| First Author | Seitz R | Year | 2018 |
| Journal | Invest Ophthalmol Vis Sci | Volume | 59 |
| Issue | 6 | Pages | 2240-2251 |
| PubMed ID | 29715368 | Mgi Jnum | J:261779 |
| Mgi Id | MGI:6155267 | Doi | 10.1167/iovs.17-23403 |
| Citation | Seitz R, et al. (2018) Cross-Inhibition of Norrin and TGF-beta Signaling Modulates Development of Retinal and Choroidal Vasculature. Invest Ophthalmol Vis Sci 59(6):2240-2251 |
| abstractText | Purpose: Norrin is essential for the formation of the retinal vasculature during development and promotes its repair after damage via activation of Wnt/beta-catenin signaling. Since retinal TGF-beta signaling has essentially opposite effects on the retinal vasculature we investigated if and how Norrin inhibits TGF-beta signaling, and vice versa. Methods: Eyes from transgenic mice with an overexpression of Norrin (betaB1-Norrin) and/or active TGF-beta (betaB1-TGF-beta1) in the lens were generated and analyzed by light microscopy, immunohistochemistry, and TUNEL. Further on, protein as well as mRNA levels were investigated by Western blot analyses and real-time RT-PCR, respectively. Results: In betaB1-TGF-beta1 mice, the lack of retinal vascular development and choriocapillaris maintenance was rescued when transgenic Norrin was additionally overexpressed in the eye. In addition, retinal Wnt/beta-catenin signaling and the levels of SMAD7, an inhibitor of the canonical TGF-beta pathway, were substantially suppressed in retinae of betaB1-TGF-beta1 mice. In contrast, Norrin normalized Wnt/beta-catenin signaling and SMAD7 levels in double transgenic mice. Moreover, in retinae of betaB1-TGF-beta1 mice, the amounts of phosphorylated SMAD3, a downstream mediator of TGF-beta signaling, were increased compared to those of betaB1-Norrin/betaB1-TGF-beta1 mice. In vitro, Norrin substantially reduced the TGF-beta-mediated induction of target genes, an effect that was blocked by Dickkopf-1, a specific inhibitor of Wnt/beta-catenin signaling. Conclusions: High amounts of TGF-beta in the eye cause a substantial reduction in the activity of Wnt/beta-catenin signaling. This effect is inhibited in the presence of high amounts of Norrin, which further induce the expression of SMAD7 to inhibit TGF-beta signaling. |
