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This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 294/2/H891    most recent 01248.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fontijn, R. D. Articles by Horrevoets, A. J. G. Search for Related Content PubMed PubMed Citation Articles by Fontijn, R. D. Articles by Horrevoets, A. J. G.

SOX-18 controls endothelial-specific claudin-5 gene expression and barrier function

¹Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and ²Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands

Submitted 29 October 2007 ; accepted in final form 5 December 2007

Members of the claudin family constitute tight junction strands and are major determinants in specificity and selectivity of paracellular barriers. Transcriptional control of claudin gene expression is essential to establish individual claudin expression patterns and barrier properties. Using full genome expression profiling, we now identify sex-determining region Y-box (SOX)-18, a member of the SOX family of high-mobility group box transcription factors, as one of the most differentially induced genes during establishment of the endothelial barrier. We show that overexpression of SOX-18 and a dominant-negative mutant thereof, as well as SOX-18 silencing, greatly affect levels of claudin-5 (CLDN5). The relevance of an evolutionary conserved SOX-binding site in the CLDN5 promoter is shown using sequential promoter deletions, as well as point mutations. Furthermore, SOX-18 silencing abrogates endothelial barrier function, as measured by electric cell-substrate impedance sensing. Thus an obligatory role for SOX-18 in the regulation of CLDN5 gene expression in an endothelial-specific and cell density-dependent manner is established, as well as a crucial, nonredundant role for specifically SOX-18 in the formation of the endothelial barrier.

endothelium; claudin; promoter; sox