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

Powell C, Cornblath E, Elsaeidi F, Wan J, Goldman D - Sci Rep (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Behavioral Neuroscience Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 USA.

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.

No MeSH data available.


Related in: MedlinePlus

MG-derived progenitors are multipotent and generate unneeded neurons.Fish were given an intraperitoneal injection of BrdU at 2 dpi and sacrificed at 30 dpi. Immunostaining for BrdU and retinal cell type-specific markers was then performed against: GS, MG; Zpr1, red/green cones; HuC/D, amacrine and ganglion cells. Representative immunofluorescence images of retinal sections following (A–C) needle poke, (D–F) PA, or (G–I) NMDA injury. Retinal sections were stained with antibodies detecting BrdU and (A,D,G) GS, (B,E,H) Zpr1, or (C,F,I) HuC/D. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 2.
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f6: MG-derived progenitors are multipotent and generate unneeded neurons.Fish were given an intraperitoneal injection of BrdU at 2 dpi and sacrificed at 30 dpi. Immunostaining for BrdU and retinal cell type-specific markers was then performed against: GS, MG; Zpr1, red/green cones; HuC/D, amacrine and ganglion cells. Representative immunofluorescence images of retinal sections following (A–C) needle poke, (D–F) PA, or (G–I) NMDA injury. Retinal sections were stained with antibodies detecting BrdU and (A,D,G) GS, (B,E,H) Zpr1, or (C,F,I) HuC/D. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 2.

Mentions: Although previous studies have demonstrated that progenitors migrating to retinal layers differentiate into layer appropriate neurons, we confirmed this is also true when they migrated to undamaged retinal layers. For this analysis, injured fish received an IP injection of BrdU at 2 dpi and were sacrificed at 30 dpi. Retinal sections were then analyzed for BrdU and retinal cell type-specific immunofluorescence. In retinas with a needle poke injury that damaged all retinal layers, we detected regenerated (BrdU+) cells that co-expressed the MG marker, GS; the red/green cone marker, Zpr1; and the amacrine and ganglion cell marker, HuC/D, in the INL and GCL (Fig. 6A–C). In retinas where damage was restricted to photoreceptors (PA model) we not only identified regenerated photoreceptors (BrdU+/Zpr1+) in the ONL, but also regenerated amacrine and ganglion cells (BrdU+/HuC/D+) in the INL and GCL (Fig. 6D–F). In retinas with damage restricted to the INL and GCL (NMDA model), we detected regenerated amacrine and ganglion (BrdU+/HuC/D+) cells in the INL and GCL, respectively, along with regenerated photoreceptors (BrdU+/Zpr1+) in the ONL (Fig. 6G–I). As expected, in all instances we identify BrdU+/GS+ MG in the INL whose cell division was responsible for progenitor formation (Fig. 6). Thus, MG-derived progenitors are not restricted to regenerating only ablated cell types, but rather seem to be programmed to produce all major retinal cell types that seed all retinal layers with new neurons regardless of the injury paradigm.


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

Powell C, Cornblath E, Elsaeidi F, Wan J, Goldman D - Sci Rep (2016)

MG-derived progenitors are multipotent and generate unneeded neurons.Fish were given an intraperitoneal injection of BrdU at 2 dpi and sacrificed at 30 dpi. Immunostaining for BrdU and retinal cell type-specific markers was then performed against: GS, MG; Zpr1, red/green cones; HuC/D, amacrine and ganglion cells. Representative immunofluorescence images of retinal sections following (A–C) needle poke, (D–F) PA, or (G–I) NMDA injury. Retinal sections were stained with antibodies detecting BrdU and (A,D,G) GS, (B,E,H) Zpr1, or (C,F,I) HuC/D. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837407&req=5

f6: MG-derived progenitors are multipotent and generate unneeded neurons.Fish were given an intraperitoneal injection of BrdU at 2 dpi and sacrificed at 30 dpi. Immunostaining for BrdU and retinal cell type-specific markers was then performed against: GS, MG; Zpr1, red/green cones; HuC/D, amacrine and ganglion cells. Representative immunofluorescence images of retinal sections following (A–C) needle poke, (D–F) PA, or (G–I) NMDA injury. Retinal sections were stained with antibodies detecting BrdU and (A,D,G) GS, (B,E,H) Zpr1, or (C,F,I) HuC/D. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 2.
Mentions: Although previous studies have demonstrated that progenitors migrating to retinal layers differentiate into layer appropriate neurons, we confirmed this is also true when they migrated to undamaged retinal layers. For this analysis, injured fish received an IP injection of BrdU at 2 dpi and were sacrificed at 30 dpi. Retinal sections were then analyzed for BrdU and retinal cell type-specific immunofluorescence. In retinas with a needle poke injury that damaged all retinal layers, we detected regenerated (BrdU+) cells that co-expressed the MG marker, GS; the red/green cone marker, Zpr1; and the amacrine and ganglion cell marker, HuC/D, in the INL and GCL (Fig. 6A–C). In retinas where damage was restricted to photoreceptors (PA model) we not only identified regenerated photoreceptors (BrdU+/Zpr1+) in the ONL, but also regenerated amacrine and ganglion cells (BrdU+/HuC/D+) in the INL and GCL (Fig. 6D–F). In retinas with damage restricted to the INL and GCL (NMDA model), we detected regenerated amacrine and ganglion (BrdU+/HuC/D+) cells in the INL and GCL, respectively, along with regenerated photoreceptors (BrdU+/Zpr1+) in the ONL (Fig. 6G–I). As expected, in all instances we identify BrdU+/GS+ MG in the INL whose cell division was responsible for progenitor formation (Fig. 6). Thus, MG-derived progenitors are not restricted to regenerating only ablated cell types, but rather seem to be programmed to produce all major retinal cell types that seed all retinal layers with new neurons regardless of the injury paradigm.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Behavioral Neuroscience Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 USA.

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.

No MeSH data available.


Related in: MedlinePlus