Neurofibromatosis 1 (NF1) heterozygosity results in a cell-autonomous growth advantage for astrocytes.
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.
Bajenaru
M L
ML
Department of Neurology, Washington University School of Medicine, 860 S. Euclid Avenue, St. Louis, MO 63110, USA.
Donahoe
J
J
Corral
T
T
Reilly
K M
KM
Brophy
S
S
Pellicer
A
A
Gutmann
D H
DH
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000502:physiology*; D001254:Astrocytoma / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics; D002452:Cell Count; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D025542:Neurofibromin 1; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D016160:Retinoblastoma Protein / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)