Oligodendrocyte RasG12V expressed in its endogenous locus disrupts myelin structure through increased MAPK, nitric oxide, and notch signaling.
Glia
; 65(12): 1990-2002, 2017 12.
Article
em En
| MEDLINE
| ID: mdl-28856719
ABSTRACT
Costello syndrome (CS) is a gain of function Rasopathy caused by heterozygous activating mutations in the HRAS gene. Patients show brain dysfunction that can include abnormal brain white matter. Transgenic activation of HRas in the entire mouse oligodendrocyte lineage resulted in myelin defects and behavioral abnormalities, suggesting roles for disrupted myelin in CS brain dysfunction. Here, we studied a mouse model in which the endogenous HRas gene is conditionally replaced by mutant HRasG12V in mature oligodendrocytes, to separate effects in mature myelinating cells from developmental events. Increased myelin thickness due to decompaction was detectable within one month of HRasG12V expression in the corpus callosum of adult mice. Increases in active ERK and Nitric Oxide (NO) were present in HRas mutants and inhibition of NO synthase (NOS) or MEK each partially rescued myelin decompaction. In addition, genetic or pharmacologic inhibition of Notch signaling improved myelin compaction. Complete rescue of myelin structure required dual drug treatments combining MAPK, NO, or Notch inhibition; with MEK + NOS blockade producing the most robust effect. We suggest that individual or concomitant blockade of these pathways in CS patients may improve aspects of brain function.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligodendroglia
/
Proteínas Proto-Oncogênicas p21(ras)
/
Quinases de Proteína Quinase Ativadas por Mitógeno
/
Sistema de Sinalização das MAP Quinases
/
Receptores Notch
/
Bainha de Mielina
/
Óxido Nítrico
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article