. In our previous studies, we demonstrated increased numbers of proliferating astrocytes in Nf1 heterozygote (Nf1 +/-) mice in vivo. We now show that cultured Nf1 +/- astrocytes exhibit a cell-autonomous growth advantage in vitro associated with increased p21-ras pathway activation. Furthermore, we demonstrate that Nf1 +/-;wild-type N-ras mice have a similar astrocyte growth advantage in vitro and in vivo as either oncogenic N-ras or Nf1 +/-;oncogenic N-ras mice. Lastly, mice heterozygous for targeted defects in both Nf1 and p53 as well as Nf1 and Rb exhibit 3- and 2.5-fold increases in astrocyte proliferation in vivo, respectively, suggesting that abnormalities in Nf1- and p53/Rb-regulated pathways cooperate in the heterozygous state to confer a growth advantage for brain astrocytes. Collectively, these results provide evidence for a cell-autonomous growth advantage in Nf1 +/- astrocytes and suggest that some of the brain pathology in individuals with NF1 might result from reduced, but not absent, NF1 gene function.

Original languageEnglish (US)
Pages (from-to)314-323
Number of pages10
JournalGlia
Volume33
Issue number4
DOIs
StatePublished - 2001

Keywords

  • Glioma
  • GTPase-activating protein
  • Neurofibromin
  • p21-ras

ASJC Scopus subject areas

  • Immunology

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    Bajenaru, M. L., Donahoe, J., Corral, T., Reilly, K. M., Brophy, S., Pellicer, A., & Gutmann, D. H. (2001). Neurofibromatosis 1 (NF1) heterozygosity results in a cell-autonomous growth advantage for astrocytes. Glia, 33(4), 314-323. https://doi.org/10.1002/1098-1136(20010315)33:4<314::AID-GLIA1030>3.0.CO;2-Q