Seitz, Roswitha and Weber, Gregor and Albrecht, Sebastian and Fuchshofer, Rudolf and Tamm, Ernst R. and Ohlmann, Andreas (2018) Cross-Inhibition of Norrin and TGF-beta Signaling Modulates Development of Retinal and Choroidal Vasculature. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 59 (6). pp. 2240-2251. ISSN 0146-0404, 1552-5783
Full text not available from this repository. (Request a copy)Abstract
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 (beta Bl-Norrin) and/or active TGF-beta (beta B1-TGF-beta 1) 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 beta B1-TGF-beta l 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 beta B1-TGF-beta 1 mice. In contrast, Norrin normalized Wnt/beta-catenin signaling and SMAD7 levels in double transgenic mice. Moreover, in retinae of beta B1-TGF-beta 1 mice, the amounts of phosphorylated SMAD3, a downstream mediator of TGF-beta signaling, were increased compared to those of beta B1-Norrin/ beta B1-TGF-beta 1 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. CONCULSIONS. 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR; TRABECULAR MESHWORK; PIGMENT EPITHELIUM; DIABETIC-RETINOPATHY; WNT/BETA-CATENIN; DOWN-REGULATION; KNOCKOUT MICE; WNT; DISEASE; CELLS; Norrin; Wnt/beta-catenin signaling; TGF-beta signaling; crosstalk; retinal vasculature; SMAD7 |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Humananatomie und Embryologie > Prof. Dr. Ernst Tamm |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2020 12:28 |
| Last Modified: | 06 Apr 2020 05:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14655 |
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