Abstract
The Sno oncogene (Snoo or dSno in Drosophila) is a highly conserved protein and a well-established antagonist of Transforming Growth Factor-β signaling in overexpression assays. However, analyses of Sno mutants in flies and mice have proven enigmatic in revealing developmental roles for Sno proteins. Thus, to identify developmental roles for dSno we first reconciled conflicting data on the lethality of dSno mutations. Then we conducted analyses of wing development in dSno loss of function genotypes. These studies revealed ectopic margin bristles and ectopic campaniform sensilla in the anterior compartment of the wing blade suggesting that dSno functions to antagonize Wingless (Wg) signaling. A subsequent series of gain of function analyses yielded the opposite phenotype (loss of bristles and sensilla) and further suggested that dSno antagonizes Wg signal transduction in target cells. To date Sno family proteins have not been reported to influence the Wg pathway during development in any species. Overall our data suggest that dSno functions as a tissue-specific component of the Wg signaling pathway with modest antagonistic activity under normal conditions but capable of blocking significant levels of extraneous Wg, a role that may be conserved in vertebrates.
Highlights
Transforming Growth Factor-b (TGF-b) family members perform essential tasks during development in all animals more complex than sponges [1]
We found that overexpression of dSno resulted in small wings with multiple vein truncations suggesting antagonism for TGF-b family members in the Decapentaplegic/Bone Morphogenetic Protein (Dpp/BMP) subfamily
Taken together the dSno174 studies suggest that: 1) all of the reported dSno mutants are likely allelic, 2) the extent of viability for dSno homozygous deletions varies between laboratories due to environmental factors, and 3) a developmental role for dSno is to facilitate Activin signaling during optic lobe development as we reported previously [8]
Summary
Transforming Growth Factor-b (TGF-b) family members perform essential tasks during development in all animals more complex than sponges [1]. TGF-b functions are implemented in target cells by Smad tumor suppressor genes that function as signal transducers and transcription factors [2]. Analyses of Smads have identified many proteins that regulate their activity. Among the Smad regulators are oncogenic Sno family proteins that bind to Smad. High levels of SnoN are correlated with poor outcome in estrogenreceptor positive breast tumors and gene amplification at the Sno locus is associated with squamous cell carcinoma of the esophagus. Mechanistic studies in mammalian cells revealed that SnoN, as part of a histone deacetylase complex, binds to Smad and blocks its ability to transduce TGF-b signals. Sno proteins were initially thought to be obligate antagonists of TGF-b signaling [3]
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