Over the last few years the Wingless (Wg)/Wnt patway has been shown to function in cell-fate determination and morphogenesis in both vertebrates and invertebrates. Many members of the signalling cascade downstream of Wg/Wnt have been identified, especially in Drosophila, and include the seven-transmembrane-span receptor Frizzled (Fz). However, the precise mechanism of Wg/Wnt transduction across the membrane of responding cells is still not clearly understood. Three recent papers, by Wherl et al. (Nature 407, 527–520; 2000), Tamai et al. (Nature 407, 530–535; 2000) and Pinson et al. ( Nature 407, 535–538; 2000), identify a new member of the pathway in Drosophila, Xenopus and mouse.

Drosophila embryos homozygous for the null allele of arrow, which encodes a member of the low-density lipoprotein (LDL) receptor-related protein family, have severe embryonic defects that mimic the phenotype of wg-null animals (upper-left picture). Arrow is homologous to Xenopus/murine/human LRP6, and mice homozygous for LRP6 exhibit developmental defects, including neural-tube closure, that are very similar to those of homozygous Wnt embryos (upper-right picture). In Xenopus, overexpression of LRP6 leads to duplication of the embryonic dorsal axis, induction of Wnt-responsive genes, and enhanced development of neural-crest cells (lower picture). These phenotypes mimic those of Wnt overexpression. From these phenotypic studies it seems that Arrow/LRP6 acts within the Wg pathway, but where?

Experiments conducted using both Drosophila and Xenopus indicate that Arrow/LRP6 acts in the cells that receive and respond to the Wg/Wnt signal, rather than in those that produce it. Further epistatic experiments in Drosophila indicate that arrow acts downstream of wg, but upstream of dishevelled (dsh, an intracellular downstream component of the Wg pathway). It was then demonstrated, using Xenopus, that the extracellular domain of LRP6 binds to Wnt-1 and forms a complex with the Fz receptor, but only in a Wnt-1-dependent manner. From this it seems that when Arrow/LRP6 is bound to Wg/Wnt it acts in a complex with Fz to regulate the incoming signal. How Arrow/LRP6 interacts with the proteoglycan molecules that are known to mediate Wg signalling remains to be identified, but yet again the world of Wg/Wnt signalling has become more complicated.