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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 paradigms stimulate regenerative response signatures that exhibit both commonality and uniqueness.Fish were given an intraperitoneal injection of BrdU at 2 dpi and then sacrificed at 2 dpi (3 hours post BrdU injection), 4, 7, 14 and 30 dpi. (A–C) BrdU+ nuclei were counted and the percentage of BrdU+ nuclei residing in the (A) ONL, (B) INL and (C) GCL was determined for individual samples for each injury model. Data represents means ± s.d. (n ≥ 3). *P < 0.04549. (D–I) Representative images of retinal sections analyzed in (A–C) that were immunostained for BrdU at (D–F) 2 dpi or (G–I) 30 dpi following (D,G) needle poke, (E,H) PA or (F–I) NMDA injury. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 1.
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f3: Injury paradigms stimulate regenerative response signatures that exhibit both commonality and uniqueness.Fish were given an intraperitoneal injection of BrdU at 2 dpi and then sacrificed at 2 dpi (3 hours post BrdU injection), 4, 7, 14 and 30 dpi. (A–C) BrdU+ nuclei were counted and the percentage of BrdU+ nuclei residing in the (A) ONL, (B) INL and (C) GCL was determined for individual samples for each injury model. Data represents means ± s.d. (n ≥ 3). *P < 0.04549. (D–I) Representative images of retinal sections analyzed in (A–C) that were immunostained for BrdU at (D–F) 2 dpi or (G–I) 30 dpi following (D,G) needle poke, (E,H) PA or (F–I) NMDA injury. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 1.

Mentions: We found that the 3 different injury paradigms exhibited differences in the relative localization of BrdU+ cells at 2 dpi: a needle poke injury and photoablation resulted in more BrdU+ cells in the ONL than did NMDA neurotoxicity (Fig. 3A); photoablation and NMDA neurotoxicity resulted in more BrdU+ cells in the INL than did a needle poke injury (Fig. 3B); and a needle poke injury and NMDA neurotoxicity resulted in more BrdU+ cells in the GCL than did photoablation (Fig. 3C). At 2 dpi, the number of retinal progenitors is relatively low, so these ratio differences might be attributed to slight timing variations between the injury models or to other cell populations, such as microglia and rod progenitors, that under certain circumstances have been noted to proliferate following retinal injury143536. Consistent with these ideas, the differences seen in the localization of BrdU+ cells between the injury paradigms almost completely disappear around 4–7 dpi (Fig. 3A–C) by which time the BrdU+ MG-derived progenitors have achieved maximal rates of proliferation37.


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 paradigms stimulate regenerative response signatures that exhibit both commonality and uniqueness.Fish were given an intraperitoneal injection of BrdU at 2 dpi and then sacrificed at 2 dpi (3 hours post BrdU injection), 4, 7, 14 and 30 dpi. (A–C) BrdU+ nuclei were counted and the percentage of BrdU+ nuclei residing in the (A) ONL, (B) INL and (C) GCL was determined for individual samples for each injury model. Data represents means ± s.d. (n ≥ 3). *P < 0.04549. (D–I) Representative images of retinal sections analyzed in (A–C) that were immunostained for BrdU at (D–F) 2 dpi or (G–I) 30 dpi following (D,G) needle poke, (E,H) PA or (F–I) 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

f3: Injury paradigms stimulate regenerative response signatures that exhibit both commonality and uniqueness.Fish were given an intraperitoneal injection of BrdU at 2 dpi and then sacrificed at 2 dpi (3 hours post BrdU injection), 4, 7, 14 and 30 dpi. (A–C) BrdU+ nuclei were counted and the percentage of BrdU+ nuclei residing in the (A) ONL, (B) INL and (C) GCL was determined for individual samples for each injury model. Data represents means ± s.d. (n ≥ 3). *P < 0.04549. (D–I) Representative images of retinal sections analyzed in (A–C) that were immunostained for BrdU at (D–F) 2 dpi or (G–I) 30 dpi following (D,G) needle poke, (E,H) PA or (F–I) NMDA injury. Scale bar is equal to 50 μm. Abbreviations are as in Fig. 1.
Mentions: We found that the 3 different injury paradigms exhibited differences in the relative localization of BrdU+ cells at 2 dpi: a needle poke injury and photoablation resulted in more BrdU+ cells in the ONL than did NMDA neurotoxicity (Fig. 3A); photoablation and NMDA neurotoxicity resulted in more BrdU+ cells in the INL than did a needle poke injury (Fig. 3B); and a needle poke injury and NMDA neurotoxicity resulted in more BrdU+ cells in the GCL than did photoablation (Fig. 3C). At 2 dpi, the number of retinal progenitors is relatively low, so these ratio differences might be attributed to slight timing variations between the injury models or to other cell populations, such as microglia and rod progenitors, that under certain circumstances have been noted to proliferate following retinal injury143536. Consistent with these ideas, the differences seen in the localization of BrdU+ cells between the injury paradigms almost completely disappear around 4–7 dpi (Fig. 3A–C) by which time the BrdU+ MG-derived progenitors have achieved maximal rates of proliferation37.

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