ADAMTSL2, a missing link in Wnt/ß-catenin regulated CNS vascular development

Context dependent molecular cues shape the formation of the cerebral vascular network and the function of the blood-brain barrier (BBB). The Wnt/ß-catenin pathway is orchestrating CNS vascular development, but downstream mediators have not been characterized. Here we generated an endothelial cell-specific R26-Axin1 overexpression (AOE) mouse model to inhibit Wnt/ß-catenin signaling. In AOE mice we discovered that blockade of Wnt/ß-catenin pathway leads to premature regression and remodeling without compromising BBB integrity. Importantly, by comparing transcriptomes of endothelial cells from wildtype and AOE mice, we identified ADAMTSL2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the BBB during development. Zebrafish loss-of-function and gain-of-function models, further demonstrated that ADAMTSL2 is crucial for normal vascular development and could rescue vascular phenotypes in AOE zebrafish brains. In conclusion, the studies presented here reveal a hitherto unrecognized role of ADAMTSL2 as an endothelial cell-specific mediator of Wnt/ß-catenin signaling during CNS vascular development and BBB-formation. Examination of expression changes in mouse brain endothelial cells when overexpressing Axin1

依赖于微环境的分子信号调控脑血管网络的形成与血脑屏障（blood-brain barrier, BBB）的功能。Wnt/β-连环蛋白（Wnt/ß-catenin）通路统筹调控中枢神经系统（central nervous system, CNS）的血管发育，但其下游介导因子尚未被阐明。本研究构建了内皮细胞特异性过表达R26-Axin1（AOE）的小鼠模型，以抑制Wnt/β-连环蛋白信号通路。在该AOE小鼠模型中，我们发现阻断Wnt/β-连环蛋白通路会导致血管过早退化与重塑，且不会损害血脑屏障的完整性。重要的是，通过对比野生型与AOE小鼠内皮细胞的转录组，我们鉴定出ADAMTSL2是一种全新的Wnt/β-连环蛋白诱导分泌因子，其在发育过程中对维持血脑屏障稳定性发挥关键作用。利用斑马鱼功能缺失与功能获得性模型，我们进一步证实ADAMTSL2对正常血管发育至关重要，且能够挽救AOE斑马鱼脑部的血管表型。综上，本研究揭示了ADAMTSL2此前未被认知的功能：它是中枢神经系统血管发育与血脑屏障形成过程中，内皮细胞特异性的Wnt/β-连环蛋白信号通路介导因子。对过表达Axin1的小鼠脑内皮细胞的基因表达变化进行检测