p38 MAPK Activation Promotes Denervated Schwann Cell Phenotype and Functions as a Negative Regulator of Schwann Cell Differentiation and Myelination

Abstract

Physical damage to the peripheral nerves triggers Schwann cell injury response in the distal nerves in an event termed Wallerian degeneration: the Schwann cells degrade their myelin sheaths and de-differentiate, reverting to a phenotype that supports axon regeneration and nerve repair. The molecular mechanisms regulating Schwann cell plasticity in the PNS remain to be elucidated. Using both in vivo and in vitro models for peripheral nerve injury, here we show that inhibition of p38 MAPK activity in mice blocks Schwann cell demyelination and de-differentiation following nerve injury, suggesting that the kinase mediates the injury signal that triggers distal Schwann cell injury response. In myelinating co-cultures, p38 MAPK also mediates myelin breakdown induced by Schwann cell growth factors, such as neuregulin and FGF-2. Furthermore, ectopic activation of p38 MAPK is sufficient to induce myelin breakdown and drives differentiated Schwann cells to acquire phenotypic features of immature Schwann cells. We also show that p38 MAPK concomitantly functions as a negative regulator of Schwann cell differentiation: enforced p38 MAPK activation blocks cAMP-induced expression of Krox 20 and myelin proteins, but induces expression of c-Jun. As expected of its role as a negative signal for myelination, inhibition of p38 MAPK in co-cultures promotes myelin formation by increasing the number as well as the length of individual myelin segments. Altogether, our data identify p38 MAPK as an important regulator of Schwann cell plasticity and differentiation.

The c-Jun kinase signaling cascade promotes glial engulfment activity through activation of draper and phagocytic function

“…29 Intriguingly, peripheral nerve injury also leads to activation of JNK signaling in mammalian Schwann cells through the p38 mitogen-activated protein kinase cascade, apparently promoting Schwann cell de-differentiation as a part of nerve repair. 30 Moreover, expression of mammalian Draper, MEGF10, is dramatically upregulated in Schwann cells after sciatic nerve lesion. 31 Thus, activation of glial JNK signaling and ultimately expression of Draper/MEGF10 appears to be a conserved glial response to axonal injury.…”

N-cadherin expression is regulated by UTP in schwannoma cells

“…In contrast, the role of the p38 MAPK in SCs is controversial. Some authors have suggested that it is associated with regulation of myelination [53,54], and others that it is a negative regulator of SC differentiation and myelination [55]. Thus, activation of the MAPK pathway by extracellular UTP seems to mediate the increase of N-cadherin expression and could explain the relationship of MAPKs with cell adhesion, migration and dedifferentiation.…”

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…This protein has been shown to stimulate a local inflammatory response via interaction with RAGE 103 , leading to activation of mitogen-activated protein kinases (MAPKs), NF-κB and apoptosis 104,105 . Similarly, MAPKs (such as p38 MAPK, MAPK1, MAPK3, MAPK8 and MAPK10) are activated by high glucose levels in human Schwann cell cultures 106 ; p38 is of particular interest, as it is a negative regulator of Schwann cell differentiation and myelination 107 .…”