Rac1 and Rac3 have opposite functions in Schwann cells during developmental myelination. (14th May 2021) - Pellegatta, Marta
Highlights: Rac1 and Rac3 have opposite roles in radial sorting and peripheral myelination during development. Rac3 acts via PAK1 activation, lamellipodia formation and Schwann cell differentiation to compete with Rac1. Neuronal Rac3 is not necessary for axonal integrity. Rac3 only antagonizes Rac1 action in a precise time window, with a global predominance of Rac1 in Schwann cell function. Abstract: Small Rho GTPases such as Cdc42 and Rac1 regulate peripheral myelination during development. Deletion of Rac1 in Schwann cell conditional knockout mice causes a delay in the process of radial sorting, followed by hypomyelination as well as defective PAK1 activation and high number of immature Oct6 + Schwann cells. Rac3 has been shown to have redundant, specific and even opposite functions to Rac1 depending on the cell type, age and other factors. In neuronal cells, evidence suggests that Rac3 may oppose Rac1 by disrupting PAK1-GIT1-Paxillin signaling thus preventing cell differentiation and extension of lamellipodia. Therefore, we tested if these Rho GTPases have similar or opposite functions in Schwann cells, by deleting the genes for both proteins in mice during peripheral myelination. At P30, global deletion of Rac3 alleviates the developmental defects on axonal sorting and hypomyelination that are caused by Schwann cell conditional ablation of Rac1. Moreover, Rac3 deletion also reverses the arrest of Schwann cells at the Oct6 + stage and ameliorates the defects in PAK1 phosphorylation observed in Rac1 deficient mice. This partial rescue of the phenotype declines later on with aging. Since double transgenic animals showed dysmyelination without axonal degeneration at P60, we postulate that this deterioration is not likely due to loss of Rac3 in neurons, but it seems to be a Schwann cell-specific defect in the maintenance of myelin.