LRP6 and Arrow Function in Wnt Signaling

Abstract

Three papers shed new light on Wnt signaling by characterizing the function of a low density lipoprotein (LDL) receptor-like protein (LRP). Tamai et al. showed in Xenopus that LRP6 acts as a Wnt coreceptor. Injection of LRP6 mRNA into early embryos resulted in the formation of a new dorsal axis and increased expression of Xnr3, a gene transcriptionally activated by Wnt signaling. Injection of Wnt-5a and LRP6 into adjacent cells in a four-cell-stage embryo also yielded axis duplication, indicating that LRP6 probably acts in Wnt-responding cells. Experiments with LRP6 truncation mutants demonstrated that the cytoplasmic tail is important for downstream Wnt signal transduction, whereas the LRP6 NH2-terminal binds Wnt and then binds Frizzled (Fz) in a Wnt-dependent manner. Pinson et al. screened for lethal recessive mutants in mice and identified LRP6 using a gene trapping method. LRP6-/- mice had severe developmental abnormalities similar to those in mice with Wnt signaling defects. By crossing mice harboring Wnt3a mutants [vestigial tail (vt)] with LPR6-deficient mice, the authors demonstrated that tail abnormalities were more severe in mice carrying both mutations, thus indicating that LRP6 and Wnt3a lie in the same signaling path. Wehrli et al. identified arrow in Drosophila as the gene most similar to LRP5 and LRP6 of humans. They demonstrate that overexpression of Wingless (the Wnt counterpart in flies) cannot compensate for the arrow phenotype. Similar to the observations in Xenopus, Arrow is important for cells that respond to Wingless (the Wnt counterpart in flies). Additional overexpression and loss of function experiments strongly suggest that Arrow and DFz2, a Drosophila Frizzled protein, act as coreceptors for Wg.Kamai, T., Semenov, M., Kato, Y., Spokony, R., Liu, C., Katsuyama, Y., Hess, F., Saint-Jeannet, J.-P., and He, X. (2000) LDL-receptor-related proteins in Wnt signal transduction. Nature 407: 530-535.[Online Journal]Pinson, K.I., Brennan, J., Monkley, S., Avery, B.J., Skarnes, W.C. (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407: 535-538.[Online Journal]Wehrli, M., Dougan, S.T., Caldwell, K., O'Keefe, L., Schwartz, S., Vaizel-Ohayon, D., Schejter, E., Tomlinso, A., and Dinardo, S. (2000) arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407: 527-530.[Online Journal]