A Frizzled4-LRP5 agonist promotes blood-retina barrier function by inducing a Norrin-like transcriptional response
Lingling Zhang,
Md. Abedin,
Ha-Neul Jo,
Jacklyn Levey,
Quynh Chau Dinh,
Zhe Chen,
Stephane Angers,
Harald J. Junge
Affiliations
Lingling Zhang
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA; Corresponding author
Md. Abedin
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA
Ha-Neul Jo
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA; Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA
Jacklyn Levey
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA; Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA
Quynh Chau Dinh
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA
Zhe Chen
Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
Stephane Angers
Department of Biochemistry, University of Toronto, Toronto, ON, Canada; Terrence Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
Harald J. Junge
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA; Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA; Corresponding author
Summary: Norrin (NDP) and WNT7A/B induce and maintain the blood-brain and blood-retina barrier (BBB, BRB) by stimulating the Frizzled4-LDL receptor related protein 5/6 (FZD4-LRP5/6) complex to induce beta-catenin-dependent signaling in endothelial cells (ECs). Recently developed agonists for the FZD4-LRP5 complex have therapeutic potential in retinal and neurological diseases. Here, we use the tetravalent antibody modality F4L5.13 to identify agonist activities in Tspan12−/− mice, which display a complex retinal pathology due to impaired NDP-signaling. F4L5.13 administration during development alleviates BRB defects, retinal hypovascularization, and restores neural function. In mature Tspan12−/− mice F4L5.13 partially induces a BRB de novo without inducing angiogenesis. In a genetic model of impaired BRB maintenance, administration of F4L5.13 rapidly and substantially restores the BRB. scRNA-seq reveals perturbations of key mediators of barrier functions in juvenile Tspan12−/− mice, which are in large parts restored after F4L5.13 administration. This study identifies transcriptional and functional activities of FZD4-LRP5 agonists.
