Gpr124 is essential for blood-brain barrier integrity in central nervous system disease

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption

Informal settlement upgrading: Bridging the gap between the de facto and the de jure

In order Tor informal settlement upgrading ro build the institutions necessary to ensure continuity of the improvement. process, planners must move beyond a narrow concern with legality and illegality. Upgrading should comprise a gradation of strategies that legitimize and integrate aspects of settlements' de facto institutions into the planning process. In so doing, it is possible to contribute to legal regulatory frameworks that are more appropriate to informal settlements. This article considers planning, tenure delivery, and public participation as three aspects of a recent upgrade in South Africa, and the extent to which they bridged the gap between the de jure and de facto