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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

The localization of proliferating MG-derived progenitors by 6 dpi demonstrate injury-specific biases.Fish were given an injection of EdU 2 hours before harvesting at 6 dpi. (A) EdU+ cells were counted and the percentage of EdU+ nuclei residing in the ONL, INL, and GCL was determined for each injury model. Data represents means ± s.d. (n ≥ 3). *P < 0.02764. (B–D) Representative images of retinal sections analyzed in (A) that were stained for EdU following (B) needle poke, (C) PA or (D) NMDA injury. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 1.
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f5: The localization of proliferating MG-derived progenitors by 6 dpi demonstrate injury-specific biases.Fish were given an injection of EdU 2 hours before harvesting at 6 dpi. (A) EdU+ cells were counted and the percentage of EdU+ nuclei residing in the ONL, INL, and GCL was determined for each injury model. Data represents means ± s.d. (n ≥ 3). *P < 0.02764. (B–D) Representative images of retinal sections analyzed in (A) that were stained for EdU following (B) needle poke, (C) PA or (D) NMDA injury. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 1.

Mentions: The above data suggested that MG-derived progenitors/neurons may receive feedback inhibition from surviving neurons to limit their proliferation or survival at late stages of regeneration. To directly test if progenitor proliferation was affected, injured fish were given an IP injection of EdU at 6 dpi and sacrificed 2 hours later. Retinal sections were prepared and assayed for EdU incorporation. Quantification of EdU+ cells in each retinal layer for each type of injury revealed that progenitor proliferation is enhanced in the ONL when photoreceptors are ablated (needle poke and photoablation) compared to when progenitors occupy an intact ONL (NMDA) (Fig. 5A–D). Similarly, progenitor proliferation is enhanced in the INL and GCL when resident neurons are ablated (needle poke and NMDA) compared to when progenitors occupy an intact INL and GCL (photoablation) (Fig. 5A–D). These data suggest that progenitors receive feedback inhibition from surviving retinal neurons that limits their proliferation and that this inhibition is relieved by cell ablation.


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)

The localization of proliferating MG-derived progenitors by 6 dpi demonstrate injury-specific biases.Fish were given an injection of EdU 2 hours before harvesting at 6 dpi. (A) EdU+ cells were counted and the percentage of EdU+ nuclei residing in the ONL, INL, and GCL was determined for each injury model. Data represents means ± s.d. (n ≥ 3). *P < 0.02764. (B–D) Representative images of retinal sections analyzed in (A) that were stained for EdU following (B) needle poke, (C) PA or (D) NMDA injury. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: The localization of proliferating MG-derived progenitors by 6 dpi demonstrate injury-specific biases.Fish were given an injection of EdU 2 hours before harvesting at 6 dpi. (A) EdU+ cells were counted and the percentage of EdU+ nuclei residing in the ONL, INL, and GCL was determined for each injury model. Data represents means ± s.d. (n ≥ 3). *P < 0.02764. (B–D) Representative images of retinal sections analyzed in (A) that were stained for EdU following (B) needle poke, (C) PA or (D) NMDA injury. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 1.
Mentions: The above data suggested that MG-derived progenitors/neurons may receive feedback inhibition from surviving neurons to limit their proliferation or survival at late stages of regeneration. To directly test if progenitor proliferation was affected, injured fish were given an IP injection of EdU at 6 dpi and sacrificed 2 hours later. Retinal sections were prepared and assayed for EdU incorporation. Quantification of EdU+ cells in each retinal layer for each type of injury revealed that progenitor proliferation is enhanced in the ONL when photoreceptors are ablated (needle poke and photoablation) compared to when progenitors occupy an intact ONL (NMDA) (Fig. 5A–D). Similarly, progenitor proliferation is enhanced in the INL and GCL when resident neurons are ablated (needle poke and NMDA) compared to when progenitors occupy an intact INL and GCL (photoablation) (Fig. 5A–D). These data suggest that progenitors receive feedback inhibition from surviving retinal neurons that limits their proliferation and that this inhibition is relieved by cell ablation.

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