Defining physiological functions of syndecan-1 in health and disease using the syndecan-1 null mice

Children's Hospital Boston
posted on 03/18/2010

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Cell surface heparan sulfate proteoglycans (HSPG) bind to a wide variety of bioactive molecules and regulate a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation, tumour metastasis, infection, and inflammation. Syndecan-1 is the major epithelial cell membrane HSPG in mammals. Dr. Pyong Park, PhD, from the Department of Respiratory Diseases, has developed a knock-out mouse by homologous recombination (mutation of exon 1 in a c57BL6 background) to study the physiological functions of syndecan-1 in health and in disease. Despite the variety of functional interactions that have been reported for syndecan-1 in cultured cells, Sdc1–/– mice are ostensibly normal and fertile. Dr. Park has shown that newborn mice deficient in syndecan-1 resist P. aeruginosa lung infection but become susceptible when given purified syndecan-1 ectodomains or heparin, but not when given ectodomain core protein, indicating that the ectodomain's heparan sulphate chains are the effectors. In wild-type newborn mice, inhibition of syndecan-1 shedding or inactivation of the shed ectodomain's heparan sulphate chains prevents lung infection. He also found that a pathogenetic mechanism in which a host response to tissue injury, syndecan-1 shedding, is exploited to enhance microbial virulence apparently by modulating host defenses. Additional work with the syndecan-1 knockout mice in tumorigenesis provided both genetic and biochemical evidence that syndecan-1 can modulate Wnt signalling, and is critical for Wnt-1–induced tumorigenesis of the mouse mammary gland. Further, recent studies indicate that syndecan-1 assures the correct functioning of inflammation by attenuating pro-inflammatory factors and facilitating the resolution of inflammation in a heparan sulfate-dependent manner.