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Functions of heparan sulfate proteoglycans in cell signaling during development. Development. 2004; 131:6009-6021.","DOI":"10.1242\/dev.01522"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6. Bernfield M, G\u00f6tte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem. 1999; 68:729-777.","DOI":"10.1146\/annurev.biochem.68.1.729"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7. Koziel L, Kunath M, Kelly OG, Vortkamp A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell. 2004; 6:801-813.","DOI":"10.1016\/j.devcel.2004.05.009"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8. Clement A, Wiweger M, von der Hardt S, Ruber MA, Crome A, Schulte-Merker S, Knust E. Regulation of zebrafish skeletogenesis by ext2\/dackel and papst1\/pinscher. 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