R-ras1 and r-ras2 are essential for oligodendrocyte differentiation and survival for correct myelination in the central nervous system
EntityUAM. Departamento de Biología Molecular; Centro de Biología Molecular Severo Ochoa (CBM)
PublisherSociety for Neuroscience
10.1523/JNEUROSCI.3364-17.2018Journal of Neuroscience 38.22 (2018): 5096-5110
ISSN0270-6474 (print); 1529-2401 (online)
Funded byThis work was supported by the Spanish Ministry of Economy and Competitiveness (BFU2015-64829-S and SAF2012-31279) to B.C. and (SAF2015-70368-R) to F.W.
ProjectGobierno de España. (BFU2015-64829-S; Gobierno de España. SAF2012-31279; Gobierno de España. SAF2015-70368-R
SubjectsDifferentiation; Myelin; Oligodendrocyte; Oligodendrocyte progenitor cell; Ras; Biología y Biomedicina / Biología
Rights© 2018 the authors
Rapid and effective neural transmission of information requires correct axonal myelination. Modifications in myelination alter axonal capacity to transmit electric impulses and enable pathological conditions. In the CNS, oligodendrocytes (OLs) myelinate axons, a complex process involving various cellular interactions. However, we know little about the mechanisms that orchestrate correct myelination. Here, we demonstrate that OLs express R-Ras1 and R-Ras2. Using female and male mutant mice to delete these proteins, we found that activation of the PI3K/Akt and Erk1/2-MAPK pathways was weaker in mice lacking one or both of these GTPases, suggesting that both proteins coordinate the activity of these two pathways. Loss of R-Ras1 and/or R-Ras2 diminishes the number of OLs in major myelinated CNS tracts and increases the proportion of immature OLs. In R-Ras1-/-and R-Ras2-/--null mice, OLs show aberrant morphologies and fail to differentiate correctly into myelin-forming phenotypes. The smaller OL population and abnormal OL maturation induce severe hypomyelination, with shorter nodes of Ranvier in R-Ras1-/-and/or R-Ras2-/-mice. These defects explain the slower conduction velocity of myelinated axons that we observed in the absence of R-Ras1 and R-Ras2. Together, these results suggest that R-Ras1 and R-Ras2 are upstream elements that regulate the survival and differentiation of progenitors into OLs through the PI3K/Akt and Erk1/2-MAPK pathways for proper myelination.
Google Scholar:Sanz-Rodríguez, Miriam - Gruart, Agnès - Escudero-Ramirez, Juan - Castro, Fernando de - Delgado-García, José María - Wandosell, Francisco - Cubelos Álvarez, Beatriz
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