Fgf Signaling is Required for Photoreceptor Maintenance in the Adult Zebrafish Retina

Abstract

Fibroblast growth factors (Fgf) are secreted signaling molecules that have mitogenic, patterning, neurotrophic and angiogenic properties. Their importance during embryonic development in patterning and morphogenesis of the vertebrate eye is well known, but less is known about the role of Fgfs in the adult vertebrate retina. To address Fgf function in adult retina, we determined the spatial distribution of components of the Fgf signaling pathway in the adult zebrafish retina. We detected differential expression of Fgf receptors, ligands and downstream Fgf targets within specific retinal layers. Furthermore, we blocked Fgf signaling in the retina, by expressing a dominant negative variant of Fgf receptor 1 conditionally in transgenic animals. After blocking Fgf signaling we observe a fast and progressive photoreceptor degeneration and disorganization of retinal tissue, coupled with cell death in the outer nuclear layer. Following the degeneration of photoreceptors, a profound regeneration response is triggered that starts with proliferation in the inner nuclear layer. Ultimately, rod and cone photoreceptors are regenerated completely. Our study reveals the requirement of Fgf signaling to maintain photoreceptors and for proliferation during regeneration in the adult zebrafish retina.

Retinal Injury, Growth Factors, and Cytokines Converge on β-Catenin and pStat3 Signaling to Stimulate Retina Regeneration

“…For this analysis we used hsp70:dnfgfr1-egfp transgenic fish that harbor the hsp70 promoter driving expression of a dominant/negative Fgfr1-GFP fusion protein (dnFgfr1) (Lee et al, 2005). We found that conditional expression of dnFgfr1 suppressed MG proliferation in the injured retina (Figures 2G and 2H), which is consistent with that found when photoreceptors are damaged (Hochmann et al, 2012). …”

“…Fgfs and their receptors are expressed in the INL of the zebrafish retina (Hochmann et al, 2012); however, the effects of Fgf signaling on MG proliferation are controversial (Hochmann et al, 2012; Qin et al, 2011). Therefore, we investigated Fgf signaling in our mechanical injury model.…”

“…The role for FGFR signaling is controversial with one report indicating it stimulates injury-dependent MG proliferation (Hochmann et al, 2012) and another indicating it has little effect (Qin et al, 2011). Finally, in the accompanying paper by Zhao et al, we report an important role for Jak/Stat3 signaling in controlling MG reprogramming and proliferation.…”

Müller glial cell reprogramming and retina regeneration

“… * One study reports no effect of dnfgfr on progenitor proliferation following light damage and that fgf signaling is necessary for rod maintenance 115 , while the other study shows dnfgfr suppresses progenitor proliferation following light damage and that fgf signaling is necessary for rod and cone maintenance 123 . ! Notch signaling inhibits progenitor formation and proliferation in the injured retina 83 . …”

Retina regeneration in zebrafish

“…Although injury-induced Müller-glia derived progenitors have the potential to regenerate all major retinal cell types, some reports suggest they predominantly regenerate ablated neurons 41,43,44 . Other studies suggest progenitors in the injured retina may retain a multipotent character regardless of the type of neuron ablated since ectopic neurons appear outside the injury site and are also found in uninjured retinas treated with a variety of growth factors and cytokines 20–22,24 .…”