The Wnt family of secreted signalling molecules are essential in embryo dev
elopment and tumour formation(1). The Frizzled (Fz) family of serpentine re
ceptors function as Wnt receptors(2-10), but how Fz proteins transduce sign
alling is not understood. In Drosophila, arrow phenocopies the wingless (DW
nt-1) phenotype(11), and encodes a transmembrane protein(11) that is homolo
gous to two members of the mammalian low-density lipoprotein receptor (LDLR
)-related protein (LRP) family, LRP5 and LRP6 (refs 12-15). Here we report
that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopu
s embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive gen
es, dorsal axis duplication and neural crest formation. An LRP6 mutant lack
ing the carboxyl intracellular domain blocked signalling by Wnt or Wnt-Fz,
but not by Dishevelled or beta-catenin, and inhibited neural crest developm
ent. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in
a Wnt-dependent manner. Our results indicate that LRP6 may be a component
of the Wnt receptor complex.