This is a nice example of a rather unexpected discovery: by studying the development of the blood vessels of the brain, researchers at Université libre de Bruxelles have just shed light on a question that was pending for 10 years! They provide a molecular mechanism conferring ligand specificity to Wnt signaling, an ancestral communication pathway present in all vertebrates. Their research is published in Science.

Led by Benoit Vanhollebeke, WELBIO investigator at the Université libre de Bruxelles (ULB), the
Laboratory of Neurovascular Signaling (ULB’s Faculty of Sciences and ULB Neuroscience Institute) has solved an important enigma of cell signaling related to Wnt signaling specificity. Wnt is ancient pathway, whose evolutionary appearance dates back to the emergence of multicellular animals. It plays pivotal roles in cell to cell communication and governs several aspects of embryonic development and tissue homeostasis. When dysfunctional, Wnt signaling can be at the origin of many diseases, in particular several cancers. With 10 receptors and 19 ligands, recognizing each other, the complexity of the pathway seemed dizzying. How do vertebrate cells manage to interpret the many Wnt signals they encounter and trigger an adequate response? It is such an interpretation mechanism that ULB researchers have just discovered.

Previous findings had shown that two proteins expressed by cerebral endothelial cells, Gpr124 and Reck, are required for cerebrovascular development in response Wnt7 ligands. The team went on to study the mechanism by which the complex operates. Using genetic, biophysical and zebrafish experiments, researchers have shown that the complex Gpr124 / Reck acts as a decoding module: Reck recognizes the Wnt7 ligand, but the presence of Gpr124 is necessary to trigger Wnt7 signaling via Frizzled receptors. Their results are detailed in Science. These discoveries will enable researchers to refine their understanding of Wnt signaling and its multiple regulations. This would also make it possible to consider new treatments for diseases, such as cancers or neurovascular diseases.

This work was conducted in collaboration with the teams of Abel Garcia-Pino (WELBIO investigator at the Université libre de Bruxelles, Belgium), David Alsteens (Université catholique de Louvain) and Didier Stainier (Max Planck Institute for Heart and Lung Research, Germany).

The Neurovascular Signaling Laboratory is supported by the Welbio (Walloon Excellence in Life Sciences and Biotechnology), the FNRS, the ULB Foundation, the FMRE (Queen Elisabeth Medical Foundation for Neuroscience) and an ARC (Concerted Research Action). Benoit Vanhollebeke is also part of the ULB's Center for Microscopy and Molecular Imaging (CMMI).

A Molecular mechanism for Wnt ligand-specific signaling.
Eubelen M./Bostaille N., Cabochette P., Gauquier A., Tebabi P., Dumitru A.C., Koehler M., Gut P., Alsteens D., Stainier D.Y.R., Garcia-Pino A. and Vanhollebeke B.
doi : 10.1126/science.aat1178

July 13, 2020 - 3:26 PM - URL: http://welbio.org/cms/c_10382/en/new-findings-on-inter-cellular-communication