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

doi:10.1016/j.isci.2023.107415

A Frizzled4-LRP5 agonist promotes blood-retina barrier function by inducing a Norrin-like transcriptional response

iScience. 2023 Jul 18;26(8):107415. doi: 10.1016/j.isci.2023.107415. eCollection 2023 Aug 18.

Authors

Lingling Zhang¹, Md Abedin¹, Ha-Neul Jo^{1

2}, Jacklyn Levey^{1

2}, Quynh Chau Dinh¹, Zhe Chen³, Stephane Angers^{4

5

6}, Harald J Junge^{1

2}

Affiliations

¹ Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.
² Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA.
³ Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
⁴ Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
⁵ Terrence Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON, Canada.
⁶ Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.

Abstract

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.

Keywords: Biological sciences; Molecular neuroscience; Neuroscience; Omics; Transcriptomics.

Abstract

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