Mice with GFAP‐targeted loss of neurofibromin demonstrate increased axonal MET expression with aging

Abstract

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.

Dynamic gene and protein expression patterns of the autism‐associated met receptor tyrosine kinase in the developing mouse forebrain

“…This may reflect additional roles for Met in response to stress. For instance, Met is dramatically upregulated in cortical and hippocampal axons in adult animals with genetically compromised astrocytic populations (Su et al, 2007). HGF and Met are also upregulated in the cerebral cortex subsequent to a transient ischemic insult, though it is not known if Met protein levels specifically increase in cortical axons in this case (Honda et al, 1995).…”

Tissue-specific ablation of Prkar1a causes schwannomas by suppressing neurofibromatosis protein production

“…In contrast to the observations in the Prkar1a +/− model, neither Nf1 +/− nor Nf2 +/− mice develop Schwann cell tumors [7]. However, tissue-specific KO of these genes does recapitulate neoplasia in Schwann cells and other tissues [8][9][10][11].…”

“…As described above, mutations in NF1 or NF2 cause human schwannomas and tissue-specific KO of these genes in mice can also cause tumorigenesis [8][9][10][11]. To determine the effects of Prkar1a KO on the NF proteins, the expression pattern of each of these gene products was tested in TEC3KO schwannomas.…”

Association of tumor location, extent of resection, and neurofibromatosis status with clinical outcomes for 221 spinal nerve sheath tumors

“…Indeed, there is a biological rationale based on pathology and laboratory data that supports this notion. 23 Among schwannomas included in this study, the rate of GTR was 66% (8 of 12) among patients with NF and 84% (127 of 151) among those without NF, although the difference was not statistically significant (p = 0.261), probably because of small numbers.…”