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 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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Mayes
authors.forename: Tilat A
authors.initials: TA
authors.lastname: Rizvi
authors.forename: Haley
authors.initials: H
authors.lastname: Titus-Mitchell
authors.forename: Rachel
authors.initials: R
authors.lastname: Oberst
authors.forename: Georgianne M
authors.initials: GM
authors.lastname: Ciraolo
authors.forename: Charles V
authors.initials: CV
authors.lastname: Vorhees
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Robinson
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D025542:Neurofibromin 1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D018631:ras Proteins
references.citation: Biochim Biophys Acta. 2004 Mar 23;1662(1-2):3-21
references.pmid: 15033576
references.citation: Expert Rev Mol Med. 2008 Dec 09;10:e37
references.pmid: 19063751
references.citation: Nat Protoc. 2006;1(2):848-58
references.pmid: 17406317
references.citation: Glia. 2011 Jul;59(7):1064-74
references.pmid: 21538560
references.citation: J Histochem Cytochem. 2006 Jan;54(1):53-61
references.pmid: 16087703
references.citation: Cell Stem Cell. 2007 Oct 11;1(4):443-57
references.pmid: 18371380
references.citation: J Neurosci. 2003 Aug 6;23(18):7207-17
references.pmid: 12904481
references.citation: J Psychiatr Res. 2012 Apr;46(4):451-5
references.pmid: 22257388
references.citation: Biochem Biophys Res Commun. 1993 Dec 15;197(2):523-8
references.pmid: 7505570
references.citation: J Child Neurol. 2010 Jul;25(7):834-41
references.pmid: 20142468
references.citation: Vascul Pharmacol. 2002 Jun;38(6):323-37
references.pmid: 12529927
references.citation: J Pathol. 2004 Apr;202(4):503-10
references.pmid: 15095278
references.citation: Handb Clin Neurol. 2012;105:607-13
references.pmid: 22230521
references.citation: J Signal Transduct. 2012;2012:365769
references.pmid: 22175014
references.citation: J Neurosci. 2003 Oct 8;23(27):9254-62
references.pmid: 14534260
references.citation: Genes Cancer. 2011 Mar;2(3):359-72
references.pmid: 21779505
references.citation: Genes Dev. 1994 May 1;8(9):1019-29
references.pmid: 7926784
references.citation: J Neurosci Res. 2008 Apr;86(5):992-1006
references.pmid: 17972320
references.citation: Cancer Res. 2011 Jul 1;71(13):4675-85
references.pmid: 21551249
references.citation: Clin Cancer Res. 2012 Sep 15;18(18):5020-30
references.pmid: 22811580
references.citation: Genesis. 2003 Jan;35(1):63-72
references.pmid: 12481300
references.citation: Nitric Oxide. 1999 Aug;3(4):327-39
references.pmid: 10444372
references.citation: J Physiol Pharmacol. 2009 Sep;60(3):63-9
references.pmid: 19826183
references.citation: Metab Brain Dis. 2013 Sep;28(3):429-38
references.pmid: 23378107
references.citation: Curr Biol. 2005 Nov 8;15(21):1961-7
references.pmid: 16271875
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):9071-6
references.pmid: 22611193
references.citation: AJNR Am J Neuroradiol. 2008 Apr;29(4):816-22
references.pmid: 18339726
references.citation: ASN Neuro. 2010 Mar 15;2(2):e00030
references.pmid: 20396375
references.citation: Nat Neurosci. 2012 Mar 18;15(4):528-36
references.pmid: 22426254
references.citation: Oncogene. 2014 Jan 16;33(3):289-99
references.pmid: 23318450
references.citation: Neurotoxicol Teratol. 2012 Jul;34(4):450-7
references.pmid: 22580179
references.citation: FASEB J. 2011 Nov;25(11):4063-72
references.pmid: 21825035
references.citation: Anat Rec A Discov Mol Cell Evol Biol. 2006 Sep;288(9):1000-8
references.pmid: 16892422
references.citation: J Neurol Neurosurg Psychiatry. 2007 Oct;78(10):1088-91
references.pmid: 17299016
references.citation: Genes Brain Behav. 2009 Feb;8(1):60-71
references.pmid: 18823404
references.citation: Mol Cell Biochem. 2011 Jan;347(1-2):163-73
references.pmid: 20963625
references.citation: Pediatrics. 2009 Jan;123(1):124-33
references.pmid: 19117870
references.citation: Nat Protoc. 2007;2(2):277-81
references.pmid: 17406586
references.citation: Pediatr Res. 2003 Jul;54(1):69-76
references.pmid: 12700363
references.citation: Proc West Pharmacol Soc. 2011;54:41-8
references.pmid: 22423579
references.citation: J Pediatr Gastroenterol Nutr. 2012 Apr;54(4):463-70
references.pmid: 22197938
references.citation: Nat Genet. 2007 Apr;39(4):476-85
references.pmid: 17369827
references.citation: PLoS One. 2011 Jan 13;6(1):e16187
references.pmid: 21249153
references.citation: Neuron. 2012 Sep 20;75(6):1035-50
references.pmid: 22998872
references.citation: Radiology. 1995 Jun;195(3):721-4
references.pmid: 7754001
references.citation: ScientificWorldJournal. 2010 Apr 13;10:624-32
references.pmid: 20419275
references.citation: Am J Med Genet A. 2012 Sep;158A(9):2225-32
references.pmid: 22821737
references.citation: PLoS One. 2012;7(10):e47854
references.pmid: 23094098
references.citation: Glia. 2007 Mar;55(4):400-11
references.pmid: 17186502
references.citation: Mol Cell Neurosci. 2005 Jul;29(3):405-13
references.pmid: 15886014
references.citation: Am J Physiol Renal Physiol. 2008 Oct;295(4):F867-76
references.pmid: 18480174
references.citation: Neuron. 1992 Mar;8(3):415-28
references.pmid: 1550670
references.citation: Mutat Res. 2009 Jan 15;660(1-2):51-6
references.pmid: 19026667
references.citation: Neuroscience. 2010 Sep 29;170(1):178-88
references.pmid: 20600672
references.citation: Cell. 2012 Aug 17;150(4):816-30
references.pmid: 22901811