Jak/Stat Signaling Stimulates Zebrafish Optic Nerve Regeneration and Overcomes the Inhibitory Actions of Socs3 and Sfpq

Abstract

The regenerative failure of mammalian optic axons is partly mediated by Socs3-dependent inhibition of Jak/Stat signaling (Smith et al., 2009(Smith et al., , 2011. Whether Jak/Stat signaling is part of the normal regenerative response observed in animals that exhibit an intrinsic capacity for optic nerve regeneration, such as zebrafish, remains unknown. Nor is it known whether the repression of regenerative inhibitors, such as Socs3, contributes to the robust regenerative response of zebrafish to optic nerve damage. Here we report that Jak/Stat signaling stimulates optic nerve regeneration in zebrafish. We found that IL-6 family cytokines, acting via Gp130-coupled receptors, stimulate Jak/Stat3 signaling in retinal ganglion cells after optic nerve injury. Among these cytokines, we found that CNTF, IL-11, and Clcf1/Crlf1a can stimulate optic axon regrowth. Surprisingly, optic nerve injury stimulated the expression of Socs3 and Sfpq (splicing factor, proline/ glutamine rich) that attenuate optic nerve regeneration. These proteins were induced in a Jak/Stat-dependent manner, stimulated each other's expression and suppressed the expression of regeneration-associated genes. In vivo, the injury-dependent induction of Socs3 and Sfpq inhibits optic nerve regeneration but does not block it. We identified a robust induction of multiple cytokine genes in zebrafish retinal ganglion cells that may contribute to their ability to overcome these inhibitory factors. These studies not only identified mechanisms underlying optic nerve regeneration in fish but also suggest new molecular targets for enhancing optic nerve regeneration in mammals.

miR-146a suppresses STAT3/VEGF pathways and reduces apoptosis through IL-6 signaling in primary human retinal microvascular endothelial cells in high glucose conditions

“…It has been reported that the IL-6 family stimulates Jak/STAT3 signaling in the eye (35–37). Also, high glucose can stimulate STAT3 phosphorylation in retinal endothelial and RPE cells (38–40).…”

Anti-inflammatory effect of resveratrol through the suppression of NF-κB and JAK/STAT signaling pathways

“…Cells were pretreated with PDTC and then stimulated with LPS. As shown in Resveratrol inhibits the LPS-induced activation of the JAK/STAT pathway STAT1 and STAT3 are important transcription factors in the immune response, and also play roles in the inflammatory signaling cascades triggered by LPS, interferon-gamma, and other cytokines [19,20]. Therefore, we investigated whether the anti-inflammatory effects of resveratrol on the expression of HMGB1 and IL-6 were exerted by inhibiting the JAK/STAT signaling pathway.…”

Cardiotrophin-like cytokine factor 1 (CLCF1) and neuropoietin (NP) signalling and their roles in development, adulthood, cancer and degenerative disorders

“…Secondly, involvement in neural repair mechanisms was suggested by the observation that CLCF1, CRLF1, CNTFR, leukaemia inhibitory factor, LIFR, IL-11 and IL-11 receptor mRNA levels are all elevated after optic nerve lesion in zebrafish [44] and sciatic nerve injury in mice [45]. Indeed, knockdown of either CLCF1 or CRLF1 genes in zebrafish retinal explants suppressed optic axon regrowth [44] suggesting CLCF1/CRLF1 may enhance optic nerve regeneration in mammals.…”