| Summary: | <p>Abstract</p> <p>Background</p> <p>The Notch signaling pathway is fundamental to the regulation of many cell fate decisions in eumetazoans. Not surprisingly, members of this pathway are highly conserved even between vertebrates and invertebrates. There is one notable exception, Hairless, which acts as a general Notch antagonist in <it>Drosophila</it>. Hairless silences Notch target genes by assembling a repressor complex together with Suppressor of Hairless [Su(H)] and the co-repressors Groucho (Gro) and C-terminal binding protein (CtBP). Now with the availability of genomic databases, presumptive Hairless homologues are predicted, however only in insect species. To further our understanding of Hairless structure and function, we have cloned the <it>Hairless </it>gene from <it>Apis mellifera </it>(<it>A.m.H</it>) and characterized its functional conservation in <it>Drosophila</it>.</p> <p>Results</p> <p>The <it>Apis </it>Hairless protein is only one third of the size of the <it>Drosophila </it>orthologue. Interestingly, the defined Suppressor of Hairless binding domain is interrupted by a nonconserved spacer sequence and the N-terminal motif is sufficient for binding. In contrast to <it>Apis </it>Hairless, the <it>Drosophila </it>orthologue contains a large acidic domain and we provide experimental evidence that this acidic domain is necessary to silence Hairless activity in vivo. Despite the dramatic size differences, <it>Apis </it>Hairless binds to the <it>Drosophila </it>Hairless interactors Su(H), Gro, CtBP and Pros26.4. Hence, <it>Apis </it>Hairless assembles a repressor complex with <it>Drosophila </it>components that may have a different topology. Nevertheless, <it>Apis </it>Hairless is sufficient to repress the Notch target gene <it>vestigial </it>in <it>Drosophila</it>. Moreover, it is able to rescue <it>Hairless </it>mutant phenotypes, providing in vivo evidence for its function as a bona fide Notch antagonist.</p> <p>Conclusion</p> <p>This is the first interspecies-complementation analysis of the Hairless gene. Guided by evolutionary comparisons, we hope to eventually identify all the relevant structural domains and cofactors of Hairless, thereby opening an avenue for further insights into the repressor-complexes that down-regulate Notch signaling also in other, higher eukaryotes.</p>
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