Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell. 2012 Dec 7;151(6):1332-44. doi: 10.1016/j.cell.2012.10.042.
Norrin/Frizzled4 (Fz4) signaling activates the canonical Wnt pathway to control retinal vascular development. Using genetically engineered mice, we show that precocious Norrin production leads to premature retinal vascular invasion and delayed Norrin production leads to characteristic defects in intraretinal vascular architecture. In genetic mosaics, wild-type endothelial cells (ECs) instruct neighboring Fz4(-/-) ECs to produce an architecturally normal mosaic vasculature, a cell nonautonomous effect. However, over the ensuing weeks, Fz4(-/-) ECs are selectively eliminated from the mosaic vasculature, implying the existence of a quality control program that targets defective ECs. In the adult retina and cerebellum, gain or loss of Norrin/Fz4 signaling results in a cell-autonomous gain or loss, respectively, of blood retina barrier and blood brain barrier function, indicating an ongoing requirement for Frizzled signaling in barrier maintenance and substantial plasticity in mature CNS vascular structure.
诺里恩/Frizzled4 (Fz4) 信号激活经典 Wnt 通路，控制视网膜血管发育。利用基因工程小鼠，我们发现过早的诺里恩产生会导致视网膜血管过早侵入，而诺里恩产生延迟会导致视网膜内血管结构的特征性缺陷。在遗传嵌合体中，野生型内皮细胞 (EC) 指导邻近的 Fz4(-/-) EC 产生结构正常的嵌合脉管系统，这是一种细胞非自主性效应。然而，在接下来的几周内，Fz4(-/-) EC 会从嵌合脉管系统中被选择性清除，这表明存在一个质量控制系统，针对的是有缺陷的 EC。在成年视网膜和小脑，诺里恩/Fz4 信号的获得或缺失分别导致血视网膜屏障和血脑屏障功能的细胞自主性获得或缺失，这表明 Frizzled 信号在屏障维持中具有持续的需求，并且成熟中枢神经系统血管结构具有很大的可塑性。
