Abstract
Unlike mammals, zebrafish can regenerate a damaged retina. This remarkable regenerative response is mediated by Müller glia (MG) that undergo a reprogramming event that drives their proliferation and the generation of multipotent progenitors for retinal repair. The mechanisms that drive MG reprogramming are poorly understood. Here, we report that Leptin and Gp130-coupled receptors, acting via a Jak/Stat signaling pathway, stimulate MG reprogramming and progenitor formation in the injured retina. Importantly, we find that ascl1a gene expression, which drives MG reprogramming in fish and mammals, is regulated in a Jak/Stat-dependent manner and requires consensus Stat-binding sites for injury-dependent activation. Finally, we identify cytokines that are induced by retinal injury and exhibit a remarkable synergy in their ability to activate Jak/Stat signaling and MG reprogramming in the uninjured retina. Our study not only furthers our understanding of retina regeneration in zebrafish but also suggests new strategies for awakening retina regeneration in mammals.
Highlights
Because of their robust regenerative powers, zebrafish have become an ideal model system for studying retina regeneration
P-Stat3 stained processes in the outer plexiform and ganglion cell layers in the uninjured retina, there was no labeling of cells in the inner nuclear layer (INL) where Müller glia (MG) cell bodies reside (Figure S1A)
Following retinal injury with a needle poke, we observed phosphorylated Stat3 (p-Stat3) staining in the INL that was restricted to BrdU+ cells at the injury site (Figures 1A and S1A)
Summary
Because of their robust regenerative powers, zebrafish have become an ideal model system for studying retina regeneration. Stat expression is induced in the injured retina (Kassen et al, 2007; Kassen et al, 2009; Nelson et al, 2012) This expression is detected in all retinal layers and in the inner nuclear layer (INL), quiescent MG as well as proliferating MG express Stat (Kassen et al, 2007; Nelson et al, 2012). This expression pattern, along with the assumption that injury-induced Stat expression reflects that of activated p-Stat (Kassen et al, 2007), has led to models assigning different roles for injury-induced Stat in quiescent MG, MG stem cells and MGderived progenitors (Gorsuch and Hyde, 2013; Nelson et al, 2013; Nelson et al, 2012). It remains unknown whether total Stat is a true indicator of p-Stat in the injured retina, nor is it known if endogenous cytokines acting via Jak/Stat signaling stimulate MG reprogramming and retina regeneration following retinal injury
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