title: 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, 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.
authors: Molecular and Behavioral Neuroscience Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors: Fairouz
authors: F
authors: Elsaeidi
authors: Michael A
authors: MA
authors: Bemben
authors: Xiao-Feng
authors: XF
authors: Zhao
authors: Daniel
authors: D
authors: Goldman
mesh_terms: D000818:Animals; D005455:Fluorescent Antibody Technique; D017403:In Situ Hybridization; D053612:Janus Kinases / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology*; D009900:Optic Nerve / Q000378:metabolism*; D000072670:PTB-Associated Splicing Factor; D016133:Polymerase Chain Reaction; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism; D050791:STAT Transcription Factors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins; D050791:STAT Transcription Factors; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D029961:Zebrafish Proteins; C540940:socs3a protein, zebrafish; D053612:Janus Kinases
keywords: Jak; Stat; optic nerve; regeneration; retina; retinal ganglion cell