Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

Abstract

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from the slow growth of axons. This impairs axonal regeneration and causes a significant clinical problem. In mice, we find that repair cells express reduced c-Jun protein as the regenerative support provided by these cells declines in aging animals and during chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates the success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, and suggests molecular pathways that can be targeted to promote repair in the PNS.

The Presence of Myelinated Nerves and Schwann Cells in White Adipose Tissue: Proximity to Synaptic Vesicle Containing Nerve Terminals and Potential Role in BTBR ob/ob Demyelinating Diabetic Neuropathy

“…The copyright holder for this preprint this version posted September 8, 2022. ; https://doi.org/10.1101/2022.08.25.505298 doi: bioRxiv preprint (GDNF). Previous studies have demonstrated the decreased ability of aged mice to regenerate nerves post-injury when compared to their younger counterparts as a result of decreased c-Jun expression [17], and neuropathic diseases such as CIDP are characterized by a loss of SC plasticity [57]. Notably, qPCR of c-Jun in scWAT revealed almost no difference between young and old mice while displaying upregulation in obese BTBR ob/ob mice (Figure 6).…”

“…A hallmark feature of SCs is their ability to shift towards a repair phenotype in response to injury, releasing neurotrophic factors such as BDNF and glial cell line-derived neurotrophic factor Schwann Cells in Subcutaneous Adipose Tissue (GDNF). Previous studies have demonstrated the decreased ability of aged mice to regenerate nerves post-injury when compared to their younger counterparts as a result of decreased c-Jun expression [17], and neuropathic diseases such as CIDP are characterized by a loss of SC plasticity [57]. Notably, qPCR of c-Jun in scWAT revealed almost no difference between young and old mice while displaying upregulation in obese BTBR ob/ob mice (Figure 6).…”

“…have not yet been examined. We investigated gene expression changes in scWAT with obesity, aging, cold exposure, and exercise using six SC specific markers: the pan-SC markers Sox10 [25; 26], oligodendrocyte marker 4 (O4) [37], and neurotrophin receptor p75 (p75) [37; 38]; the myelin-specific markers Mpz and Krox20 [39; 40]; and the repair SC transcription factor c-Jun [17]. Because the associated changes in innervation status are likely to impact the total number of SCs, we also normalized gene expression to the pan-SC gene to investigate changes not confounded by changes in total SC number (Figure 6).…”

“…The conversion, or transdifferentiation, of mature SCs to repair SCs involves downregulation of myelin-production genes (such as myelin basic protein (MBP), Krox20, and myelin protein zero (MPZ)), and upregulation of glial fibrillary acidic protein (GFAP), the neurotrophic factor receptor p75NTR, and c-Jun [16]. Restoration of c-Jun expression in SCs is able to rescue failed nerve regeneration in aging mice [17], and is thus considered a master regulator of repair SC phenotypic conversion. The exact signals from damaged nerves (released during a process known as Wallerian degeneration) that promote SC conversion to repair SCs is currently unknown.…”

Melatonin signalling in Schwann cells during neuroregeneration

“…Since RSC96 is a transformed cell line, further studies using primary Schwann cells need to be carried out to confirm these results. Nevertheless, SHH has been shown to stimulate in Schwann cells activation of c–Jun, a downstream transcription factor of the MAP kinases ( Wagstaff et al, 2020 ). Therefore, the pathways via SHH, c–Jun, and MAPK seem to be interconnected.…”