Head formation requires Dishevelled degradation that is mediated by March2 in concert with Dapper1

Dishevelled (Dvl/Dsh) is a key scaffold protein that propagates Wnt signaling essential for embryogenesis and homeostasis. However, whether antagonism of Wnt signaling necessary for vertebrate head formation can be achieved through regulation of Dsh protein stability is unclear. Here we show that membrane-associated RING-CH2 (March2), a RING-type E3 ubiquitin ligase, antagonizes Wnt signaling by regulating the turnover of Dsh protein via ubiquitin-mediated lysosomal degradation in prospective head region of Xenopus. We further found that March2 acquires regional and functional specificities for head formation from the Dsh-interacting protein Dapper1 (Dpr1). Dpr1 stabilizes interaction between March2 and Dsh for mediating ubiquitination and subsequent degradation of Dsh protein only in the dorso-animal region of Xenopus embryo. These results suggest that March2 restricts cytosolic pools of Dsh protein and leads to subsequent limitation of Wnt signaling for the precise vertebrate head development.