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

iScience (Aug 2023)

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

Journal volume & issue: Vol. 26, no. 8
p. 107415

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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