Cross-Inhibition of Norrin and TGF-b Signaling ModulatesDevelopment of Retinal and Choroidal Vasculature

Investigative Ophthalmology & Visual Science

article

Roswitha Seitz¹  Gregor Weber¹  Sebastian Albrecht¹  Rudolf Fuchshofer¹  Ernst R. Tamm¹  Andreas Ohlmann¹ 

[1] Institute of Human Anatomy and Embryology, University of Regensburg;Department of Ophthalmology, Ludwig-Maximilians-University Munich

关键词: Norrin;    Wnt/b-catenin signaling;    TGF-b signaling;    crosstalk;    retinal vasculature;    SMAD7;   

DOI  :  10.1167/iovs.17-23403

学科分类：社会科学、人文和艺术（综合）

来源: Association for Research in Vision and Ophthalmology

【 摘 要 】

PURPOSE. Norrin is essential for the formation of the retinal vasculature during developmentand promotes its repair after damage via activation of Wnt/b-catenin signaling. Since retinalTGF-b signaling has essentially opposite effects on the retinal vasculature we investigated ifand how Norrin inhibits TGF-b signaling, and vice versa.METHODS. Eyes from transgenic mice with an overexpression of Norrin (bB1-Norrin) and/oractive TGF-b (bB1-TGF-b1) in the lens were generated and analyzed by light microscopy,immunohistochemistry, and TUNEL. Further on, protein as well as mRNA levels wereinvestigated by Western blot analyses and real-time RT-PCR, respectively.RESULTS. In bB1-TGF-b1 mice, the lack of retinal vascular development and choriocapillarismaintenance was rescued when transgenic Norrin was additionally overexpressed in the eye.In addition, retinal Wnt/b-catenin signaling and the levels of SMAD7, an inhibitor of thecanonical TGF-b pathway, were substantially suppressed in retinae of bB1-TGF-b1 mice. Incontrast, Norrin normalized Wnt/b-catenin signaling and SMAD7 levels in double transgenicmice. Moreover, in retinae of bB1-TGF-b1 mice, the amounts of phosphorylated SMAD3, adownstream mediator of TGF-b signaling, were increased compared to those of bB1-Norrin/bB1-TGF-b1 mice. In vitro, Norrin substantially reduced the TGF-b–mediated induction oftarget genes, an effect that was blocked by Dickkopf-1, a specific inhibitor of Wnt/b-cateninsignaling.CONCLUSIONS. High amounts of TGF-b in the eye cause a substantial reduction in the activity ofWnt/b-catenin signaling. This effect is inhibited in the presence of high amounts of Norrin,which further induce the expression of SMAD7 to inhibit TGF-b signaling.

【 授权许可】

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