Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood–retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological balance is fundamental to visual function by facilitating the delivery of nutrients and oxygen and for protection from blood-borne toxins. The inner BRB (iBRB), composed mostly of inner retinal vasculature, controls substance exchange mainly via transportation processes between (paracellular) and through (transcellular) the retinal microvascular endothelium. Disruption of iBRB, characterized by retinal edema, is observed in many eye diseases and disturbs the physiological quiescence in the retina’s extracellular space, resulting in vision loss. Consequently, understanding the mechanisms of iBRB formation, maintenance, and breakdown is pivotal to discovering potential targets to restore function to compromised physiological barriers. These unraveled targets can also inform potential drug delivery strategies across the BRB and the blood–brain barrier into retinas and brain tissues, respectively. This review summarizes mechanistic insights into the development and maintenance of iBRB in health and disease, with a specific focus on the Wnt signaling pathway and its regulatory role in both paracellular and transcellular transport across the retinal vascular endothelium.

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The Role of Wnt and R-spondin in the Stomach During Health and Disease

Biomedicines ◽

10.3390/biomedicines7020044 ◽

2019 ◽

Vol 7 (2) ◽

pp. 44 ◽

Cited By ~ 3

Author(s):

Anne-Sophie Fischer ◽

Michael Sigal

Keyword(s):

Gastric Cancer ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Regulatory Function ◽

Healthy State ◽

Organ Systems ◽

Proliferation And Differentiation ◽

Health And Disease ◽

H Pylori

The Wnt signaling pathway is one of the most prominent developmental signals. In addition to its functions in development, there is emerging evidence that it is also crucial for various organ functions in adult organisms, where Wnt signaling controls tissue stem cell behavior, proliferation and differentiation. Deregulation of Wnt signaling is involved in various pathological conditions and has been linked to malignant tissue transformation in different organ systems. The study of the Wnt signaling pathway has revealed a complex regulatory network that tightly balances the quality and strength of Wnt signaling in tissues. In this context, R-spondins are secreted proteins that stabilize Wnt receptors and enhance Wnt signaling. In this review we focus on new insights into the regulatory function of Wnt and R-spondin signaling in the stomach. In addition to its function in the healthy state, we highlight the connection between Wnt signaling and infection with Helicobacter pylori (H. pylori), a pathogen that colonizes the stomach and is the main risk factor for gastric cancer. In addition to experimental data that link Wnt signaling to carcinogenesis, we discuss that Wnt signaling is affected in a substantial proportion of patients with gastric cancer, and provide examples for potential clinical implications for altered Wnt signaling in gastric cancer.

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

Science Advances ◽

10.1126/sciadv.aba7457 ◽

2020 ◽

Vol 6 (35) ◽

pp. eaba7457

Author(s):

Zhongxiao Wang ◽

Chi-Hsiu Liu ◽

Shuo Huang ◽

Zhongjie Fu ◽

Yohei Tomita ◽

...

Keyword(s):

Wnt Signaling ◽

Vision Loss ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Basic Function ◽

Major Facilitator Superfamily ◽

Dependent Manner ◽

Omega 3 ◽

Blood Retinal Barrier ◽

Major Facilitator

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.

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