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

被引：4

作者：

Zhang, Lingling ^{[1
]}

Abedin, Md. ^{[1
]}

Jo, Ha-Neul ^{[1
,2
]}

Levey, Jacklyn ^{[1
,2
]}

Dinh, Quynh Chau ^{[1
]}

Chen, Zhe ^{[3
]}

Angers, Stephane ^{[4
,5
,6
]}

Junge, Harald J. ^{[1
,2
]}

机构：

[1] Univ Minnesota, Dept Ophthalmol & Visual Neurosci, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Grad Program Mol Cellular Dev Biol & Genet, Minneapolis, MN 55455 USA

[3] Univ Minnesota, Dept Neurosci, Minneapolis, MN USA

[4] Univ Toronto, Dept Biochem, Toronto, ON, Canada

[5] Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON, Canada

[6] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON, Canada

来源：

ISCIENCE | 2023年 / 26卷 / 08期

基金：

加拿大健康研究院;

关键词：

BRAIN-BARRIER; CANONICAL WNT; VASCULAR DEVELOPMENT; DISEASE; GPR124; CNS; ANGIOGENESIS; TSPAN12; INTEGRITY; SURROGATE;

D O I：

10.1016/j.isci.2023.107415

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Norrin (NDP) and WNT7A/B induce and maintain the blood-brain and blood -retina barrier (BBB, BRB) by stimulating the Frizzled4-LDL receptor related pro-tein 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 de-fects, retinal hypovascularization, and restores neural function. In mature Tspan12-/- mice F4L5.13 partially induces a BRB de novo without inducing angio-genesis. In a genetic model of impaired BRB maintenance, administration of F4L5.13 rapidly and substantially restores the BRB. scRNA-seq reveals perturba-tions of key mediators of barrier functions in juvenile Tspan12-/- mice, which are in large parts restored after F4L5.13 administration. This study identifies tran-scriptional and functional activities of FZD4-LRP5 agonists.

引用

页数：20