Ye Xin, Wang Yanshu, Cahill Hugh, Yu Minzhong, Badea Tudor C, Smallwood Philip M, Peachey Neal S, Nathans Jeremy
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell. 2009 Oct 16;139(2):285-98. doi: 10.1016/j.cell.2009.07.047.
Disorders of vascular structure and function play a central role in a wide variety of CNS diseases. Mutations in the Frizzled-4 (Fz4) receptor, Lrp5 coreceptor, or Norrin ligand cause retinal hypovascularization, but the mechanisms by which Norrin/Fz4/Lrp signaling controls vascular development have not been defined. Using mouse genetic and cell culture models, we show that loss of Fz4 signaling in endothelial cells causes defective vascular growth, which leads to chronic but reversible silencing of retinal neurons. Loss of Fz4 in all endothelial cells disrupts the blood brain barrier in the cerebellum, whereas excessive Fz4 signaling disrupts embryonic angiogenesis. Sox17, a transcription factor that is upregulated by Norrin/Fz4/Lrp signaling, plays a central role in inducing the angiogenic program controlled by Norrin/Fz4/Lrp. These experiments establish a cellular basis for retinal hypovascularization diseases due to insufficient Frizzled signaling, and they suggest a broader role for Frizzled signaling in vascular growth, remodeling, maintenance, and disease.
血管结构和功能紊乱在多种中枢神经系统疾病中起核心作用。卷曲蛋白4（Fz4）受体、低密度脂蛋白受体相关蛋白5（Lrp5）共受体或诺林（Norrin）配体的突变会导致视网膜血管生成不足，但Norrin/Fz4/Lrp信号传导控制血管发育的机制尚未明确。利用小鼠遗传和细胞培养模型，我们发现内皮细胞中Fz4信号缺失会导致血管生长缺陷，进而导致视网膜神经元长期但可逆的沉默。所有内皮细胞中Fz4缺失会破坏小脑的血脑屏障，而Fz4信号过度则会破坏胚胎血管生成。Sox17是一种受Norrin/Fz4/Lrp信号上调的转录因子，在诱导由Norrin/Fz4/Lrp控制的血管生成程序中起核心作用。这些实验为因卷曲蛋白信号不足导致的视网膜血管生成不足疾病建立了细胞基础，并提示卷曲蛋白信号在血管生长、重塑、维持和疾病中具有更广泛的作用。
