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Series GSE122564 Query DataSets for GSE122564
Status Public on Feb 12, 2019
Title Fine tuning of Sox17 and canonical Wnt coordinates the permeability properties of the blood-brain barrier
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Contributor(s) Corada M, Orsenigo F, Bhat GP, Conze LL, Breviario F, Cunha SI, Classeon-Welsh L, Beznoussenko GV, Mironov AA, Bacigaluppi M, Martino G, Pitulescu ME, Adams RH, Magnusson P, Dejana E
Citation(s) 30591003
Submission date Nov 15, 2018
Last update date Feb 12, 2019
Contact name Elisabetta Dejana
Organization name Uppsala University
Department Immunology, Genetics and Pathology
Street address Dag Hammarskjolds väg 20
City Uppsala
ZIP/Postal code 751 85
Country Sweden
Platforms (1)
GPL16331 Ion Torrent PGM (Mus musculus)
Samples (24)
GSM3473961 E15.5_wt_1
GSM3473962 E15.5_wt_2
GSM3473963 E15.5_wt_3
BioProject PRJNA505620
SRA SRP168743

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Supplementary file Size Download File type/resource
GSE122564_RAW.tar 32.1 Mb (http)(custom) TAR (of TXT)
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Raw data are available in SRA
Processed data provided as supplementary file

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