Molecular mechanisms of Oligodendrocyte-Neuron interaction & pathologies associated with myelin (Cubelos Lab)

Rapid and effective neural transmission of information requires correct axonal myelination. Modifications in myelination alter axonal capacity to transmit electric impulses. 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. Our lab has demonstrated that OLs express R-Ras1 and R-Ras2. 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. These defects explain the slower conduction velocity of myelinated axons that we observed in the absence of R-Ras1 and R-Ras2.  In addition, 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.  However little is known about the role that R-Ras1 and R-Ras2 play in the neurons. Specifically, alterations in myelin produce an important illnesses such as Multiple Sclerosis, optic neuromyelitis and hypomyelinating leukodystrophies (ELA) among others. Demyelinating diseases present a moderate-high prevalence, presenting 60 cases each 100.000 inhabitants, this implies that in Spain more than 50.000 people suffer this kind of pathologies. Establishing the molecular bases implicated in mielination constitutes an important target for our research group. In our laboratory we investigate the role that R-Ras subfamily members play in the regulation of differentiation and survival processes of oligodendrocytes and neurons through PI3K/AKT molecular pathway.