TY - JOUR
T1 - SOX-18 controls endothelial-specific claudin-5 gene expression and barrier function
AU - Fontijn, Ruud D.
AU - Volger, Oscar L.
AU - Fledderus, Joost O.
AU - Reijerkerk, Arie
AU - de Vries, Helga E.
AU - Horrevoets, Anton J. G.
PY - 2008
Y1 - 2008
N2 - 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
AB - 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
U2 - https://doi.org/10.1152/ajpheart.01248.2007
DO - https://doi.org/10.1152/ajpheart.01248.2007
M3 - Article
C2 - 18065521
SN - 0363-6135
VL - 294
SP - H891-H900
JO - American journal of physiology. Heart and circulatory physiology
JF - American journal of physiology. Heart and circulatory physiology
IS - 2
ER -