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Published October 11, 2005 | Supplemental Material
Journal Article Open

The Heparan Sulfate Proteoglycan Syndecan Is an In Vivo Ligand for the Drosophila LAR Receptor Tyrosine Phosphatase


Background: Receptor tyrosine phosphatases (RPTPs) are essential for axon guidance and synaptogenesis in Drosophila. Each guidance decision made by embryonic motor axons during outgrowth to their muscle targets requires a specific subset of the five neural RPTPs. The logic underlying these requirements, however, is still unclear, partially because the ligands recognized by RPTPs at growth cone choice points have not been identified. RPTPs in general are still "orphan receptors" because, while they have been found to interact in vitro with many different proteins, their in vivo ligands are unknown. Results: Here we use a new type of deficiency screen to identify the transmembrane heparan sulfate proteoglycan Syndecan (Sdc) as a ligand for the neuronal RPTP LAR. LAR interacts with the glycosaminoglycan chains of Syndecan in vitro with nanomolar affinity. Genetic interaction studies using Sdc and Lar LOF mutations demonstrate that Sdc contributes to LAR's function in motor axon guidance. We also show that overexpression of Sdc on muscles generates the same phenotype as overexpression of LAR in neurons and that genetic removal of LAR suppresses the phenotype produced by ectopic muscle Sdc. Finally, we show that there is at least one additional, nonproteoglycan, ligand for LAR encoded in the genome. Conclusions: Taken together, our results demonstrate that Sdc on muscles can interact with neuronal LAR in vivo and that binding to Sdc increases LAR's signaling efficacy. Thus, Sdc is a ligand that can act in trans to positively regulate signal transduction through LAR within neuronal growth cones.

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© 2005 Elsevier Ltd. Received: August 3, 2005; Accepted: August 4, 2005; Published: October 11, 2005. We thank Aloisia Schmid for many contributions to the ligand project; Anya Vlasak and Violana Nesterova for technical assistance; Peter Snow and Inderjit Nangiana of the Caltech Protein Expression Facility for fusion proteins; John Thomas for discussions on fusion protein staining of embryos; David Chang for assistance with mammalian transfection; Devin Tesar, Andrew Tapper, and Pamela Bjorkman for discussions on in vitro binding experiments; members of the Zinn group for other helpful discussions; Tim Heslip and Michael O'Connor for communication of unpublished results on Sdc; David Van Vactor, John Flanagan, Karl Johnson, and Alan Tenney for communicating their results prior to publication; and Karl Johnson for unpublished Drosophila lines. We thank Tim Heslip, Michael O'Connor, David Van Vactor, John Flanagan, Xinhua Lin, Scott Selleck, Norbert Perrimon, Hiroshi Nakato, John Lincecum, Gerd Vorbruggen, and Daniela Dieterich for essential fly stocks, antibody reagents, and AP fusion proteins. We thank the Developmental Studies Hybridoma Bank (DSHB) for its repository of available antibodies. K.Z. thanks Brad Olwin, Tin Tin Su, and Leslie Leinwand for hospitality and lab space during a sabbatical at the University of Colorado, where some of this work was performed. This work was supported by an RO1 grant to K.Z., NS28182. A.N.F. was supported by an NIH postdoctoral fellowship. We dedicate this paper to the memory of Peter M. Snow.

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