Single-cell control mechanism of brain angiogenesis and blood-brain barrier formation

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, neuronal progenitors release Wnt7a/b ligands that restrict brain access to endothelial cells that properly initiate the BBB differentiation cascade. In this seminar, the molecular and cellular regulation of this organotypic quality control mechanism will be discussed. In order to recognize and respond in an appropriate manner to Wnt7a, CNS endothelial cells were shown to assemble a unique receptor complex composed of Gpr124 and its co-receptor Reck1. The Gpr124/Reck complex enables brain endothelial cells to selectively respond to Wnt7a/b. This selective Wnt recognition or “decoding” capacity is intriguing because Wnt/Frizzled interactions are largely incompatible with monospecific recognition. Mechanistic studies revealed that Gpr124 and Reck share tasks in this process. Reck was found to bind with low micromolar affinity to the intrinsically disordered linker region of Wnt7a/b. Availability of Reck-bound Wnt7a/b for Frizzled signaling relies on the interaction between Gpr124 and Frizzled, through diverse bridging mechanisms. These bridging mechanisms assemble dynamic signalosomes, resulting in increased local concentrations of Wnt7a/b available for Frizzled signaling2,3. Gpr124/Reck-dependent Wnt signaling provides insights into the Wnt decoding capacities of vertebrate cells and unravels structural determinants of the functional diversification of Wnt family members. 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 the Wnt7a ligands4. Mosaic genetic studies have revealed that the Wnt7a-mediated control of brain angiogenesis operates at the level of the angiogenic tip cells, but how endothelial Wnt/β-catenin signalling impacts the process of angiogenic sprouting selectively in the brain remains unknown. Combining light-instructed spatial transcriptomic characterisation of perineural vessels with genetic investigations in zebrafish and mice embryos, we reveal that Wnt/β-catenin is required to remodel the meningeal layers surrounding the brain5. Upon genetic interference with pial basement membrane composition, the Wnt/β-catenin-dependent organotypic control of brain angiogenesis is lost, resulting in properly patterned yet BBB-defective cerebrovasculatures. This organ-specific angiogenic control mechanism illustrates how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements.