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Sci Adv . 2020 Aug 28;6(35):eaba7457. doi: 10.1126/sciadv.aba7457. eCollection 2020 Aug.

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

August 28, 2020
Zhongxiao Wang 1, Chi-Hsiu Liu 1, Shuo Huang 1, Zhongjie Fu 1, Yohei Tomita 1, William R Britton 1, Steve S Cho 1, Chuck T Chen 2, Ye Sun 1, Jian-Xing Ma 3, Xi He 4, Jing Chen 1

1Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

2Section on Nutritional Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Room 3N-01, North Bethesda, MD 20852, USA.

3Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

4The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.


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.

Major facilitator superfamily domain containing 2a (Mfsd2a)