R-RAS1 AND R-RAS2 ARE ESSENTIAL FOR THE OLIGODENDROCYTE-AXON INTERACTION

Axonal myelination is an essential process for the rapid, efficient, and coordinated transmission of nerve impulses. In the Central Nervous System, oligodendrocytes are responsible for generating the myelin sheaths that envelop axons through a process tightly regulated by adhesion proteins and a dynamic cytoskeleton. Although it has been established that β1 integrin is critical for myelination, the molecular mechanisms regulating its activation during the oligodendrocyte-axon interaction remain unresolved. Previous work from our laboratory had demonstrated that the GTPases R-Ras1 and R-Ras2 are essential for oligodendrocyte survival and maturation. In this study, we report that R-Ras1 and R-Ras2 act as regulators of β1integrin activity during oligodendrocyte maturation and myelination. Through protein interaction studies, we found that R-Ras1 and R-Ras2 associate with β1 integrin in oligodendrocytes and that their absence leads to a significant reduction in β1 integrin activity and defects in the actin cytoskeleton reorganisation necessary for axonal sheathing. Consistently, ultrastructural analyses revealed that the absence of R-Ras1 and/or R-Ras2 impaired proper axonal ensheathment and resulted in hypomyelination. Our findings establish a new regulatory axis between R-Ras1, R-Ras2, β1 integrin, and the actin cytoskeleton as a fundamental mechanism controlling Central Nervous System myelination.