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Papers In Press, published online ahead of print September 24, 2004
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wi 53706
Corresponding Author: dsgreens{at}facstaff.wisc.edu
Signaling by bone morphogenetic proteins (BMPs) plays central roles in early embryonic patterning, organogenesis and homeostasis in a broad range of species. Chordin, an extracellular antagonist of BMP signaling, is thought to readily diffuse in tissues, thus forming gradients of BMP inhibition that result in reciprocal gradients of BMP signaling. The latter determine cell fates along the embryonic dorsoventral axis. The secreted protein Twisted Gastrulation is thought to help shape BMP signaling gradients by acting as a cofactor that enhances Chordin’s inhibition of BMP signaling. Here we demonstrate that mammalian Chordin binds heparin with an affinity similar to that of factors known to functionally interact with heparan sulfate proteoglycans (HSPGs) in tissues. We further demonstrate that Chordin binding in mouse embryonic tissues is dependent upon its interaction with cell surface HSPGs and that Chordin binds to cell surface HSPGs (e.g. syndecans), but not to basement membranes containing the HSPG perlecan. Surprisingly, mammalian twisted gastrulation does not bind heparin unless prebound to Chordin and/or BMP-4, although Drosophila Twisted gastrulation has been reported to bind heparin on its own. Importantly, results are also presented which indicate that Chordin-HSPG interactions strongly potentiate the antagonism of BMP signaling by Chordin and are necessary for the retention and uptake of Chordin by cells. These data and others regarding Chordin diffusion have implications for the paradigm of how Chordin is thought to regulate BMP signaling in the extracellular space and how gradients of BMP signaling are formed.
J. Biol. Chem, 10.1074/jbc.M408129200
Submitted on July 19, 2004
Revised on September 13, 2004
Accepted on September 20, 2004
Cell surface heparan sulfate proteoglycans potentiate chordin's antagonism of BMP signaling and are necessary for cellular uptake of chordin
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