Abstract
Fish retinal ganglion cells (RGCs) can regenerate their axons after optic nerve injury, whereas mammalian RGCs normally fail to do so. Interleukin 6 (IL-6)-type cytokines are involved in cell differentiation, proliferation, survival, and axon regrowth; thus, they may play a role in the regeneration of zebrafish RGCs after injury. In this study, we assessed the expression of IL-6-type cytokines and found that one of them, leukemia inhibitory factor (LIF), is upregulated in zebrafish RGCs at 3 days post-injury (dpi). We then demonstrated the activation of signal transducer and activator of transcription 3 (STAT3), a downstream target of LIF, at 3–5 dpi. To determine the function of LIF, we performed a LIF knockdown experiment using LIF-specific antisense morpholino oligonucleotides (LIF MOs). LIF MOs, which were introduced into zebrafish RGCs via a severed optic nerve, reduced the expression of LIF and abrogated the activation of STAT3 in RGCs after injury. These results suggest that upregulated LIF drives Janus kinase (Jak)/STAT3 signaling in zebrafish RGCs after nerve injury. In addition, the LIF knockdown impaired axon sprouting in retinal explant culture in vitro; reduced the expression of a regeneration-associated molecule, growth-associated protein 43 (GAP-43); and delayed functional recovery after optic nerve injury in vivo. In this study, we comprehensively demonstrate the beneficial role of LIF in optic nerve regeneration and functional recovery in adult zebrafish.
Highlights
Fish retinal ganglion cells (RGCs) are able to survive and regenerate their axons even after transection of the optic nerve, whereas mammalian RGCs cannot survive after injury [1,2]
A very weak positive signal of leukemia inhibitory factor (LIF) mRNA was observed in the lower part of the inner nuclear layer (INL) and the photoreceptor layer (PRL)
This study shows the intrinsic upregulation of LIF and activation of signal transducer and activator of transcription 3 (STAT3) in zebrafish RGCs after optic nerve injury
Summary
Fish retinal ganglion cells (RGCs) are able to survive and regenerate their axons even after transection of the optic nerve, whereas mammalian RGCs cannot survive after injury [1,2]. A number of studies have searched for the factors that enable fish RGCs to survive and regrow their axons after optic nerve injury (for review, see [3,4]). Interleukin 6 (IL-6)-type cytokines, such as IL-6, ciliary neurotrophic factor (CNTF), oncostatin M (OSM), cardiotrophin-1 (CT-1), and leukemia inhibitory factor (LIF), perform important and versatile functions in intercellular communication via membrane receptors and the Janus kinase (Jak)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. The phosphorylated Jak subsequently phosphorylates the STAT3 protein, which in turn forms a homodimer and works as a transcription factor [7,8,9]
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