Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation.
Individuals affected with neurofibromatosis 1 (NF1) harbor increased numbers of GFAP-immunoreactive cerebral astrocytes and develop astrocytomas that can lead to blindness and death. Mice heterozygous for a targeted Nf1 mutation (Nf1+/-) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neurofibromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is sufficient for abnormal astrocyte proliferation. Here, we report that Nf17+/- mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/- astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were cocultured with C17 neuronal cells. This C17 neuronal cell-induced Nf1+/- increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-ras-dependent effect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These findings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be sufficient for the development of astrocytic growth abnormalities in patients with NF1.
Gutmann
D H
DH
Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Loehr
A
A
Zhang
Y
Y
Kim
J
J
Henkemeyer
M
M
Cashen
A
A
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016514:Genes, Neurofibromatosis 1; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000473:pathology; D025542:Neurofibromin 1; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D011506:Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one