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

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.