Nf1 loss and Ras hyperactivation in oligodendrocytes induce NOS-driven defects in myelin and vasculature

Cell Rep. 2013 Sep 26;4(6):1197-212. doi: 10.1016/j.celrep.2013.08.011. Epub 2013 Sep 12.


Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1-NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / cytology
  • Blood Vessels / enzymology
  • Blood Vessels / metabolism
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myelin Sheath / metabolism*
  • Neurofibromin 1 / deficiency*
  • Neurofibromin 1 / genetics
  • Neurofibromin 1 / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / metabolism*
  • Oligodendroglia / cytology
  • Oligodendroglia / enzymology
  • Oligodendroglia / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Neurofibromin 1
  • Nitric Oxide
  • Nitric Oxide Synthase
  • ras Proteins