The Neuregulin‐Rac‐MKK7 pathway regulates antagonistic c‐jun/Krox20 expression in Schwann cell dedifferentiation

Abstract

Schwann cells respond to nerve injury by dedifferentiating into immature states and producing neurotrophic factors, two actions that facilitate successful regeneration of axons. Previous reports have implicated the Raf-ERK cascade and the expression of c-jun in these Schwann cell responses. Here we used cultured primary Schwann cells to demonstrate that active Rac1 GTPase (Rac) functions as a negative regulator of Schwann cell differentiation by upregulating c-jun and downregulating Krox20 through the MKK7-JNK pathway, but not through the Raf-ERK pathway. The activation of MKK7 and induction of c-jun in sciatic nerves after axotomy was blocked by Rac inhibition. Microarray experiments revealed that the expression of regeneration-associated genes, such as glial cell line-derived neurotrophic factor and p75 neurotrophin receptor, after nerve injury was dependent on Rac but not on ERK. Finally, the inhibition of ErbB2 signaling prevented MKK7 activation, c-jun induction, and Rac-dependent gene expression in sciatic nerve explant cultures. Taken together, our results indicate that the neuregulin-Rac-MKK7-JNK/c-jun pathway regulates Schwann cell dedifferentiation following nerve injury.

Epigenomic Regulation of Schwann Cell Reprogramming in Peripheral Nerve Injury

“…Age-dependent epigenetic change can play a role because it was shown that a decline in the brain remyelination with aging is an outcome of the progressive loss of HDACmediated repression (Shen et al, 2008). Our analyses showed that several of injury-activated genes affected by aging, including Fgf5, Bdnf, Gdnf, and Igfbp2 (Painter et al, 2014), are regulated by H3K27me3, which implies that there may be age-related impairment in the demethylation dynamics.…”

“…In addition, ϳ50 -80% of Schwann cells are myelinating and the rest are nonmyelinating Schwann cells (Zorick et al, 1996;Topilko et al, 1997). For those genes expressed at very low levels in mature nerve, this would suggest, although not prove, that their expression is repressed in both Schwann cell types.…”

Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: Uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves

“…The effects of p75 NGFR on Schwann cells after injury are complex as p75 NGFR has roles in both Schwann cell apoptosis (Syroid et al, 2000) and myelination, depending on ligand presentation and intracellular binding partners (Cosgaya et al, 2002; Provenzano et al, 2008; Teng et al, 2005; Tep et al, 2012). Signaling through p75 NGFR can lead to activation of c-Jun-dependent downstream signaling pathways to regulate Schwann cell survival and differentiation (Lindwall Blom et al, 2014; Shin et al, 2013; Yeiser et al, 2004). Interestingly, c-Fos, which forms the AP1 transcription factor complex with c-Jun, was significantly upregulated in uninjured and 14dpi Cx32KO nerves, relative to WT.…”

Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

“…Another pathway implicated in the Schwann cell's response to nerve injury is the ERK pathway. For example, induced activation of the Raf-ERK pathway results in induction of demyelination, and many of the genes induced by ERK activation (Mcp1/Ccl2, Cxcl10, Timp1, TGF␤1, and Megf10) appear to be distinct from c-jun-dependent genes (20,22). In particular, Ccl2 is a critical chemokine involved in recruiting macrophages to peripheral nerves after injury and in a peripheral neuropathy induced by a myelin gene mutation (78).…”