A novel model of retinal ablation demonstrates that the extent of rod cell death regulates the origin of the regenerated zebrafish rod photoreceptors.
The adult zebrafish retina continuously produces rod photoreceptors from infrequent Müller glial cell division, yielding neuronal progenitor cells that migrate to the outer nuclear layer and become rod precursor cells that are committed to differentiate into rods. Retinal damage models suggested that rod cell death induces regeneration from rod precursor cells, whereas loss of any other retinal neurons activates Müller glia proliferation to produce pluripotent neuronal progenitors that can generate any other neuronal cell type in the retina. We tested this hypothesis by creating two transgenic lines that expressed the E. coli nitroreductase enzyme fused to EGFP (NTR-EGFP) in only rods. Treating transgenic adults with metronidazole resulted in two rod cell death models. First, killing all rods throughout the Tg(zop:nfsB-EGFP)(nt19) retina induced robust Müller glial proliferation, which yielded clusters of neuronal progenitor cells. In contrast, ablating only a subset of rods across the Tg(zop:nfsB-EGFP)(nt20) retina led to rod precursor, but not Müller glial, cell proliferation. We propose that two different criteria determine whether rod cell death will induce a regenerative response from the Müller glia rather than from the resident rod precursor cells in the ONL. First, there must be a large amount of rod cell death to initiate Müller glia proliferation. Second, the rod cell death must be acute, rather than chronic, to stimulate regeneration from the Müller glia. This suggests that the zebrafish retina possesses mechanisms to quantify the amount and timing of rod cell death.
Montgomery
Jacob E
JE
Department of Biological Sciences and the Center for Zebrafish Research, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Parsons
Michael J
MJ
Hyde
David R
DR
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D029968:Escherichia coli Proteins / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008795:Metronidazole / Q000633:toxicity; D008959:Models, Neurological; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity; D009601:Nitroreductases / Q000235:genetics; D012160:Retina / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology*; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D015027:Zebrafish / Q000502:physiology*
D029968:Escherichia coli Proteins; D009498:Neurotoxins; C485184:enhanced green fluorescent protein; D008795:Metronidazole; D049452:Green Fluorescent Proteins; D009601:Nitroreductases