Vertebrate proteins related to Drosophila naked cuticle bind dishevelled and antagonize Wnt signaling

Wnt signals control cell fate decisions and orchestrate cell behavior in me tazoan animals. In the fruit fly Drosophila, embryos defective in signaling mediated by the Wnt protein Wingless (Wg) exhibit severe segmentation defe cts. The Drosophila segment polarity gene naked cuticle (nkd) encodes an EF hand protein that regulates early Wg activity by acting as an inducible an tagonist. Nkd antagonizes Wg via a direct interaction with the Wnt signalin g component Dishevelled (Dsh). Here we describe two mouse and human protein s, Nkd1 and Nkd2, related to fly Nkd. The most conserved region among the f ly and vertebrate proteins, the EFX domain, includes the putative EE hand a nd flanking sequences. EFX corresponds to a minimal domain required for fly or vertebrate Nkd to interact with the basic/PDZ domains of fly Dsh or ver tebrate Dvl proteins in the yeast two-hybrid assay. During mouse developmen t, nkd1 and nkd2 are expressed in multiple tissues in partially overlapping , gradient-like patterns, some of which correlate with known patterns of Wn t activity. Mouse Nkd1 can block Wnt1-mediated, but not beta -catenin-media ted, activation of a Wnt-dependent reporter construct in mammalian cell cul ture. Misexpression of mouse nkd1 in Drosophila antagonizes Wg function. Th e data suggest that the vertebrate Nkd-related proteins, similar to their f ly counterpart, may act as inducible antagonists of Wnt signals. (C) 2001 A cademic Press.