Animal embryogenesis requires input from diverse signaling pathways to coordinate proper placement and organization of body structures, tissues, and organs. Activation and deactivation of signaling pathways at the right time and place is essential for embryogenesis, with defects in signaling often leading to inborn errors of development. A molecular and biochemical understanding of signal transduction pathways is important for proper diagnosis and treatment of congenital developmental abnormalities. Our lab uses the fruit fly, Drosophila melanogaster, to understand developmental defects caused by alterations in Decapentaplegic (Dpp) signaling. Dpp is a homologue of vertebrate BMP2/4 and is a member of the TGF-β family of cytokines. In the fly, both losses and gains of Dpp signaling result in embryonic lethality with associated defects in dorso-ventral patterns and structures.
While we have previously reported that loss of the mummy (mmy)-encoded UDP-N-acetylglucosamine diphosphorylase results in ectopic Dpp signaling and embryonic lethality, here we provide mechanistic insight into the specific role of GlcNAc in Dpp signal antagonism. Our studies have their foundation in our discovery of super sex combs (sxc), the Drosophila O-GlcNAc transferase, in an RNAi screen for glycosyltransferases that share loss-of-function phenotypes with mmy. Here we show that, like Mmy, Sxc is a Dpp signaling antagonist that functions to restrict Dpp signal transduction in the Drosophila embryonic epidermis. Loss of sxc results in ectopic Dpp phenotypes, including an expanded pMad domain and a loss of larval ventral denticle belts. Notably, these markers of ectopic Dpp signaling persist in the absence of the Dpp Type I receptor Thickveins (Tkv), but require Saxophone (Sax). Taken together, our data point to Sax as a potent Dpp signal transducer in the embryonic epidermis, with the capacity to activate Mad well beyond the domain normally specified by Tkv. We speculate that epidermal Tkv and Sax function as short- and long-range signaling receptors, respectively, and that Sxc-mediated inhibition of Sax limits epidermal Dpp signaling to Tkv. Our studies are the first to: 1) demonstrate a role for Sxc in embryogenesis, and 2) provide mechanistic insight into the role of GlcNAc in modulating responses to Dpp.