A Frizzled4-LRP5 agonist promotes blood-retina barrier function by inducing a Norrin-like transcriptional response.
A Frizzled4-LRP5 agonist promotes blood-retina barrier function by inducing a Norrin-like transcriptional response.
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DOI：
10.1016/j.isci.2023.107415
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发表时间：
2023-08-18
期刊：
影响因子：
5.8
通讯作者：
Junge, Harald J.
中科院分区：
文献类型：
--
作者：
Zhang, Lingling;Abedin, Md.;Jo, Ha-Neul;Levey, Jacklyn;Dinh, Quynh Chau;Chen, Zhe;Angers, Stephane;Junge, Harald J.
Norrin（NDP）和WNT 7A/B通过刺激卷曲4-LDL受体相关蛋白5/6（FZD 4-LRP 5/6）复合物以诱导内皮细胞（EC）中的β-连环蛋白依赖性信号传导来诱导和维持血脑屏障和血视网膜屏障（BB B，BR B）。最近开发的FZD 4-LRP 5复合物激动剂在视网膜和神经系统疾病中具有治疗潜力。在这里，我们使用四价抗体模态F4L5.13来鉴定Tspan 12 −/−小鼠中的激动剂活性，该小鼠由于受损的NDP信号传导而显示出复杂的视网膜病理学。在发育过程中给予F4L5.13可减轻BRB缺陷、视网膜血管形成不足，并恢复神经功能。在成熟的Tspan 12 −/−小鼠中，F4L5.13部分诱导BRB新生，而不诱导血管生成。在受损的BRB维持的遗传模型中，F4L5.13的施用快速且实质性地恢复BRB。scRNA-seq揭示了幼年Tspan 12 −/−小鼠中屏障功能的关键介质的扰动，在F4L5.13给药后大部分恢复。本研究鉴定了FZD 4-LRP 5激动剂的转录和功能活性。Frizzled 4-LRP 5激动剂在视网膜血管生成和屏障形成中模拟Norrin在屏障发育失败后诱导成年小鼠重新形成屏障促血管生成作用是环境依赖性的，仅限于发育内皮细胞分化和转运的转录调控生物科学;神经科学;分子神经科学;组学;转录组学
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. Frizzled4-LRP5 agonist mimics Norrin in retinal angiogenesis and barriergenesis Induces de novo barrier formation in adult mice after failed barrier development Proangiogenic effects are context-dependent and are limited to development Transcriptional regulation of endothelial cell differentiation and transport Biological sciences; Neuroscience; Molecular neuroscience; Omics; Transcriptomics
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影响因子：
16.6
作者：
Ding, Jie;Lee, Sung-Jin;Vlahos, Lukas;Yuki, Kanako;Rada, Cara C.;van Unen, Vincent;Vuppalapaty, Meghah;Chen, Hui;Sura, Asmiti;McCormick, Aaron K.;Tomaske, Madeline;Alwahabi, Samira;Nguyen, Huy;Nowatzke, William;Kim, Lily;Kelly, Lisa;Vollrath, Douglas;Califano, Andrea;Yeh, Wen-Chen;Li, Yang;Kuo, Calvin J.
通讯作者：
Kuo, Calvin J.
影响因子：
1.8
作者：
Díaz-Coránguez M;Ramos C;Antonetti DA
通讯作者：
Antonetti DA
影响因子：
64.5
作者：
Junge, Harald J.;Yang, Stacey;Ye, Weilan
通讯作者：
Ye, Weilan
影响因子：
7.7
作者：
Cho, Chris;Wang, Yanshu;Nathans, Jeremy
通讯作者：
Nathans, Jeremy
影响因子：
8.8
作者：
Lai MB;Zhang C;Shi J;Johnson V;Khandan L;McVey J;Klymkowsky MW;Chen Z;Junge HJ
通讯作者：
Junge HJ