RhoA Enhances Schwann Cell Microtubule Dynamics and Myelination via a YAP1/TEAD3/CDK2/ASPM/p60-Katanin Axis

RhoA is well known as a key molecular switch for cytoskeleton remodeling, and previous studies reveal RhoA plays a pivotal role in Schwann cell myelination which is highly dependent on the dynamics regulation of the actin and microtubule cytoskeleton. Existing evidence indicates RhoA modulates myelination and other biofunctions by targeting actin filament turnover; however, the role of RhoA in microtubule dynamics remains unknown. Herein, Bulk mRNA sequencing and bioinformatic analysis enriched microtubule dynamics-related ontology terms in RhoA knockout Schwann cells, and identified that microtubules contribute to RhoA deficiency-caused hypomyelination. Both in vivo and in vitro experiments demonstrated that genetic ablation or pharmacological inhibition of RhoA attenuates microtubule dynamics in Schwann cells, whereas activated RhoA overexpression or RhoA agonist enhances the microtubule dynamics. RhoA conditional knockout (cKO) in Schwann cells led to hypomyelination, dysmyelination and nerve functional deficits in mice. Mechanistically, the present study identified CDK2 as a crucial mediating molecule for RhoA regulating microtubule dynamics. CDK2 overexpression could reverse the reduced microtubule dynamics, hypomyelination and motor deficits in RhoA cKO mice. Furthermore, RhoA modulating CDK2 is dependent on YAP/TEAD signaling, and the ASPM/p60-Katanin axis mediates the role of CDK2 in controlling microtubule dynamics. Collectively, this study uncovered a novel RhoA/YAP1/TEAD3/CDK2/ASPM/p60-Katanin axis in regulating microtubule dynamics during Schwann cell myelination, which indicates that this pathway may be utilized as new targets for repairing congenital hypomyelination/dysmyelination neuropathy or peripheral nerve injury.