Institute of Zoology, University of Regensburg, Regensburg, Germany.
PLoS One. 2012;7(8):e42349. doi: 10.1371/journal.pone.0042349. Epub 2012 Aug 7.
The TGF-β/BMP signaling cascades control a wide range of developmental and physiological functions in vertebrates and invertebrates. In Drosophila melanogaster, members of this pathway can be divided into a Bone Morphogenic Protein (BMP) and an Activin-ß (Act-ß) branch, where Decapentaplegic (Dpp), a member of the BMP family has been most intensively studied. They differ in ligands, receptors and transmitting proteins, but also share some components, such as the Co-Smad Medea (Med). The essential role of Med is to form a complex with one of the two activating Smads, mothers against decapentaplegic (Mad) or dSmad, and to translocate together to the nucleus where they can function as transcriptional regulators of downstream target genes. This signaling cascade underlies different mechanisms of negative regulation, which can be exerted by inhibitory Smads, such as daughters against decapentaplegic (dad), but also by the Ski-Sno family. In this work we identified and functionally analyzed a new member of the Ski/Sno-family, fussel (fuss), the Drosophila homolog of the human functional suppressing element 15 (fussel-15). fuss codes for two differentially spliced transcripts with a neuronal expression pattern. The proteins are characterized by a Ski-Sno and a SAND homology domain. Overexpression studies and genetic interaction experiments clearly reveal an interaction of fuss with members of the BMP pathway, leading to a strong repression of BMP-signaling. The protein interacts directly with Medea and seems to reprogram the Smad pathway through its influence upon the formation of functional Mad/Medea complexes. This leads amongst others to a repression of downstream target genes of the Dpp pathway, such as optomotor blind (omb). Taken together we could show that fuss exerts a pivotal role as an antagonist of BMP signaling in Drosophila melanogaster.
TGF-β/BMP 信号级联控制脊椎动物和无脊椎动物的广泛发育和生理功能。在黑腹果蝇中，该途径的成员可分为骨形态发生蛋白 (BMP) 和激活素-β (Act-ß) 分支，其中骨形态发生蛋白家族的成员 Decapentaplegic (Dpp) 被研究得最为深入。它们在配体、受体和转导蛋白上有所不同，但也有一些共同的成分，如 Co-Smad Medea (Med)。Med 的重要作用是与两个激活 Smads 之一形成复合物，即 Mothers against decapentaplegic (Mad) 或 dSmad，并一起转位到细胞核，在那里它们可以作为下游靶基因的转录调节剂发挥作用。这个信号级联包含不同的负调控机制，可以通过抑制性 Smads 发挥作用，如 daughters against decapentaplegic (dad)，也可以通过 Ski-Sno 家族发挥作用。在这项工作中，我们鉴定并分析了 Ski/Sno 家族的一个新成员 fussel (fuss)，即人类功能抑制元件 15 (fussel-15) 的果蝇同源物。fuss 编码两个具有神经元表达模式的差异剪接转录本。这些蛋白质的特征是具有 Ski-Sno 和 SAND 同源结构域。过表达研究和遗传相互作用实验清楚地表明，fuss 与 BMP 途径的成员相互作用，导致 BMP 信号的强烈抑制。该蛋白与 Medea 直接相互作用，并通过其对功能性 Mad/Medea 复合物形成的影响，似乎重新编程了 Smad 途径。这导致 Dpp 途径的下游靶基因，如 optomotor blind (omb) 等基因的表达受到抑制。总的来说，我们证明了 fuss 在黑腹果蝇中作为 BMP 信号的拮抗剂发挥着关键作用。
