Low wnt/β-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice

Author:

Benz Fabienne1ORCID,Wichitnaowarat Viraya1,Lehmann Martin1,Germano Raoul FV2ORCID,Mihova Diana1,Macas Jadranka1ORCID,Adams Ralf H3ORCID,Taketo M Mark4,Plate Karl-Heinz15678,Guérit Sylvaine1,Vanhollebeke Benoit29ORCID,Liebner Stefan156ORCID

Affiliation:

1. Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany

2. Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Bruxelles, Belgium

3. Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, University of Münster, Faculty of Medicine, Münster, Germany

4. Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

5. Excellence Cluster Cardio-Pulmonary systems (ECCPS), Partner site Frankfurt, Frankfurt, Germany

6. German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany

7. German Center for Cardiovascular Research (DZHK), Partner site Frankfurt/Mainz, Frankfurt, Germany

8. German Cancer Research Center (DKFZ), Heidelberg, Germany

9. Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wallonia, Belgium

Abstract

The circumventricular organs (CVOs) in the central nervous system (CNS) lack a vascular blood-brain barrier (BBB), creating communication sites for sensory or secretory neurons, involved in body homeostasis. Wnt/β-catenin signaling is essential for BBB development and maintenance in endothelial cells (ECs) in most CNS vessels. Here we show that in mouse development, as well as in adult mouse and zebrafish, CVO ECs rendered Wnt-reporter negative, suggesting low level pathway activity. Characterization of the subfornical organ (SFO) vasculature revealed heterogenous claudin-5 (Cldn5) and Plvap/Meca32 expression indicative for tight and leaky vessels, respectively. Dominant, EC-specific β-catenin transcription in mice, converted phenotypically leaky into BBB-like vessels, by augmenting Cldn5+vessels, stabilizing junctions and by reducing Plvap/Meca32+ and fenestrated vessels, resulting in decreased tracer permeability. Endothelial tightening augmented neuronal activity in the SFO of water restricted mice. Hence, regulating the SFO vessel barrier may influence neuronal function in the context of water homeostasis.

Funder

Deutsche Forschungsgemeinschaft

Horizon 2020 Framework Programme

Goethe University Frankfurt - Line A

Landes-Offensive zur Entwicklung Wissenschaftlich- ökonomischer Exzellenz (LOEWE), Program of the Center for Personalized Translational Epilepsy Research, CePTER

German Centre for Heart and Circulation Research

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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