Benoit Vanhollebeke (University of Brussels)

Functional coupling of brain vascularization and blood-brain barrier formation through an organotypic angiogenic program

Host: Stefan Schulte-Merker

Endothelial cells of the brain are endowed with neuroprotective blood-brain barrier (BBB) properties that restrict the penetration of blood-borne components into the neural tissue. To ensure brain protection from the earliest developmental steps, neural progenitors release Wnt ligands that restrict brain access to endothelial cells that properly initiate the BBB differentiation cascade. To recognize and respond mono-specifically to neural-derived Wnt7a/b ligands, CNS endothelial cells assemble a unique receptor complex composed of Gpr124 and its co-receptor Reck. This selective Wnt recognition or "decoding" capacity is intriguing because Wnt/Frizzled interactions are largely incompatible with monospecific recognition. Gpr124/Reck-dependent Wnt signaling thus provides insights into the Wnt decoding capacities of vertebrate cells and unravels structural determinants of the functional diversification of Wnt family members (Eubelen et al. Science, 2018). The Gpr124/Reck mechanism also provides an opportunity for the targeted treatment of human brain disorders with neurovascular involvement, including stroke and brain cancer, after some molecular adjustments in Wnt7a ligands (Martin et al. Science, 2022). Mosaic genetic studies further revealed that Wnt7a/b ligands control brain angiogenesis at the level of the perineural tip cells. A Wnt/β-catenin-dependent and brain-specific endothelial enzymatic machinery was shown to control the remodeling of the meningeal layers surrounding the brain, thereby identifying an organ-specific angiogenesis mechanism, and illustrating how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements (Schevenels et al. Nature, in press).

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