naked cuticle encodes an inducible antagonist of Wnt signalling

Abstract

During animal development, cells have to respond appropriately to localized secreted signals. Proper responses to Hedgehog, transforming growth factor-beta, epidermal growth factor and fibroblast growth factor/Ras signals require cognate inducible antagonists such as Patched, Dad, Argos and Sprouty. Wnt signals are crucial in development and neoplasia. Here we show that naked cuticle (nkd), a Drosophila segment-polarity gene, encodes an inducible antagonist for the Wnt signal Wingless (Wg). In fly embryos and imaginal discs nkd transcription is induced by Wg. In embryos, decreased nkd function has an effect similar to excess Wg; at later stages such a decrease appears to have no effect. Conversely, overproduction of Nkd in Drosophila and misexpression of Nkd in the vertebrate Xenopus laevis result in phenotypes resembling those of loss of Wg/Wnt function. nkd encodes a protein with a single EF hand (a calcium-binding motif) that is most similar to the recoverin family of myristoyl switch proteins. Nkd may therefore link ion fluxes to the regulation of the potency, duration or distribution of Wnt signals. Signal-inducible feedback antagonists such as nkd may limit the effects of Wnt proteins in development and disease.

A Targeted Mutation of Nkd1 Impairs Mouse Spermatogenesis

“…Development-An important role of Drosophila nkd in early embryogenesis has been demonstrated (32). Given the high similarity of the EF-hand between Drosophila nkd and mouse Nkd1 proteins, our finding that Nkd1 Ϫ/Ϫ mice can develop normally is somewhat unexpected.…”

Wnt Signaling from Development to Disease: Insights from Model Systems

“…Both bind Dvl (e.g., Rousset et al 2001;Wharton et al 2001), but their function is unknown. Fly Nkd is a key negative regulator (Zeng et al 2000), although signaling is not activated to quite the same degree as is seen on complete destruction complex inactivation. Overexpressing zebrafish Nkd homologs suppresses both canonical and noncanonical Wnt signaling (Van Raay et al 2007).…”

Wnt/β-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency

“…PP2A regulates the Wnt signaling cascade at multiple levels (23,24). Recently, PR72/130 has been shown to interact with the protein Naked cuticle (Nkd), a negative regulatory component of the Wnt signaling pathway (25), thereby modulating Wnt signaling (26). We hypothesized that the interaction of IQ-1 with PR72/130 results in the disruption of the PP2A/PR72/130/Nkd complex, and inhibits ''negative'' regulation of canonical Wnt/␤-catenin signaling.…”