Zebrafish Müller glia-derived progenitors are multipotent, exhibit proliferative biases and regenerate excess neurons

Curtis Powell,Fairouz Elsaeidi,Daniel Goldman,Jin Wan,Eli Cornblath

doi:10.1038/srep24851

Abstract

Unlike mammals, zebrafish can regenerate a damaged retina. Key to this regenerative response are Müller glia (MG) that respond to injury by reprogramming and adopting retinal stem cell properties. These reprogrammed MG divide to produce a proliferating population of retinal progenitors that migrate to areas of retinal damage and regenerate lost neurons. Previous studies have suggested that MG-derived progenitors may be biased to produce that are lost with injury. Here we investigated MG multipotency using injury paradigms that target different retinal nuclear layers for cell ablation. Our data indicate that regardless of which nuclear layer was damaged, MG respond by generating multipotent progenitors that migrate to all nuclear layers and differentiate into layer-specific cell types, suggesting that MG-derived progenitors in the injured retina are intrinsically multipotent. However, our analysis of progenitor proliferation reveals a proliferative advantage in nuclear layers where neurons were ablated. This suggests that feedback inhibition from surviving neurons may skew neuronal regeneration towards ablated cell types.

Highlights

Unlike mammals, zebrafish can regenerate a damaged retina
To selectively damage neurons in the inner nuclear layer (INL) and ganglion cell layer (GCL), but spare photoreceptors, we took advantage of NMDA-mediated neurotoxicity that was reported to damage these neurons in the goldfish retina[33]
The relatively low level of cell death noted in the INL and GCL after a needle poke injury is likely an underestimate as many of these neurons are mechanically displaced into the vitreous as the needle is inserted through the retina and could not be included in cell death counts because their layer of origin could not be determined

Summary

Introduction

Key to this regenerative response are Müller glia (MG) that respond to injury by reprogramming and adopting retinal stem cell properties. These reprogrammed MG divide to produce a proliferating population of retinal progenitors that migrate to areas of retinal damage and regenerate lost neurons. When retinal cell ablation was restricted to neurons residing in the retina’s INL and ganglion cell layer (GCL), excess cells were not observed in the retina’s ONL22 These data suggest that progenitors are biased towards regenerating ablated cell types. Correspondence and requests for materials should be addressed to D.G. (email: neuroman@ umich.edu) www.nature.com/scientificreports/

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Conclusion