Elsaeidi, F., Bemben, M.A., Zhao, X.F., and Goldman, D. (2014) Jak/Stat signaling stimulates zebrafish optic nerve regeneration and overcomes the inhibitory actions of Socs3 and Sfpq. The Journal of neuroscience : the official journal of the Society for Neuroscience. 34(7):2632-2644.
The regenerative failure of mammalian optic axons is partly mediated by Socs3-dependent inhibition of Jak/Stat signaling (Smith et al., 2009, 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.