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

Individuals with neurofibromatosis 1 (NF1) develop low-grade astrocytomas a t an increased frequency. To gain insight into the function of the Nf1 gene product as a growth regulator for astrocytes, we examined mice heterozygou s for a targeted Nf1 mutation. In our previous studies, we demonstrated inc reased numbers of proliferating astrocytes in Nf1 heterozygote (Nf1(+/-)) m ice in vivo. We now show that cultured Nf1(+/-) astrocytes exhibit a cell-a utonomous growth advantage in vitro associated with increased p21-ras pathw ay activation. Furthermore, we demonstrate that Nf1(+/-);wild-type N-ras mi ce have a similar astrocyte growth advantage in vitro and in vivo as either oncogenic N-ras or Nf1(+/-);oncogenic N-ras mice. Lastly, mice heterozygou s 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, s uggesting that abnormalities in Nf1- and p53/Rb-regulated pathways cooperat e in the heterozygous state to confer a growth advantage for brain astrocyt es. Collectively, these results provide evidence for a cell-autonomous grow th advantage in Nf1(+/-) astrocytes and suggest that some of the brain path ology in individuals with NF1 might result from reduced, but not absent, NF 1 gene function. GLIA 33:314-323, 2001. (C) 2001 Wiley-Liss, Inc.