Natural history of neurofibromatosis 1-associated optic nerve glioma in mice

Ann Neurol. 2005 Jan;57(1):119-27. doi: 10.1002/ana.20337.


Children affected with the inherited tumor predisposition syndrome, neurofibromatosis 1 (NF1), are prone to the development of low-grade astrocytic optic pathway tumors (optic pathway glioma [OPG]). Previously, we developed a model of NF1-associated astrocytoma (GFAPCre; Nf1(flox/mut) mice) in which mice develop optic nerve and chiasm glioma. To define the molecular pathogenesis of OPG, we used this mouse model to study the natural history of OPG formation using immunohistological and radiographic approaches. We observed that whereas astrocyte hyperplasia is present in the optic nerves associated with gross optic nerve thickening at 3 weeks of age, overt neoplastic changes were not seen until 2 months of age. Astrocyte proliferation was maximal between 3 weeks and 2 months of age, suggesting that the most rapid period of growth occurs early. Mouse OPG tumors were detected by magnetic resonance imaging at 2 months of age and exhibited contrast enhancement, as seen in human OPG. In addition, the mouse OPG tumors exhibited expression of proteins associated with astroglial progenitors, including nestin and brain lipid binding protein. Last, we observed neovascularization and microglial cell infiltration by 3 weeks of age before overt neoplastic transformation, suggesting that these cellular changes participate in the early stages of tumor formation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Antigens / metabolism
  • Blood Vessels / physiology
  • Disease Models, Animal
  • Glial Fibrillary Acidic Protein / metabolism
  • Glioma / complications*
  • Glioma / metabolism
  • Immunohistochemistry / methods
  • Indoles / metabolism
  • Intermediate Filament Proteins / metabolism
  • Ki-67 Antigen / metabolism
  • Magnetic Resonance Imaging / methods
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neurofibromatosis 1 / complications*
  • Optic Nerve Neoplasms / complications*
  • Optic Nerve Neoplasms / metabolism
  • Staining and Labeling / methods
  • von Willebrand Factor / immunology


  • Antigens
  • Glial Fibrillary Acidic Protein
  • Indoles
  • Intermediate Filament Proteins
  • Ki-67 Antigen
  • NES protein, human
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Von Willebrand antigen
  • von Willebrand Factor
  • DAPI