c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling

Abstract

c-Jun in Schwann cells promotes the expression of Ret ligands GDNF and Artemin, which leads to enhanced motoneuron survival and axonal regeneration after injury.

Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

“…To our knowledge, no previous study has profiled dynamic enhancer changes during an injury process. The ChIP-seq analysis showed clear enhancer changes in major myelin genes that decrease upon nerve injury (Mag and other myelin genes), as well as injuryinduced genes, such as Gdnf and Ngfr (70). As such, profiling of H3K27ac reveals those enhancers that specifically decommissioned or activated after nerve injury.…”

“…Interestingly, c-Jun-binding motifs were found in InjuryDB peaks proximal to several c-Jun target genes, including Runx2 and Gdnf, which are induced over 40-fold after peripheral nerve injury (9,23). Glia cell-derived neurotropic factor (Gdnf) induction in Schwann cells plays a prominent role in supporting axons after nerve injury (70).…”

“…6A), such as c-Jun. Identification of the c-Jun/AP-1-binding site provides an additional validation for the data set, as c-Jun coordinates important aspects of the Schwann cell's response to nerve injury (23,69,70). Microarray analysis showed 62 injury-induced genes were reduced Ͼ2-fold in c-Jun-deficient mice after nerve injury (23).…”

c-Jun Gene-Modified Schwann Cells: Upregulating Multiple Neurotrophic Factors and Promoting Neurite Outgrowth

“…Additionally, it has been noted that GDNF and artemin (Artn), which both encode ligands for the Ret receptor tyrosine kinase, are novel direct c-Jun target genes. 26 The leukemia inhibitory factor (LIF) gene has also been demonstrated to be transcriptionally regulated by c-Jun. 27 Furthermore, a variety of nerve regeneration-related genes are indirectly regulated by c-Jun, including BDNF and NGF.…”

“…27 Furthermore, a variety of nerve regeneration-related genes are indirectly regulated by c-Jun, including BDNF and NGF. 25,26 Thus, we hypothesized that the overexpression of c-Jun might upregulate multiple NFs in SCs, which would in turn further promote neuronal survival, axonal outgrowth, and functional recovery. In addition, the grafted SCs would not only affect neuronal survival and axon regeneration, but also interact with native SCs.…”