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Neurotrophin-3 promotes peripheral nerve regeneration via induction of c-Jun in Schwann cells


As described in my book on nerve regeneration, the recovery of motor and sensory functions after a nerve lesion is unsatisfactory in many patients, although peripheral nerves can in principle regenerate after an injury.


Peripheral glia (so-called Schwann cells) are activated particularly in the distal (severed) nerve stump and, alongside macrophages and fibroblasts, participate in the removal of axons and their myelin sheath. Axons then regenerate from the proximal end of the injury to the distal end and innervate their target organs.


During this process, the reactive Schwann cells provide an essential basis for the survival of the affected nerve cells and for axonal regeneration. However, if no axons grow into the distal nerve stump distal to the injury site over a prolonged period of time, the Schwann cells lose their ability to repair and revert to an inactive state, which is not uncommon in humans due to the often long distances between the lesion site and the target tissue to be supplied. Therefore, maintaining the repair phenotype of Schwann cells during the chronic phase of nerve regeneration has become a therapeutic necessity.


For the maintenance of the neurotrophic properties of Schwann cells, c-Jun, a component of the transcription factor activator protein-1, plays an important role (however, c-Jun also acts as a negative regulator of myelination and must therefore be switched off before the onset of remyelination of regenerated axons). Previous studies have shown that c-Jun in Schwann cells is mainly upregulated by p38 mitogen-activated protein kinase (p38 MAPK), extracellular signalling-regulated kinase (ERK) and Jun N-terminal kinase (JNK). The neurotrophic factor NT-3 activates these signalling pathways and can be transported through the systemic circulation from the muscle to the axons and neurons that supply it. A therapy with recombinant (genetically engineered) NT-3 has already been tested in phase I and II clinical trials and proved to be safe and well tolerated.


In a paper published in the Journal of Translational Medicine in 2023, Xiong Xu and colleagues have now found that c-Jun is expressed at a high level in the distal nerve stumps up to 5 weeks after denervation and is only detectable at a reduced level thereafter. NT-3 maintained the high expression of c-Jun when administered at week 5, which significantly promoted axon regeneration even after 10 weeks of denervation (conversely, a reduction of c-Jun impaired the growth-promoting effect of NT-3). Further investigations showed that the administration of NT-3 activates the ERK signalling pathway, which mediates the high expression of c-Jun in Schwann cells.


In summary, this study identified the TrkC/ERK signalling pathway as an important molecular mechanism for the upregulation of c-Jun by NT-3, which therefore represents a potential therapeutic target for the clinical treatment of peripheral nerve damage after chronic denervation. Fingolimod, an agonist at the sphingosine-1-phosphate receptor, interleukin-1ß or fibroblast growth factor (FGF) 21 are also possible candidates, as they have led to an induction of c-Jun in Schwann cells in animal experiments, too.



Reference:


Xu X, Song L, Li Y, Guo J, Huang S, Du S, Li W, Cao R, Cui S (2023) Neurotrophin-3 promotes peripheral nerve regeneration by maintaining a repair state of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway. Journal of Translational Medicine 21:733


Image credit: iStock/Aldona

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