Fbxw7 is a critical regulator of Schwann cell myelinating potential

Background of this study

Myelin is a structure rich in lipids that surrounds larger axons, which allows electrical signals to propagate fast and efficiently, protects the axon from insult, and actively participates in regeneration after injury. The cells specialized in myelination are different in the central and peripheral nervous system: in the central nervous system, it is the oligodendrocyte, while in the peripheral, it is the Schwann cell. Although Schwann cells and oligodendrocytes share part of their transcriptional regulators during development and are organized similarly, their molecular composition of myelin differs. Importantly, in the central nervous system, oligodendrocytes are capable of producing myelin sheaths encapsulating multiple axons, while Schwann cells acquire a 1:1 relationship to large diameter axons in the peripheral nervous system. While several genes and signaling pathways are reported to regulate myelinating potential of oligodendrocytes and Schwann cells, what governs the decision of mono- or multi-axonal myelination still remains elusive.

Key findings

In this preprint, Harty et al. discovered that the loss of a E3 ubiquitin ligase, Fbxw7, would enable Schwann cells to form myelin sheath over multiple axons simultaneously. In the central nervous system, Fbxw7 is known to suppress oligodendrocyte formation via inhibition of Notch signaling and to regulate the myelination potential of oligodendroctyes by inhibiting mTOR signaling. To investigate the role of Fbxw7 in Schwann cells, the authors conditionally deleted Fbxw7 in Schwann cells. They reported haploinsufficiency of Fbxw7 leads to increased Schwann cell number perinatally on postnatal day 3, which is later compensated by postnatal day 42 when no difference could be detected between Fbxw7 mutant and wild type control. Myelin sheath thickened, and the size of Remak bundles decreased especially for axons with smaller caliber in Fbxw7 mutant. Beyond that, the authors observed multi-axon myelination of Schwann cells in adult mice, which is reminiscent of oligodendrocytes. To elucidate the mechanism underlying these phenotypes, Harty et al. hypothesized that mTOR signaling might be the target of Fbxw7 similar to what was reported in oligodendrocytes. To test this, they knocked out both mTOR and Fbxw7 in Schwann cells to see if mTOR signaling accounts for the changes in Schwann cells. The loss of mTOR in Fbxw7 mutants did revert myelin sheath thickness and Remak bundle size, but multi-axonal myelination persisted despite the absence of mTOR.

Why I like this paper

How functional diversity is linked to genetic regulation has been a puzzling but intriguing question. In the nervous system, slight differences in extrinsic signaling or birth timing could give rise to completely different cell types, like spinal motor neurons and oligodendrocytes; on the other hand, cells of different origin could end up performing seemingly similar tasks, like the oligodendrocytes and Schwann cells. It is thus tempting to assume there are pre-wired functional modules waiting to be selectively activated by the master regulators. Different cell types that end up performing similar tasks could thus harbor their unique set of fate determining factors, and those factors would later turn on the same functional gene module and other non-overlapping modulators to become functionally similar but different. Echoing this hypothesis, Harty et al. demonstrated that Fbxw7 could act as a hub for coordinating various signaling pathways and determine the degree and pattern of myelination in Schwann cells and oligodendrocytes.

Open Questions

1. Since the loss of Fbxw7 results in oligodendrocyte-like myelination in Schwann cells, it would be interesting to see whether excessive Fbxw7 could force oligodendrocytes to act more like Schwann cells.
2. The discovery of this study makes one wonder whether Fbxw7 is differentially expressed in different types of oligodendrocytes, which are known to behave differently in myelination.
3. Considering the previously suggested role of glial cells in regeneration failure in adult CNS injury, it would be critical to test whether the difference in myelination driven by Fbxw7 would change the regeneration potential of peripheral nervous system when Schwann cells become oligodendrocyte-like.

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