PAK2 is necessary for myelination in the peripheral nervous system

B. Hu, D. Moiseev, I. Schena, B. Faezov, R. Dunbrack, C. Jonathan, J. Li

Research output: Contribution to journalArticlepeer-review

Abstract

Myelination enables electrical impulses to propagate on axons at the highest speed, encoding essential life functions. The Rho family GTPases, RAC1 and CDC42, have been shown to critically regulate Schwann cell myelination. P21-activated kinase 2 (PAK2) is an effector of RAC1/CDC42, but its specific role in myelination remains undetermined. We produced a Schwann cell-specific knockout mouse of Pak2 (scPak2-/-) to evaluate PAK2's role in myelination. Deletion of Pak2 specifically in mouse Schwann cells resulted in severe hypomyelination, slowed nerve conduction velocity, and behavior dysfunctions in the scPak2-/- peripheral nerve. Many Schwann cells in scPak2-/-sciatic nerves were arrested at the stage of axonal sorting. These abnormalities were rescued by reintroducing Pak2, but not the kinase-dead mutation of Pak2, via lentivirus delivery to scPak2-/- Schwann cells in vivo. Moreover, ablation of Pak2 in Schwann cells blocked the promyelinating effect driven by neuregulin-1, prion protein, and inactivated RAC1/CDC42. Conversely, the ablation of Pak2 in neurons exhibited no phenotype. Such PAK2 activity can also be either enhanced or inhibited by different myelin lipids. We have identified a novel promyelinating factor, PAK2, that acts as a critical convergence point for multiple promyelinating signaling pathways. The promyelination by PAK2 is Schwann cell-autonomous. Myelin lipids, identified as inhibitors or activators of PAK2, may be utilized to develop therapies for repairing abnormal myelin in peripheral neuropathies.
Original languageAmerican English
Article numberawad413
Pages (from-to)1809-1821
Number of pages13
JournalBrain
Volume147
Issue number5
Early online dateNov 11 2023
DOIs
StatePublished - 2023

Keywords

  • Pak2 knock-out mouse GTPases Rac1/Cdc42 Schwann cells myelin lipids myelination peripheral nerve

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