Abstract
The blood-brain barrier (BBB) is comprised of a single layer of endothelial cells with uniquely restrictive properties required for maintaining a tightly controlled homeostatic environment in the brain. Classic quail-chick grafting experiments showed that BBB properties are not intrinsic to brain endothelial cells, but instead are induced by signals from the embryonic brain microenvironment. Here we have identified a neuronally produced signal, Spock1, that specifically regulates BBB functional development in both zebrafish and mice without affecting angiogenesis. Using a combination of mosaic genetic analysis, tracer leakage assays and live imaging we show that Spock1 from neurons can regulate brain vasculature permeability non-cell autonomously. Electron microscopy analyses of spock1 mutants revealed that the leakage arises predominantly through increased endothelial transcytosis of both clathrin-independent small and large vesicles due to altered pericyte-endothelial interactions. Single-cell RNA sequencing analyses revealed a reduction in vascular expression of the cell adhesion molecule mcamb in the spock1 mutants, and this down-regulation of mcamb occurred specifically in regions with increased BBB leakage. These analyses indicate that the neuronal signal Spock1 regulates BBB properties by altering vascular gene expression and cellular interactions.
Competing Interest Statement
The authors have declared no competing interest.