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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
E-mail(s) elisabetta.dejana@igp.uu.se
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
Relations
BioProject PRJNA505620
SRA SRP168743

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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

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