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

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 ?-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/?-catenin/MFSD2A/CAV-1 axis as a key pathway governing endothelium transcytosis and inner BRB integrity.

SUBMITTER: Wang Z 

PROVIDER: S-EPMC7455181 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature