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

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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.

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In situ hybridization with activin A and B as well as tgfβ1a, 2 and 3 antisense probes in zebrafish after the induction of retinal degeneration by MNU.Expression of these genes was detected beginning at day 1 and peaking at day 5. The highest staining intensity was observed for tgfβ3 and activins A and B, whereas only modest staining was observed for tgfβ1a and 2. These ligands were primarily detected in the inner nuclear layer (INL). The scale bar indicates 50 μm. GC: ganglion cells, ONL: outer nuclear layer.
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pone.0167073.g003: In situ hybridization with activin A and B as well as tgfβ1a, 2 and 3 antisense probes in zebrafish after the induction of retinal degeneration by MNU.Expression of these genes was detected beginning at day 1 and peaking at day 5. The highest staining intensity was observed for tgfβ3 and activins A and B, whereas only modest staining was observed for tgfβ1a and 2. These ligands were primarily detected in the inner nuclear layer (INL). The scale bar indicates 50 μm. GC: ganglion cells, ONL: outer nuclear layer.

Mentions: In situ hybridization for activin A and B and for TGFβ1a, 2 and 3 showed expression of these genes as soon as one day after the induction of retinal degeneration. On day 5, the expression increased further, whereas it nearly returned to baseline on day 30 (Fig 3). The highest staining intensity was observed for TGFβ3, activin A and activin B, whereas only modest staining was observed for TGFβ1a and only minimal staining for TGFβ2. At day 5, the expression of these mRNAs is mainly in the INL, where the pattern corresponds to the distribution and morphology of Müller glia cells. At day 30, the (weak) expression of activin A and B is mainly in the ONL.


Inhibition of the TGF β Pathway Enhances Retinal Regeneration in Adult Zebrafish
In situ hybridization with activin A and B as well as tgfβ1a, 2 and 3 antisense probes in zebrafish after the induction of retinal degeneration by MNU.Expression of these genes was detected beginning at day 1 and peaking at day 5. The highest staining intensity was observed for tgfβ3 and activins A and B, whereas only modest staining was observed for tgfβ1a and 2. These ligands were primarily detected in the inner nuclear layer (INL). The scale bar indicates 50 μm. GC: ganglion cells, ONL: outer nuclear layer.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0167073.g003: In situ hybridization with activin A and B as well as tgfβ1a, 2 and 3 antisense probes in zebrafish after the induction of retinal degeneration by MNU.Expression of these genes was detected beginning at day 1 and peaking at day 5. The highest staining intensity was observed for tgfβ3 and activins A and B, whereas only modest staining was observed for tgfβ1a and 2. These ligands were primarily detected in the inner nuclear layer (INL). The scale bar indicates 50 μm. GC: ganglion cells, ONL: outer nuclear layer.
Mentions: In situ hybridization for activin A and B and for TGFβ1a, 2 and 3 showed expression of these genes as soon as one day after the induction of retinal degeneration. On day 5, the expression increased further, whereas it nearly returned to baseline on day 30 (Fig 3). The highest staining intensity was observed for TGFβ3, activin A and activin B, whereas only modest staining was observed for TGFβ1a and only minimal staining for TGFβ2. At day 5, the expression of these mRNAs is mainly in the INL, where the pattern corresponds to the distribution and morphology of Müller glia cells. At day 30, the (weak) expression of activin A and B is mainly in the ONL.

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