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Inhibition of the TGF β Pathway Enhances Retinal Regeneration in Adult Zebrafish

View Article: PubMed Central - PubMed

ABSTRACT

In contrast to the mammalian retina, the zebrafish retina exhibits the potential for lifelong retinal neurogenesis and regeneration even after severe damage. Previous studies have shown that the transforming growth factor beta (TGFβ) signaling pathway is activated during the regeneration of different tissues in the zebrafish and is needed for regeneration in the heart and the fin. In this study, we have investigated the role of the TGFβ pathway in the N-methyl-N-nitrosourea (MNU)-induced chemical model of rod photoreceptor de- and regeneration in adult zebrafish. Immunohistochemical staining for phosphorylated Smad3 was elevated during retinal regeneration, and phosphorylated Smad3 co-localized with proliferating cell nuclear antigen and glutamine synthetase, indicating TGFβ pathway activation in proliferating Müller glia. Inhibiting the TGFβ signaling pathway using a small molecule inhibitor (SB431542) resulted in accelerated recovery from retinal degeneration. Accordingly, we observed increased cell proliferation in the outer nuclear layer at days 3 to 8 after MNU treatment. In contrast to the observations in the heart and the fin, the inhibition of the TGFβ signaling pathway resulted in increased proliferation after the induction of retinal degeneration. A better understanding of the underlying pathways with the possibility to boost retinal regeneration in adult zebrafish may potentially help to stimulate such proliferation also in other species.

No MeSH data available.


Related in: MedlinePlus

P-Smad3 is activated in proliferating cells.Top: The co-localization of P-Smad3 and proliferating cell nuclear antigen (PCNA) indicates that Smad3 is activated in proliferating cells. Bottom: P-Smad3-positive cells in the inner nuclear layer (INL) co-localized with glutamine synthetase (GS), suggesting that these cells are Müller glia. Representative immunohistochemical staining at day 3 is depicted. Cell nuclei are stained with DAPI (blue). The scale bar indicates 25 μm. GC: ganglion cells, ONL: outer nuclear layer.
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pone.0167073.g002: P-Smad3 is activated in proliferating cells.Top: The co-localization of P-Smad3 and proliferating cell nuclear antigen (PCNA) indicates that Smad3 is activated in proliferating cells. Bottom: P-Smad3-positive cells in the inner nuclear layer (INL) co-localized with glutamine synthetase (GS), suggesting that these cells are Müller glia. Representative immunohistochemical staining at day 3 is depicted. Cell nuclei are stained with DAPI (blue). The scale bar indicates 25 μm. GC: ganglion cells, ONL: outer nuclear layer.

Mentions: Based on immunohistochemistry, double-staining for P-Smad3 and PCNA (a proliferation marker) or GS (a Müller glial marker) revealed the co-localization of these proteins, suggesting that the TGFβ pathway is activated in proliferating Müller glia (Fig 2).


Inhibition of the TGF β Pathway Enhances Retinal Regeneration in Adult Zebrafish
P-Smad3 is activated in proliferating cells.Top: The co-localization of P-Smad3 and proliferating cell nuclear antigen (PCNA) indicates that Smad3 is activated in proliferating cells. Bottom: P-Smad3-positive cells in the inner nuclear layer (INL) co-localized with glutamine synthetase (GS), suggesting that these cells are Müller glia. Representative immunohistochemical staining at day 3 is depicted. Cell nuclei are stained with DAPI (blue). The scale bar indicates 25 μm. GC: ganglion cells, ONL: outer nuclear layer.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5120850&req=5

pone.0167073.g002: P-Smad3 is activated in proliferating cells.Top: The co-localization of P-Smad3 and proliferating cell nuclear antigen (PCNA) indicates that Smad3 is activated in proliferating cells. Bottom: P-Smad3-positive cells in the inner nuclear layer (INL) co-localized with glutamine synthetase (GS), suggesting that these cells are Müller glia. Representative immunohistochemical staining at day 3 is depicted. Cell nuclei are stained with DAPI (blue). The scale bar indicates 25 μm. GC: ganglion cells, ONL: outer nuclear layer.
Mentions: Based on immunohistochemistry, double-staining for P-Smad3 and PCNA (a proliferation marker) or GS (a Müller glial marker) revealed the co-localization of these proteins, suggesting that the TGFβ pathway is activated in proliferating Müller glia (Fig 2).

View Article: PubMed Central - PubMed

ABSTRACT

In contrast to the mammalian retina, the zebrafish retina exhibits the potential for lifelong retinal neurogenesis and regeneration even after severe damage. Previous studies have shown that the transforming growth factor beta (TGFβ) signaling pathway is activated during the regeneration of different tissues in the zebrafish and is needed for regeneration in the heart and the fin. In this study, we have investigated the role of the TGFβ pathway in the N-methyl-N-nitrosourea (MNU)-induced chemical model of rod photoreceptor de- and regeneration in adult zebrafish. Immunohistochemical staining for phosphorylated Smad3 was elevated during retinal regeneration, and phosphorylated Smad3 co-localized with proliferating cell nuclear antigen and glutamine synthetase, indicating TGFβ pathway activation in proliferating Müller glia. Inhibiting the TGFβ signaling pathway using a small molecule inhibitor (SB431542) resulted in accelerated recovery from retinal degeneration. Accordingly, we observed increased cell proliferation in the outer nuclear layer at days 3 to 8 after MNU treatment. In contrast to the observations in the heart and the fin, the inhibition of the TGFβ signaling pathway resulted in increased proliferation after the induction of retinal degeneration. A better understanding of the underlying pathways with the possibility to boost retinal regeneration in adult zebrafish may potentially help to stimulate such proliferation also in other species.

No MeSH data available.


Related in: MedlinePlus