title: Inhibition of the TGFβ Pathway Enhances Retinal Regeneration in Adult Zebrafish.
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.
authors.affiliation: Department of Ophthalmology, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Tappeiner
authors.affiliation: Department of Ophthalmology, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: Ellinor
authors.initials: E
authors.lastname: Maurer
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Pauline
authors.initials: P
authors.lastname: Sallin
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bise
authors.affiliation: Department of Ophthalmology, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Enzmann
authors.affiliation: Department of Ophthalmology, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.|Department of Ophthalmology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Tschopp
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D063928:Ependymoglial Cells / Q000378:metabolism; D008770:Methylnitrosourea / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects*; D012162:Retinal Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; D008770:Methylnitrosourea