Neither the roles of Asp-His-His-Cys (DHHC)-containing proteins in embryonic cell fate specification are well defined, nor the underlying mechanisms of their activity are well understood. Here, we compared the embryonic function of zinc finger DHHC-type containing (Zdhhc13) in zebrafish embryos and in an in vitro cell model. Zdhhc13, a critical regulator of bone morphogenetic protein (BMP) signaling, specifically bound to Smad6 to induce its perinuclear accumulation and degradation through a mechanism independent of its palmitoyltransferase activity. We showed that Zdhhc13 played a crucial role during zebrafish embryogenesis in the control of germ layer specification, particularly in ectoderm and mesoderm differentiation homeostasis. Depletion of Zdhhc13 led to the neuralization of ectoderm and dorsalization of mesoderm in zebrafish embryos. Moreover, Zdhhc13 antagonized Smad6 during BMP-dependent signaling and early lineage decisions in our in vitro cell model. Our results extended the cellular role of Zdhhc13, suggesting that it acts as a regulator in BMP signaling, and established that the embryonic function of Zdhhc13 is in lineage specification.
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