Mice with GFAP-targeted loss of neurofibromin demonstrate increased axonal MET expression with aging.
Neurofibromatosis 1 (NF1) is a common genetic disease that predisposes patients to peripheral nerve tumors and central nervous system (CNS) abnormalities including low-grade astrocytomas and cognitive disabilities. Using mice with glial fibrillary acidic protein (GFAP)-targeted Nf1 loss (Nf1(GFAP)CKO mice), we found that Nf1(-/-) astrocytes proliferate faster and are more invasive than wild-type astrocytes. In light of our previous finding that aberrant expression of the MET receptor tyrosine kinase contributes to the invasiveness of human NF1-associated malignant peripheral nerve sheath tumors, we sought to determine whether MET expression is aberrant in the brains of Nf1 mutant mice. We found that Nf1(-/-) astrocytes express slightly more MET than wild-type cells in vitro, but do not express elevated MET in situ. However, fiber tracts containing myelinated axons in the hippocampus, midbrain, cerebral cortex, and cerebellum express higher than normal levels of MET in older (> or =6 months) Nf1(GFAP)CKO mice. Both Nf1(GFAP)CKO and wild-type astrocytes induced MET expression in neurites of wild-type hippocampal neurons in vitro, suggesting that astrocyte-derived signals may induce MET in Nf1 mutant mice. Because the Nf1 gene product functions as a RAS GTPase, we examined MET expression in the brains of mice with GFAP-targeted constitutively active forms of RAS. MET was elevated in axonal fiber tracts in mice with active K-RAS but not H-RAS. Collectively, these data suggest that loss of Nf1 in either astrocytes or GFAP(+) neural progenitor cells results in increased axonal MET expression, which may contribute to the CNS abnormalities in children and adults with NF1.
Su
Weiping
W
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 158th Avenue, Beaverton, OR 97006, USA.
Xing
Rubing
R
Guha
Abhijit
A
Gutmann
David H
DH
Sherman
Larry S
LS
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001369:Axons / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D025542:Neurofibromin 1; D019859:Proto-Oncogene Proteins c-met; D018631:ras Proteins