YAP and TAZ are effectors of the Hippo pathway that controls multicellular development by integrating chemical and mechanical signals. Peripheral nervous system development depends on the Hippo pathway. We previously showed that loss of YAP and TAZ impairs the development of peripheral nerve as well as Schwann cell myelination. The role of the Hippo pathway in peripheral nerve regeneration has just started to be explored. After injury, Schwann cells adopt new identities to promote regeneration by converting to a repair‐promoting phenotype. While the reprogramming of Schwann cells to repair cells has been well characterized, the maintenance of such repair phenotype cannot be sustained for a very long period, which limits nerve repair in human. First, we show that short or long‐term myelin maintenance is not affected by defect in YAP and TAZ expression. Using crush nerve injury and conditional mutagenesis in mice, we also show that YAP and TAZ are regulators of repair Schwann cell proliferation and differentiation. We found that YAP and TAZ are required in repair Schwann cells for their redifferentiation into myelinating Schwann cell following crush injury. In this present study, we describe how the Hippo pathway and YAP and TAZ regulate remyelination over time during peripheral nerve regeneration.

Peripheral nerves and Schwann cells have to sustain constant mechanical constraints, caused by developmental growth as well as stretches associated with movements of the limbs and mechanical compressions from daily activities. In Schwann cells, signaling molecules sensitive to stiffness or stretch of the extracellular matrix, such as YAP/TAZ, have been shown to be critical for Schwann cell development and peripheral nerve regeneration. YAP/TAZ have also been suggested to contribute to tumorigenesis, neuropathic pain, and inherited disorders. Yet, the role of mechanosensitive ion channels in myelinating Schwann cells is vastly unexplored. Here we comprehensively assessed the expression of mechanosensitive ion channels in Schwann cells and identified that PIEZO1 and PIEZO2 are among the most abundant mechanosensitive ion channels expressed by Schwann cells. Using classic genetic ablation studies, we show that PIEZO1 is a transient inhibitor of radial and longitudinal myelination in Schwann cells. Contrastingly, we show that PIEZO2 may be required for myelin formation, as the absence of PIEZO2 in Schwann cells delays myelin formation. We found an epistatic relationship between PIEZO1 and PIEZO2, at both the morphological and molecular levels. Finally, we show that PIEZO1 channels affect the regulation of YAP/TAZ activation in Schwann cells. Overall, we present here the first demonstration that PIEZO1 and PIEZO2 contribute to mechanosensation in Schwann cells as well myelin development in the peripheral nervous system.

BackgroundNumerous studies have indicated that myelination is the result of the interplay between extracellular signals and an intricate network of transcription factors. Yet, the identification and characterization of the full repertoire of transcription factors that modulate myelination are still incomplete. CC2D1B is a member of the Lgd/CC2D1 family of proteins highly expressed in myelinating cells in the central and peripheral nervous systems. In addition, the absence of CC2D1B limits myelin formation in vitro. Here we propose to delineate the function of CC2D1B in myelinating cells during developmental myelination in vivo in the central and peripheral nervous systems.MethodsWe used a Cc2d1b constitutive knockout mouse model and then performed morphological analyses on semithin sections of sciatic nerves and electron micrographs of optic nerves. We also performed immunohistological studies on coronal brain sections. All analyses were performed at 30 days of age.ResultsIn the peripheral nervous system, animals ablated for Cc2d1b did not show any myelin thickness difference compared to control animals. In the central nervous system, immunohistological studies did not show any difference in the number of oligodendrocytes or the level of myelin proteins in the cortex, corpus callosum, and striatum. However, optic nerves showed a hypomyelination (0.844 ± 0.022) compared to control animals (0.832 ± 0.016) of large diameter myelinated fibers.ConclusionsWe found that CC2D1B plays a role in developmental myelination in the central nervous system. These results suggest that CC2D1B could contribute to gene regulation during oligodendrocytes myelination in optic nerves.