Editors' ChoiceDevelopment

Are Two Wnt Pathways Better Than One?

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Science's STKE  28 Sep 2004:
Vol. 2004, Issue 252, pp. tw342
DOI: 10.1126/stke.2522004tw342

Frizzled proteins act as receptors for Wnts, secreted proteins that play a critical role in animal development. In the Caenorhabditis elegans vulval model of development, the anterior-posterior orientation of cells of the P7.p lineage is disrupted by mutation of lin-17 (which encodes a Frizzled protein), leading to a defect in morphology, the bivulva phenotype (see He). Interested in investigating the signaling pathway involved, Inoue et al. cloned lin-18, mutations of which produce a similar bivulva phenotype, and discovered that it encoded the C. elegans member of the Ryk (related to tyrosine kinase)-Derailed protein family. Ryk-Derailed proteins, which are unrelated to the Frizzled family, are members of the receptor tyrosine kinase superfamily. They contain a Wnt binding domain (WIF), and Drosophila Derailed is a Wnt receptor. The authors tested protein constructs containing portions of LIN-18 and found that, whereas the extracellular WIF domain was required for rescue of the lin-18 mutant phenotype, the intracellular kinase domain was not. Mutational analysis and RNAi disruption indicated that the products of three wnt genes, LIN-44, MOM-2, and CWN-2, acted redundantly in this process. Simultaneous disruption of lin-44 and mom-2, or of lin-44 and cwn-2, produced a bivulva phenotype, whereas disruption of all three genes produced a higher penetrance bivulva phenotype. Genetic analysis of receptor-ligand and receptor-receptor double mutants led the authors to propose a model in which the two receptors mediated parallel signaling pathways, with LIN-44 preferentially acting through LIN-17 and MOM-2 preferentially acting through LIN-18 to determine cell fate.

T. Inoue, H. S. Oz, D. Wiland, S. Gharib, R. Deshpande, R. J. Hill, W. S. Katz, P. W. Sternberg, C. elegans LIN-18 is a Ryk ortholog and functions in parallel to LIN-17/Frizzled in Wnt signaling. Cell 118, 795-806 (2004). [Online Journal]

X. He, Wnt signaling went derailed again: A new track via the LIN-18 receptor? Cell 118, 668-670 (2004). [Online Journal]

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