PT - JOURNAL ARTICLE AU - Wang, Zhongxiao AU - Liu, Chi-Hsiu AU - Huang, Shuo AU - Fu, Zhongjie AU - Tomita, Yohei AU - Britton, William R. AU - Cho, Steve S. AU - Chen, Chuck T. AU - Sun, Ye AU - Ma, Jian-xing AU - He, Xi AU - Chen, Jing TI - Wnt signaling activates MFSD2A to suppress vascular endothelial transcytosis and maintain blood-retinal barrier AID - 10.1126/sciadv.aba7457 DP - 2020 Aug 01 TA - Science Advances PG - eaba7457 VI - 6 IP - 35 4099 - http://advances.sciencemag.org/content/6/35/eaba7457.short 4100 - http://advances.sciencemag.org/content/6/35/eaba7457.full SO - Sci Adv2020 Aug 01; 6 AB - Breakdown of the blood-retinal barrier (BRB) causes retinal edema and vision loss. We investigated the role of Wnt signaling in maintaining the BRB by limiting transcytosis. Mice lacking either the Wnt co-receptor low-density lipoprotein receptor–related protein 5 (Lrp5−/−) or the Wnt ligand Norrin (Ndpy/−) exhibit increased retinal vascular leakage and enhanced endothelial transcytosis. Wnt signaling directly controls the transcription of an endothelium-specific transcytosis inhibitor, major facilitator superfamily domain–containing protein 2a (MFSD2A), in a β-catenin–dependent manner. MFSD2A overexpression reverses Wnt deficiency–induced transcytosis in endothelial cells and in retinas. Moreover, Wnt signaling mediates MFSD2A-dependent vascular endothelium transcytosis through a caveolin-1 (CAV-1)–positive caveolae pathway. In addition, levels of omega-3 fatty acids are also decreased in Wnt signaling–deficient retinas, reflecting the basic function of MFSD2A as a lipid transporter. Our findings uncovered the Wnt/β-catenin/MFSD2A/CAV-1 axis as a key pathway governing endothelium transcytosis and inner BRB integrity.