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

Weiping Su, Rubing Xing, Abhijit Guha, David H. Gutmann, Lawrence (Larry) Sherman

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    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 GFAPCKO 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 (≥6 months) Nf1GFAPCKO mice. Both Nf1GFAPCKO 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.

    Original languageEnglish (US)
    Pages (from-to)723-733
    Number of pages11
    JournalGLIA
    Volume55
    Issue number7
    DOIs
    StatePublished - May 2007

    Fingerprint

    Neurofibromin 1
    Glial Fibrillary Acidic Protein
    Astrocytes
    Neurofibromatosis 1
    Nervous System Malformations
    Peripheral Nervous System Neoplasms
    Central Nervous System
    Neurofibromatosis 1 Genes
    Nervous System Neoplasms
    Proto-Oncogene Proteins c-met
    Inborn Genetic Diseases
    GTP Phosphohydrolases
    Neurilemmoma
    Astrocytoma
    Brain
    Neurites
    Mesencephalon
    Cerebral Cortex
    Cerebellum
    Axons

    Keywords

    • Astrocytes
    • Hippocampal neurons
    • K-RAS
    • MET
    • Neurofibromatosis 1

    ASJC Scopus subject areas

    • Immunology

    Cite this

    Mice with GFAP-targeted loss of neurofibromin demonstrate increased axonal MET expression with aging. / Su, Weiping; Xing, Rubing; Guha, Abhijit; Gutmann, David H.; Sherman, Lawrence (Larry).

    In: GLIA, Vol. 55, No. 7, 05.2007, p. 723-733.

    Research output: Contribution to journalArticle

    Su, Weiping ; Xing, Rubing ; Guha, Abhijit ; Gutmann, David H. ; Sherman, Lawrence (Larry). / Mice with GFAP-targeted loss of neurofibromin demonstrate increased axonal MET expression with aging. In: GLIA. 2007 ; Vol. 55, No. 7. pp. 723-733.
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