Low Wnt/β-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice
- University Hospital Frankfurt, Germany
- Université libre de Bruxelles, Belgium
- Max-Planck-Institute for Molecular Biomedicine, Germany
- Kyoto University, Japan
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files are provided for Figures 4F-H, 5C, 6B, 7D, 8E-F, 9C as well as in Figure 4-figure supplement 1C, Figure 4-figure supplement 3D, Figure 8-figure supplement 1B. Raw data for all quantifications are provided in a separated MS Excel documents.
Article and author information
Author details
Benoit Vanhollebeke
Funding
Horizon 2020 Framework Programme (BtRAIN)
- Raoul F V Germano
- Benoit Vanhollebeke
- Stefan Liebner
Deutsche Forschungsgemeinschaft (LI 911/5-1)
- Fabienne Benz
- Ralf H Adams
- Sylvaine Guérit
- Stefan Liebner
Landes-Offensive zur Entwicklung Wissenschaftlich- ökonomischer Exzellenz Program of the Center for Personalized Translational Epilepsy Research (TP8)
- Stefan Liebner
Goethe University Frankfurt - Line A
- Sylvaine Guérit
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Elisabetta Dejana, FIRC Institute of Molecular Oncology, Italy
Ethics
Animal experimentation: Animals were housed under standard conditions and fed ad libitum. All experimental protocols, handling and use of mice were approved by the Regierungspräsidium Darmstadt, Germany (FK/1052 and FK/1108). All animal handling was performed to minimize suffering.
Version history
- Received: November 21, 2018
- Accepted: March 28, 2019
- Accepted Manuscript published: April 1, 2019 (version 1)
- Version of Record published: April 24, 2019 (version 2)
Copyright
© 2019, Benz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Low Wnt/β-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice
eLife 8:e43818.
https://doi.org/10.7554/eLife.43818
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