Developmental regulation of barrier- and non-barrier blood vessels in the CNS.

The blood-brain barrier (BBB) is essential for creating and maintaining tissue homeostasis in the central nervous system (CNS), which is key for proper neuronal function. In most vertebrates, the BBB is localized to microvascular endothelial cells that acquire barrier properties during angiogenesis of the neuroectoderm. Complex and continuous tight junctions, and the lack of fenestrae combined with low pinocytotic activity render the BBB endothelium a tight barrier for water-soluble molecules that may only enter the CNS via specific transporters. The differentiation of these unique endothelial properties during embryonic development is initiated by endothelial-specific flavours of the Wnt/β-catenin pathway in a precise spatiotemporal manner. In this review, we summarize the currently known cellular (neural precursor and endothelial cells) and molecular (VEGF and Wnt/β-catenin) mechanisms mediating brain angiogenesis and barrier formation. Moreover, we introduce more recently discovered crosstalk with cellular and acellular elements within the developing CNS such as the extracellular matrix. We discuss recent insights into the downstream molecular mechanisms of Wnt/β-catenin in particular, the recently identified target genes like Foxf2, Foxl2, Foxq1, Lef1, Ppard, Zfp551, Zic3, Sox17, Apcdd1 and Fgfbp1 that are involved in refining and maintaining barrier characteristics in the mature BBB endothelium. Additionally, we elute to recent insight into barrier heterogeneity and differential endothelial barrier properties within the CNS, focussing on the circumventricular organs as well as on the neurogenic niches in the subventricular zone and the hippocampus. Finally, open questions and future BBB research directions are highlighted in the context of taking benefit from understanding BBB development for strategies to modulate BBB function under pathological conditions.