HEPARAN SULFATE BIOSYNTHETIC FEEDBACKS AND EXTRACELLULAR SULFATASE EXPRESSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Sulfs are a family of extracellular endosulfatases that modify heparan sulfate (HS) chains at cell surfaces and in extracellular matrices. They release sulfate groups at the 6-O-position of a subset of glucosamine residues in HS chains. The activity of Sulf enzymes serves to potentiate activities of growth factors including GDNF, BMP, Shh, and Wnt and to reduce activities of FGF2, HP-EGF, HGF, and TGF-¿. As a result of these activities and depending on the context, Sulfs have been observed to serve as oncogenic effectors and as tumor suppressors. Sulf activities appear to induce changes in expression of biosynthetic enzymes, resulting in changes in expressed HS structure that do not necessary reflect the direct Sulf enzymatic activity. As a result, the influences of Sulf activity on cellular phenotype are complex. The goals of this work are to (1) define the HS structural phenotype in mouse embryonic fibroblast cells as a function of Sulf enzyme knockout at both the HS disaccharide and oligosaccharide levels. These results will be compared against those obtained using recombinant Sulf enzymes on purified HS. Progress update: We have published two collaborative papers on the structural phenotypes of HS related to the spermatogonal stem cell niche (1) and the glomerular filtration barrier (2) in Sulf knockout mice. 1. Langsdorf, A., Schumacher, V., Shi, X., Tran, T., Zaia, J., Jain, S., Taglienti, M., Kreidberg, J. A., Fine, A., and Ai, X. (2010) Expression regulation and function of Sulfs in the spermatogonial stem cell niche, Glycobiology 21, 152-161. 2. Schumacher, V., Schlotzer-Schrehardt, U., Karumanchi, S. A., Shi, X., Zaia, J., Jeruschke, S., Zhang, D., Pavenstaedt, H., Drenckhan, A., Amann, K., Ng, C., Hartwig, S., Ng, K.-H., Ho, J., Kreidberg, J. A., Taglienti, M., Royer-Pokora, B., and Ai, X. (2011) WT1 regulation of Sulf expression is crucial to maintaining the glomerular filtration barrier, Journal of the American Society for Nephrology Accepted 2/22/11.