Kermit, frizzled interacting protein, regulates frizzled 3 signaling in neural crest development

Wnts are a family of secreted glycoproteins that are important for multiple steps in early development. Accumulating evidence suggests that frizzled g enes encode receptors for Wnts. However, the mechanism through which frizzl eds transduce a signal and the immediate downstream components that convey that signal are unclear. We have identified a new protein, Kermit, that int eracts specifically with the C-terminus of Xenopus frizzled-3 (Xfz3). Kermi t is a 331 amino acid protein with a central PDZ domain. Kermit mRNA is exp ressed throughout Xenopus development and is localized to neural tissue in a pattern that overlaps Xfz3 expression temporally and spatially. Co-expres sion of Xfz3 and Kermit results in a dramatic translocation of Kermit to th e plasma membrane. Inhibition of Kermit function with morpholino antisense oligonucleotides directed against the 5 ' untranslated region of Kermit mRN A blocks neural crest induction by Xfz3, and this is rescued by co-injectio n of mRNA encoding the Kermit open reading frame. These observations sugges t that Kermit is required for Wnt/frizzled signaling in neural crest develo pment. To the best of our knowledge, Kermit is the first protein identified that interacts directly with the cytoplasmic portion of frizzleds to modul ate their signaling activity.