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.
Lingling Zhang  1 ,  Md Abedin  1 ,  Ha-Neul Jo  1  2 ,  Jacklyn Levey  1  2 ,  Quynh Chau Dinh  1 ,  Zhe Chen  3 ,  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.
PMID: 37559903 DOI: 10.1016/j.isci.2023.107415
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.