Nf1 Loss and Ras Hyperactivation in Oligodendrocytes Induce NOS-Driven Defects in Myelin and Vasculature

Debra A. Mayes, Tilat A. Rizvi, Haley Titus-Mitchell, Rachel Oberst, Georgianne M. Ciraolo, Charles V. Vorhees, Andrew P. Robinson, Stephen D. Miller, Jose A. Cancelas, Anat O. Stemmer-Rachamimov, Nancy Ratner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with whitematter enlargement and aberrant myelin. Tomodel these features, we induced Nf1 loss or HRashyperactivation 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

Original languageEnglish (US)
Pages (from-to)1197-1212
Number of pages16
JournalCell reports
Issue number6
StatePublished - Sep 26 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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