Replacing the promoter of the murine gene encoding P-selectin with the human promoter confers human-like basal and inducible expression in mice [Gene Regulation]

December 2nd, 2015 by Liu, Z., Zhang, N., Shao, B., Panicker, S. R., Fu, J., McEver, R. P.

In humans and mice, megakaryocytes/platelets and endothelial cells constitutively synthesize P-selectin and mobilize it to the plasma membrane to mediate leukocyte rolling during inflammation. Tumor necrosis factor (TNF)-α, interleukin-1β, and lipopolysaccharide (LPS) markedly increase P-selectin mRNA in mice but decrease P-selectin mRNA in humans. Transgenic mice bearing the entire human SELP gene recapitulate basal and inducible expression of human P-selectin, and reveal human-specific differences in P-selectin function. Differences in the human SELP and murine Selp promoters account for divergent expression in vitro, but their significance in vivo is not known. Here, we generated knock-in mice that replace the 1.4-kb proximal Selp promoter with the corresponding SELP sequence (SelpKI). SelpKI/KI mice constitutively expressed more P-selectin on platelets and more P-selectin mRNA in tissues, but only slightly increased P-selectin mRNA after injection of TNF-α or LPS. Consistent with higher basal expression, leukocytes rolled slower on P-selectin in trauma-stimulated venules of SelpKI/KI mice. However, TNF-α did not further reduce P-selectin-dependent rolling velocities. Blunted up-regulation of P-selectin mRNA during contact hypersensitivity reduced P-selectin-dependent inflammation in SelpKI/- mice. Higher basal P-selectin in SelpKI/KI mice compensated for this defect. Thus, divergent sequences in a short promoter mediate most of the functionally significant differences in expression of human and murine P-selectin in vivo.
  • Posted in Journal of Biological Chemistry, Publications
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