Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium

glycosaminoglycan hyaluronan is a key substrate for cell migration in tissu es during inflammation, wound healing, and neoplasia. Unlike other matrix c omponents, hyaluronan (HA) is turned over rapidly, yet most degradation occ urs not locally but within distant lymph nodes, through mechanisms that are not yet understood. While it is not clear which receptors are involved in binding and uptake of hyaluronan within the lymphatics, one likely candidat e is the lymphatic endothelial hyaluronan receptor LYVE-1 recently describe d in our laboratory (Banerji, S., Ni, J., Wang, S., Clasper, S., Su, J., Ta mmi, R., Jones, M., and Jackson, D.G. (1999) J. Cell Biol. 144, 789-891.). Here we present evidence that LYVE-1 is involved in the uptake of hyalurona n by lymphatic endothelial cells using a new murine LYVE-1 orthologue ident ified from the EST data base. We show that mouse LYVE-1 both binds and inte rnalizes hyaluronan in transfected 293T fibroblasts in vitro and demonstrat e using immunoelectron microscopy that it is distributed equally among the luminal and abluminal surfaces of lymphatic vessels in vivo. In addition, w e show by means of specific antisera that expression of mouse LYVE-1 remain s restricted to the lymphatics in homozygous knockout mice lacking a functi onal gene for CD44, the closest homologue of LYVE-1 and the only other Link superfamily HA receptor known to date. Together these results suggest a ro le for LYVE-1 in the transport of HA from tissue to lymph and imply that fu rther novel hyaluronan receptors must exist that can compensate for the los s of CD44 function.