ADAMTSL2, a missing link in Wnt/ß-catenin regulated CNS vascular development

Context dependent molecular cues shape the formation of the cerebral vascular network and the function of the blood-brain barrier (BBB). The Wnt/ß-catenin pathway is orchestrating CNS vascular development, but downstream mediators have not been characterized. Here we generated an endothelial cell-specific R26-Axin1 overexpression (AOE) mouse model to inhibit Wnt/ß-catenin signaling. In AOE mice we discovered that blockade of Wnt/ß-catenin pathway leads to premature regression and remodeling without compromising BBB integrity. Importantly, by comparing transcriptomes of endothelial cells from wildtype and AOE mice, we identified ADAMTSL2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the BBB during development. Zebrafish loss-of-function and gain-of-function models, further demonstrated that ADAMTSL2 is crucial for normal vascular development and could rescue vascular phenotypes in AOE zebrafish brains. In conclusion, the studies presented here reveal a hitherto unrecognized role of ADAMTSL2 as an endothelial cell-specific mediator of Wnt/ß-catenin signaling during CNS vascular development and BBB-formation. Overall design: Examination of expression changes in mouse brain endothelial cells when overexpressing Axin1

6

Jensen LD, Hot B, Ramsköld D, Germano RFV, Yokota C, Giatrellis S, Lauschke VM, Hubmacher D, Li MX, Hupe M, Arnold TD, Sandberg R, Frisén J, Trusohamn M, Martowicz A, Wisniewska-Kruk J, Nyqvist D, Adams RH, Apte SS, Vanhollebeke B, Stenman JM, Kele J