GSE122564
Fine tuning of Sox17 and canonical Wnt coordinates the permeability properties of the blood-brain barrier
Rationale. The microvasculature of the central nervous system includes the blood-brain barrier (BBB),  which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory  cells. Canonical Wnt/b-catenin signaling is responsible for the early phases of brain vascularization and  blood-brain barrier differentiation. However, this signal declines after birth and other signaling pathways  able to maintain barrier integrity at postnatal stage are still unknown. Objective. Sox17 constitutes a major downstream target of Wnt/b-catenin in endothelial cells and  regulates arterial differentiation. In the present paper, we asked whether Sox17 may act downstream of  Wnt/b-catenin in inducing BBB differentiation and maintenance. Methods and Results. Using reporter mice and nuclear staining of Sox17 and b-catenin, we report that  while b-catenin signaling declines after birth, Sox17 activation increases and remains high in the adult.  Endothelial-specific inactivation of Sox17 leads to increase of permeability of the brain microcirculation.  The severity of this effect depends on the degree of BBB maturation: it is strong in the embryo, and  progressively declines after birth. In search of Sox17 mechanism of action, RNA-Seq analysis of gene  expression of brain endothelial cells has identified members of the Wnt/b-catenin signaling pathway as  downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/b-catenin  signaling and it acts in concert with this pathway to induce and maintain BBB properties. In vivo,  inhibition of the b-catenin destruction complex or expression of a degradation-resistant b-catenin mutant,  prevent the increase in permeability and retina vascular malformations observed in the absence of Sox17. Conclusions. Our data highlight a novel role for Sox17 in the induction and maintenance of the BBB and  they underline the strict reciprocal tuning of this transcription factor and Wnt/b-catenin pathway.  Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions. Overall design: Brain endothelial cells (ECs) mRNA profiles over 4 developmental stages (from embryos to adult) of wt and Sox17iECKO mice generated, in triplicate.