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.
Department of Neurology, Washington University School of Medicine, 860 S. Euclid Avenue, St. Louis, MO 63110, USA.
M L
ML
Bajenaru
J
J
Donahoe
T
T
Corral
K M
KM
Reilly
S
S
Brophy
A
A
Pellicer
D H
DH
Gutmann
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)