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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

Injury models generate unique cell death signatures.(A) Representative images of retinal sections showing TUNEL detection (red) of apoptotic neuronal cell death 1 day following needle poke, UV light photoablation (PA), and NMDA neurotoxic injuries. (B) Relative localization of TUNEL+ nuclei by nuclear layer in the various injury models at 1 dpi. (C) Representative images of retinal sections showing TUNEL detection of apoptotic neuronal cell death at 1, 4 and 7 days following needle poke (single injury/retina), UV light photoablation, and NMDA neurotoxic injuries. (D) Quantification of TUNEL+ cells by nuclear layer in the various injury models at 1, 4 and 7 dpi. Data represents means ± s.d. (n = 4). Scale bar is equal to 50 μm. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer; PA, photoablation; dpi, days post injury.
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f1: Injury models generate unique cell death signatures.(A) Representative images of retinal sections showing TUNEL detection (red) of apoptotic neuronal cell death 1 day following needle poke, UV light photoablation (PA), and NMDA neurotoxic injuries. (B) Relative localization of TUNEL+ nuclei by nuclear layer in the various injury models at 1 dpi. (C) Representative images of retinal sections showing TUNEL detection of apoptotic neuronal cell death at 1, 4 and 7 days following needle poke (single injury/retina), UV light photoablation, and NMDA neurotoxic injuries. (D) Quantification of TUNEL+ cells by nuclear layer in the various injury models at 1, 4 and 7 dpi. Data represents means ± s.d. (n = 4). Scale bar is equal to 50 μm. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer; PA, photoablation; dpi, days post injury.

Mentions: We used TUNEL assays to quantify retinal layer-specific cell death with each of these paradigms at 1 day post injury (dpi) (Fig. 1A,B). Although TUNEL assay is generally associated with apoptosis, it has been reported to also detect necrosis and autolytic cell death34. However, the initiation of DNA damage may vary, and for this reason some dying cells may go undetected at any particular time point of analysis. Importantly, a needle poke injury stimulated cell death in all retinal layers, photoablation restricted cell death to the ONL, and NMDA neurotoxicity restricted cell death to the INL and GCL (Fig. 1). 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 therefore, could not be included in cell death counts because their layer of origin could not be determined. Our analysis of cell death at 1, 4 and 7 dpi indicated that the majority of cell death occurs at 1 dpi in all injury paradigms with little to no detectable cell death occurring at 4 and 7 dpi (Fig. 1C,D).


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)

Injury models generate unique cell death signatures.(A) Representative images of retinal sections showing TUNEL detection (red) of apoptotic neuronal cell death 1 day following needle poke, UV light photoablation (PA), and NMDA neurotoxic injuries. (B) Relative localization of TUNEL+ nuclei by nuclear layer in the various injury models at 1 dpi. (C) Representative images of retinal sections showing TUNEL detection of apoptotic neuronal cell death at 1, 4 and 7 days following needle poke (single injury/retina), UV light photoablation, and NMDA neurotoxic injuries. (D) Quantification of TUNEL+ cells by nuclear layer in the various injury models at 1, 4 and 7 dpi. Data represents means ± s.d. (n = 4). Scale bar is equal to 50 μm. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer; PA, photoablation; dpi, days post injury.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Injury models generate unique cell death signatures.(A) Representative images of retinal sections showing TUNEL detection (red) of apoptotic neuronal cell death 1 day following needle poke, UV light photoablation (PA), and NMDA neurotoxic injuries. (B) Relative localization of TUNEL+ nuclei by nuclear layer in the various injury models at 1 dpi. (C) Representative images of retinal sections showing TUNEL detection of apoptotic neuronal cell death at 1, 4 and 7 days following needle poke (single injury/retina), UV light photoablation, and NMDA neurotoxic injuries. (D) Quantification of TUNEL+ cells by nuclear layer in the various injury models at 1, 4 and 7 dpi. Data represents means ± s.d. (n = 4). Scale bar is equal to 50 μm. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer; PA, photoablation; dpi, days post injury.
Mentions: We used TUNEL assays to quantify retinal layer-specific cell death with each of these paradigms at 1 day post injury (dpi) (Fig. 1A,B). Although TUNEL assay is generally associated with apoptosis, it has been reported to also detect necrosis and autolytic cell death34. However, the initiation of DNA damage may vary, and for this reason some dying cells may go undetected at any particular time point of analysis. Importantly, a needle poke injury stimulated cell death in all retinal layers, photoablation restricted cell death to the ONL, and NMDA neurotoxicity restricted cell death to the INL and GCL (Fig. 1). 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 therefore, could not be included in cell death counts because their layer of origin could not be determined. Our analysis of cell death at 1, 4 and 7 dpi indicated that the majority of cell death occurs at 1 dpi in all injury paradigms with little to no detectable cell death occurring at 4 and 7 dpi (Fig. 1C,D).

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