PMP2 regulates myelin thickening and ATP production during remyelination.

It is well established that axonal Neuregulin 1 type 3 (NRG1t3) regulates developmental myelin formation as well as EGR2-dependent gene activation and lipid synthesis. However, in peripheral neuropathy disease context, elevated axonal NRG1t3 improves remyelination and myelin sheath thickness without increasing Egr2 expression or activity, and without affecting the transcriptional activity of canonical myelination genes. Surprisingly, Pmp2, encoding for a myelin fatty acid binding protein, is the only gene whose expression increases in Schwann cells following overexpression of axonal NRG1t3. Here, we demonstrate PMP2 expression is directly regulated by NRG1t3 active form, following proteolytic cleavage. Then, using a transgenic mouse model overexpressing axonal NRG1t3 (NRG1t3OE) and knocked out for PMP2, we demonstrate that PMP2 is required for NRG1t3-mediated remyelination. We demonstrate that the sustained expression of Pmp2 in NRG1t3OE mice enhances the fatty acid uptake in sciatic nerve fibers and the mitochondrial ATP production in Schwann cells. In sum, our findings demonstrate that PMP2 is a direct downstream mediator of NRG1t3 and that the modulation of PMP2 downstream NRG1t3 activation has distinct effects on Schwann cell function during developmental myelination and remyelination.

Cc2d1b Contributes to the Regulation of Developmental Myelination in the Central Nervous System.

Background: Numerous 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. Methods: We 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. Results: In 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. Conclusions: We 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.

YAP and TAZ regulate Schwann cell proliferation and differentiation during peripheral nerve regeneration.

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.