Papel de R-Ras1 y R-Ras2 en la mielinización del Sistema Nervioso Central

Laburpena

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 central nervous system (CNS), oligodendrocytes (OLs) myelinate axons, a complex process involving PI3K/Akt and Erk1/2/MAPK molecular pathways. However, little is known about the mechanisms that orchestrate correct myelination. In our study, we demonstrate that OLs of the principal myelinated tracts express R-Ras1 and R-Ras2. Using mutant mice lacking R-Ras1(R-Ras1-/-), R-Ras2 (R-Ras2-/-) or both proteins (R-Ras1-/-;R-Ras2-/-), we find that activation of the PI3K/Akt and Erk1/2/MAPK pathways is weaker compared with control mice, suggesting that both proteins coordinate the activity these two pathways in OLs. 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 in vitro 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 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. Therefore, we conclude that R-Ras1 and R-Ras2 are essential for the proper myelination of axons and the correct transmission of nerve impulses, essential requirements for proper sensory, motor and cognitive integration