Subsequent work has suggested that Nkd has a nucleo-cytoplasmic role, shuttling either Dvl or other signaling components out of the nucleus. Previous work in Drosophila has established that Nkd acts between Dvl and β-catenin, and its inhibitory activity is dependent on intact and active Wnt signaling. In contrast, Nkd1 does not share these functions with Nkd2 and thus far Nkd1 appears specific for Wnt signaling. But Nkd2 also has a role in escorting TGFa to the basolateral surface of polarized epithelial cells,. Functionally, Nkd2 can regulate Wnt signaling specifically by targeting Dvl1 for degradation. In contrast, nkd2 expression does not appear to be under the control of Wnt signaling. First, nkd1 expression recapitulates many, if not all, of the known Wnt signaling events during development, , and is upregulated in cancers that are known to have activating mutations in the Wnt/β-catenin pathway. But there are significant expression and functional differences between the two homologues to strongly suggest that Nkd1 is the Naked Cuticle orthologue. In vertebrates, there are two Nkd homologues: Nkd1 and Nkd2, which are equally similar to Naked Cuticle sharing approximately 45% amino acid identity and we previously demonstrated that both can inhibit canonical Wnt/β-catenin and non-canonical Wnt/PCP signaling. Whereas it has been demonstrated that Axin2 functions similarly to Axin1, by binding to β-catenin and inducing its degradation, , the mechanism by which Nkds antagonize Wnt signaling is less understood. Two consistent, and perhaps universal targets of Wnt signaling are the negative feedback regulators Naked Cuticle Homolog 1 (Nkd1) and Axin2, ,. Inhibition of this destruction complex results in cytoplasmic accumulation of β-catenin, which then translocates into the nucleus to activate its transcriptional program. This activates Disheveled (Dvl), which then inhibits the constitutively active destruction complex consisting of Axin, GSK3β and APC. Under normal conditions, canonical or Wnt/β-catenin signaling is initiated upon Wnt ligands binding to their transmembrane receptors. Consequently, dysregulation of Wnt signaling during development or in the adult can cause disease. Wnt signaling is involved in many aspects of development and again in the homeostasis of certain stem cells in the adult, such as those found in hematopoietic, hair follicle and intestinal crypt stem cells,. Given the conserved nature of Nkd1, our results shed light on the negative feedback regulation of Wnt signaling through the Nkd1-mediated negative control of nuclear accumulation of β-catenin. Further, we demonstrate that Nkd1 function is dependent on its interaction with the cell membrane. We also show that this interaction is conserved in mammalian cultured cells. We demonstrate that Nkd1 binds to β-catenin and prevents its nuclear accumulation. Here, we employ the zebrafish embryo to characterize the cellular and biochemical role of Nkd1 in vivo. The current model suggests that Nkd1 acts between Disheveled (Dvl) and β-catenin. Recently, Naked Cuticle homolog 1 (Nkd1) has been identified as a Wnt-induced intracellular negative regulator of canonical Wnt signaling.