The Role of c-Jun and Autocrine Signaling Loops in the Control of Repair Schwann Cells and Regeneration

Abstract

After nerve injury, both Schwann cells and neurons switch to pro-regenerative states. For Schwann cells, this involves reprogramming of myelin and Remak cells to repair Schwann cells that provide the signals and mechanisms needed for the survival of injured neurons, myelin clearance, axonal regeneration and target reinnervation. Because functional repair cells are essential for regeneration, it is unfortunate that their phenotype is not robust. Repair cell activation falters as animals get older and the repair phenotype fades during chronic denervation. These malfunctions are important reasons for the poor outcomes after nerve damage in humans. This review will discuss injury-induced Schwann cell reprogramming and the concept of the repair Schwann cell, and consider the molecular control of these cells with emphasis on c-Jun. This transcription factor is required for the generation of functional repair cells, and failure of c-Jun expression is implicated in repair cell failures in older animals and during chronic denervation. Elevating c-Jun expression in repair cells promotes regeneration, showing in principle that targeting repair cells is an effective way of improving nerve repair. In this context, we will outline the emerging evidence that repair cells are sustained by autocrine signaling loops, attractive targets for interventions aimed at promoting regeneration.

Sexually dimorphic transcriptional programs of early-phase response in regenerating peripheral nerves

“…After nerve injury, Schwann cells assume a pro-regenerative function ( Jessen and Mirsky, 2016 , 2021 ; Merrell and Stanger, 2016 ; Milichko and Dyachuk, 2020 ), exhibiting an exceptional phenotypic plasticity ( Jessen and Arthur-Farraj, 2019 ; Stierli et al, 2019 ; Nocera and Jacob, 2020 ) that supports their de-differentiation, proliferation, and re-differentiation into myelinating and non-myelinating phenotype to facilitate repair of the respective axons. Schwann cell reprogramming is controlled by a set of TFs ( Balakrishnan et al, 2021 ), including Myt1l, Pou3f1/Oct6, Myrf, Olig1/2, Jun, Sox-, Hox-, and Fox-family members TFs upregulated at 24 h post-axotomy predominantly in males.…”

“…Furthermore, GDNF/Gfra1 could interact with neural cell adhesion molecules such as NCAM to induce an axonal expansion ( Nielsen et al, 2009 ). GDNF family of ligands can act in a synergetic manner with other growth factors, including transforming growth factor-β (Tgf-β) and sonic hedgehog (Shh) [reviewed in Jessen and Mirsky (2021) ]. GDNF signaling can stimulate the migration of neuronal precursors and Schwann cells ( Iwase et al, 2005 ) to the injury site in both sexes.…”

“…Axonal regrowth in the damaged PNS depends on trophic, immune, metabolic, and structural support of Schwann cells ( Jessen and Mirsky, 2016 , 2021 ; Merrell and Stanger, 2016 ; Milichko and Dyachuk, 2020 ), forming immediate partnerships with axons ( McDonald et al, 2006 ). Schwann cells undergo extensive phenotypic transformation within 24 h post-injury in preparation for mitosis and alignment into bands of Büngner ( Jessen and Mirsky, 2016 , 2021 ; Merrell and Stanger, 2016 ; Milichko and Dyachuk, 2020 ).…”

“…Axonal regrowth in the damaged PNS depends on trophic, immune, metabolic, and structural support of Schwann cells ( Jessen and Mirsky, 2016 , 2021 ; Merrell and Stanger, 2016 ; Milichko and Dyachuk, 2020 ), forming immediate partnerships with axons ( McDonald et al, 2006 ). Schwann cells undergo extensive phenotypic transformation within 24 h post-injury in preparation for mitosis and alignment into bands of Büngner ( Jessen and Mirsky, 2016 , 2021 ; Merrell and Stanger, 2016 ; Milichko and Dyachuk, 2020 ). Schwann cells produce and deposit into basal lamina a plethora of growth-permissive and -inhibitory extracellular matrix (ECM) proteins and proteoglycans to guide axonal growth, such as laminin and chondroitin sulfate proteoglycans ( McDonald et al, 2006 ).…”

Sortilin Modulates Schwann Cell Signaling and Remak Bundle Regeneration Following Nerve Injury

“…The Schwann cells dedifferentiate into their repair phenotype, and the macrophages infiltrate the injured nerve to partake in myelin degradation ( Gaudet et al, 2011 ). A population of repair Schwann cells proliferate and migrate, forming the characteristic bands of Büngner to provide guidance and growth factor support (including secreted neurotrophins) for the regenerating axons, stimulate ensheathing of small-caliber fibers to reform Remak bundles, and facilitate remyelination of large-caliber axons ( Gaudet et al, 2011 ; Jessen and Arthur-Farraj, 2019 ; Jessen and Mirsky, 2019 , 2022 ). Neurotrophins elicit trophic signaling for sprouting axons but are also reported to regulate Schwann cell functions.…”