Naked cuticle (nkd) encodes an inducible antagonist of Wingless/Wnt signal transduction.    . K.A. Wharton, Jr. ¹, R. Rousset ¹, J. Mack ¹, W. Zeng ¹, P.S. Klein ², J.D. Axelrod ¹, K. Suyama ¹, M.P. Scott ¹. 1) Howard Hughes Medical Institute; Departments of Developmental Biology, Genetics, and Pathology, Stanford University School of Medicine, Stanford, CA 94305; 2) Department of Internal Medicine, University of Pennsylvania, Philadelphia, PN 19104.

   
   Excess Wnt or Hedgehog (Hh) signaling causes many forms of human cancer. Consequently, antagonists of these signal transduction pathways such as APC and Patched (Ptc) are tumor suppressor genes. Components of both of these signal transduction pathways were initially discovered by their essential genetic role in fruit fly segmentation. Saturating genetic screens by Wieschaus and Nusslein-Volhard over 20 years ago revealed only one zygotically acting antagonist each for the Wnt and Hh pathways: naked cuticle (nkd) and ptc. All other signaling components are maternally provided to the egg during oogenesis. Ptc is a transmembrane receptor for Hh and also acts as inducible antagonist for Hh signaling. A vertebrate homolog, ptc1, is the causative gene for basal cell nevus (Gorlins) syndrome and is frequently mutated in basal cell carcinoma and medulloblastoma. Here we describe nkd, a novel EF hand protein which acts as an inducible antagonist of the Wnt pathway in flies and in the vertebrate Xenopus laevis. nkd mutants resemble embryos exposed to excess Wingless, as well as embryos which lack maternal and zygotic contributions of genes that normally antagonize Wg, including zeste-white3, D-axin, or D-APC2. Genetic, biochemical, and cell biological experiments suggest Nkd antagonizes the Wnt pathway via a direct interaction with the Wnt signaling component Dishevelled (Dsh). An in vivo structure-function study of fly Nkd suggests that distinct domains of Nkd mediate Wnt antagonism.