Myelinating Schwann cells ensheath multiple axons in the absence of E3 ligase component Fbxw7

Breanne L Harty,David A Lyons,Jonah R Chan,Kelly R Monk,Fernanda Coelho,Sarah E Pease-Raissi,Amit Mogha,Sarah D Ackerman,Amy L Herbert,Judith P Golden,Robert W Gereau

doi:10.1038/s41467-019-10881-y

Abstract

In the central nervous system (CNS), oligodendrocytes myelinate multiple axons; in the peripheral nervous system (PNS), Schwann cells (SCs) myelinate a single axon. Why are the myelinating potentials of these glia so fundamentally different? Here, we find that loss of Fbxw7, an E3 ubiquitin ligase component, enhances the myelinating potential of SCs. Fbxw7 mutant SCs make thicker myelin sheaths and sometimes appear to myelinate multiple axons in a fashion reminiscent of oligodendrocytes. Several Fbxw7 mutant phenotypes are due to dysregulation of mTOR; however, the remarkable ability of mutant SCs to ensheathe multiple axons is independent of mTOR signaling. This indicates distinct roles for Fbxw7 in SC biology including modes of axon interactions previously thought to fundamentally distinguish myelinating SCs from oligodendrocytes. Our data reveal unexpected plasticity in the myelinating potential of SCs, which may have important implications for our understanding of both PNS and CNS myelination and myelin repair.

Highlights

In the central nervous system (CNS), oligodendrocytes myelinate multiple axons; in the peripheral nervous system (PNS), Schwann cells (SCs) myelinate a single axon
To delete Fbxw[7] in SCs, we crossed Dhhcre with an Fbxw7fl/fl transgenic line in which loxP sites flank exons 5 and 6 of Fbxw[711]. This creates a frameshift upon Cre activity resulting in a null allele, which we confirmed using RTPCR to visualize the absence of mRNA (Supplementary Fig. 1a)
In addition to mTOR, we found that several other well-known targets of Fbxw[7] including cJun[25], Notch, and Cyclin E are expressed in normal sciatic nerves at postnatal day 3 (P3) and P21 (Fig. 6a). c-Jun stood out among these possible targets because it is required for the acquisition of the repair SC phenotype[26,27,28], the multipolar morphology assumed by Fbxw[7] mutant SCs is reminiscent of branched repair SCs29, and loss of Fbxw[7] has previously been shown to elevate c-Jun levels[30]

Summary

Introduction

In the central nervous system (CNS), oligodendrocytes myelinate multiple axons; in the peripheral nervous system (PNS), Schwann cells (SCs) myelinate a single axon. Oligodendrocytes (OLs) and Schwann cells (SCs) are specialized glial cells that generate the myelin sheaths of the central nervous system (CNS) and peripheral nervous system (PNS), respectively. Even in the absence of mTOR, Fbxw[7] mutant SCs appear to retain the ability to myelinate multiple axons, as well as simultaneously myelinate large axons while ensheathing small unmyelinated axons. This suggests that the molecular mechanisms that regulate the fundamental difference in myelinating potential between SCs and OLs are independent of mTOR signaling. Our findings show that the restriction of myelinating SCs to myelinate a single axon may be mutable and that Fbxw[7] is a critical player in regulating the myelinating potential of SCs

Methods

Results

Conclusion