Wnt signaling activates MFSD2A to suppress vascular endothelial transcytosis and maintain blood-retinal barrier

Zhongxiao Wang, Chi Hsiu Liu, Shuo Huang, Zhongjie Fu, Yohei Tomita, William R. Britton, Steve S. Cho, Chuck T. Chen, Ye Sun, Jian Xing Ma, Xi He, Jing Chen

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbereaba7457
JournalScience Advances
Volume6
Issue number35
DOIs
Publication statusPublished - 2020 Aug
Externally publishedYes

ASJC Scopus subject areas

  • General

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