2023
bioRxiv

PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

Authors:

Lucas Baudouin, Noémie Adès, Kadia Kanté, Corinne Bachelin, Hatem Hmidan, Cyrille Deboux, Radmila Panic, Rémy Ben Messaoud, Yoan Velut, Soumia Hamada, Cédric Pionneau, Kévin Duarte, Sandrine Poëa-Guyon, Jean-Vianney Barnier, Brahim Nait Oumesmar, Lamia Bouslama-Oueghlani

Keywords:

myelin; oligodendrocytes; actin dynamics; actin; myelination; PAK1; P21-activated kinase; NF2; Merlin

Abstract:

In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts the axon, while a drastic shift to actin depolymerization is required to enable the following step of wrapping and expansion of myelin membranes. The molecular mechanisms triggering this switch, essential for proper myelination, have yet to be elucidated. Here, we identify P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. We show that PAK1 accumulates in OLs in a kinase inhibited form, triggering actin disassembly and, consequently, myelin expansion. Remarkably, we identify NF2/Merlin as an endogenous inhibitor of PAK1 by proteomics analysis of its binding partners. We found that Nf2 knockdown in OLs results in PAK1 activation and impairs myelin formation, and that pharmacological inhibition of PAK1 in Nf2-knockdown OLs rescues these defects. Moreover, we demonstrate that modulating PAK1 activity in OLs controls myelin expansion and provide compelling evidence indicating that specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that PAK1-NF2/Merlin duo plays a key role in actin cytoskeleton remodeling in OLs, required for proper myelin formation. These findings have broad mechanistic and therapeutic implications for demyelinating diseases and neurodevelopmental disorders.