Sox2 expression in Schwann cells inhibits myelination in vivo and induces influx of macrophages to the nerve

Abstract

Correct myelination is crucial for the function of the peripheral nervous system. Both positive and negative regulators within the axon and Schwann cell function to ensure the correct onset and progression of myelination during both development and following peripheral nerve injury and repair. The Sox2 transcription factor is well known for its roles in the development and maintenance of progenitor and stem cell populations, but has also been proposed as a negative regulator of myelination in Schwann cells. We wished to test fully whether Sox2 regulates myelination and show here that, in mice, sustained Sox2 expression blocks myelination in the peripheral nerves and maintains Schwann cells in a proliferative non-differentiated state, which is also associated with increased inflammation within the nerve. The plasticity of Schwann cells allows them to re-myelinate regenerated axons following injury and we show that re-myelination is also blocked by Sox2 expression in Schwann cells. These findings identify Sox2 as a physiological regulator of Schwann cell myelination and its potential to play a role in disorders of myelination in the peripheral nervous system.

Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

“…In addition to the phagocytic activity, our data suggest that L‐PGDS may control other processes regulating macrophage number in injured nerves. Previous studies have reported cell proliferation (Mueller et al, ), altered BNB permeability (Liu et al, ; Omura et al, ), chemokines production (DeFrancesco‐Lisowitz et al, ), and more recently, enhanced expression of the transcription factor SOX2 in Schwann cells (Dun et al, ; Roberts et al, ).…”

“…Lastly, we determined whether altered expression of the transcription factor SOX2 could influence macrophage recruitment. SOX2 is upregulated in Schwann cells soon after injury (Le et al, ) and its overexpression increases macrophage number in uncrushed and crushed nerves (Roberts et al, ). Notably, recent studies have shown that glial SOX2 modulates the signaling between Schwann cells and macrophages to regulate nerve bridge formation after injury (Dun et al, ).…”

“…Although our data do not clarify the mechanism, L‐PGDS might downregulate Sox2 expression in Schwann cells after injury, similarly to what observed in embryonic male germ cells, where PGD 2 treatment represses it (Moniot et al, ). Thus, prolonged SOX2 expression might induce accumulation of macrophages in L ‐ pgds −/− nerves, as SOX2 overexpression in Schwann cells increases the number of macrophages (Roberts et al, ). A recent work demonstrated that SOX2 expression in breast cancer cells regulates the recruitment of tumor‐associated macrophages through the secretion of cytokines (Mou et al, ).…”

Schwann cell plasticity‐roles in tissue homeostasis, regeneration, and disease

“…However, the requirement of Sox‐2 to induce collective SC migration is a previously unappreciated role for a stemness factor to control other aspects of progenitor‐cell behavior such as sustained migration. However, the expression of Sox‐2 needs to be tightly regulated, as sustained expression of Sox‐2 following nerve injury appears to be sufficient to maintain SCs in their dedifferentiated state (Roberts et al, ).…”

Transcriptional control of myelination and remyelination

“…Repair Schwann cells also express Sox2 (Parrinello et al, ) (Figure c). This transcription factor keeps repair Schwann cells in a proliferative state (Roberts et al, ), and may additionally help to redistribute N‐cadherin downstream of EphB receptors on the Schwann cell surface to allow collective migration and Bungner band formation (Parrinello et al, ). Repair Schwann cells also depend on Stat3 activity to maintain their properties and survive (Benito et al, ) (Figure c).…”