@article{4e092411694c4d959dfae728a6455073,
title = "Nf1 Loss and Ras Hyperactivation in Oligodendrocytes Induce NOS-Driven Defects in Myelin and Vasculature",
abstract = "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",
author = "Mayes, {Debra A.} and Rizvi, {Tilat A.} and Haley Titus-Mitchell and Rachel Oberst and Ciraolo, {Georgianne M.} and Vorhees, {Charles V.} and Robinson, {Andrew P.} and Miller, {Stephen D.} and Cancelas, {Jose A.} and Stemmer-Rachamimov, {Anat O.} and Nancy Ratner",
note = "Funding Information: We thank Brian Popko (University of Chicago) for providing the inducible Plp-Cre-ERT mice, and Luis Parada (UTSW) for the Nf1fl/fl mice. We also thank Nathan Kalasinski for carrying out some of the mouse genotyping for this project, and Peter Pytel (University of Chicago) for performing the autopsy on the NF1 patient studied. This work was supported by grants from the DAMD Program on Neurofibromatosis (W81XWH-06-1-0114 and W81XWH-10-1-0116 to N.R.) and a Drug Discovery Initiative Award from the Children{\textquoteright}s Tumor Foundation. D.A.M. was partially supported by grants from the NIH NRSA (T32CA117846) and the National Multiple Sclerosis Society (FG1762A1/1). D.A.M. performed all animal work and experiments, analyzed and interpreted data, identified the phenotypes and developed the mechanism, created the figures, and wrote and edited the paper. T.A.R. performed the Ras activation assay, characterized cells affected by the HRas mutation in the CNP-HRas animals, and performed the NOS stain on sections. G.C. prepared sections for electron microscopy. R.O. helped in animal behavior experiments and C.V. analyzed animal behavior. H.T.M. and J.C. performed the flow cytometry and interpreted the results. A.P.R. and S.D.M. provided the mature oligodendrocyte dissociation protocol for flow cytometry. A.O.S. analyzed stained brain and optic-nerve section histology and pathology. N.R. conceptualized the original experimental plan, aided in data analysis and interpretation, and edited the paper and figures. ",
year = "2013",
month = sep,
day = "26",
doi = "10.1016/j.celrep.2013.08.011",
language = "English (US)",
volume = "4",
pages = "1197--1212",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}