Decapentaplegic

Decapentaplegic (Dpp) is a key morphogen involved in the development of the fruit fly Drosophila melanogaster and is the first validated secreted morphogen. It is known to be necessary for the correct patterning and development of the early Drosophila embryo and the fifteen imaginal discs, which are tissues that will become limbs and other organs and structures in the adult fly. It has also been suggested that Dpp plays a role in regulating the growth and size of tissues. Flies with mutations in decapentaplegic fail to form these structures correctly, hence the name (decapenta-, fifteen, -plegic, paralysis). Dpp is the Drosophila homolog of the vertebrate bone morphogenetic proteins (BMPs), which are members of the TGF-β superfamily, a class of proteins that are often associated with their own specific signaling pathway. Studies of Dpp in Drosophila have led to greater understanding of the function and importance of their homologs in vertebrates like humans. Decapentaplegic (Dpp) is a key morphogen involved in the development of the fruit fly Drosophila melanogaster and is the first validated secreted morphogen. It is known to be necessary for the correct patterning and development of the early Drosophila embryo and the fifteen imaginal discs, which are tissues that will become limbs and other organs and structures in the adult fly. It has also been suggested that Dpp plays a role in regulating the growth and size of tissues. Flies with mutations in decapentaplegic fail to form these structures correctly, hence the name (decapenta-, fifteen, -plegic, paralysis). Dpp is the Drosophila homolog of the vertebrate bone morphogenetic proteins (BMPs), which are members of the TGF-β superfamily, a class of proteins that are often associated with their own specific signaling pathway. Studies of Dpp in Drosophila have led to greater understanding of the function and importance of their homologs in vertebrates like humans. Dpp is a classic morphogen, which means that it is present in a spatial concentration gradient in the tissues where it is found, and its presence as a gradient gives it functional meaning in how it affects development. The most studied tissues in which Dpp is found are the early embryo and the imaginal wing discs, which later form the wings of the fly. During embryonic development, Dpp is uniformly expressed at the dorsal side of the embryo, establishing a sharp concentration gradient. In the imaginal discs, Dpp is strongly expressed in a narrow stripe of cells down the middle of the disc where the tissue marks the border between the anterior and posterior sides. Dpp diffuses from this stripe towards the edges of the tissue, forming a gradient as expected of a morphogen. However, although cells in the Dpp domain in the embryo do not proliferate, cells in the imaginal wing disc proliferate heavily, causing tissue growth. Although gradient formation in the early embryo is well understood, how the Dpp morphogen gradient forms in the wing imaginal disc remains controversial. At the early blastoderm stage, Dpp signaling is uniform and low along the dorsal side. A sharp signaling profile emerges at the dorsal midline of the embryo during cellularization, with high levels of Dpp specifying the extraembryonic amnioserosa and low levels specifying the dorsal ectoderm. Dpp signaling also incorporates a positive feedback mechanism that promotes future Dpp binding. The morphogen gradient in embryos is established via a known active transport mechanism. Gradient formation depends on the BMP inhibitors Short gastrulation (Sog) and Twisted gastrulation (Tsg), and other extracellular proteins such as Tolloid (Tld), and Screw (Scw). Sog is produced in the ventral-lateral region of the embryo (perpendicular to the Dpp gradient) and forms a BMP-inhibiting gradient that prevents Dpp from binding to its receptor. Sog and Tsg form a complex with Dpp and are actively transported toward the dorsal midline (middle of the embryo), following the Sog concentration gradient. Tld, a metalloprotease, releases Dpp from the complex by mediating Sog processing, activating Dpp signaling at the midline. After gastrulation of the embryo, the Dpp gradient induces cardiac and visceral mesoderm formation. Dpp, like its vertebrate homologs, is a signaling molecule. In Drosophila, the receptor for Dpp is formed by two proteins, Thickveins (Tkv) and Punt. Like Dpp itself, Tkv and Punt are highly similar to homologs in other species. When a cell receives a Dpp signal, the receptors are able to activate an intracellular protein called mothers against Dpp (mad) by phosphorylation. The initial discovery of mad in Drosophila paved the way for later experiments that identified the responder to TGF-β signaling in vertebrates, called SMADs. Activated Mad is able to bind to DNA and act as a transcription factor to affect the expression of different genes in response to Dpp signaling. Genes activated by Dpp signaling include optomotor blind (omb) and spalt, and activity of these genes are often used as indicators of Dpp signaling in experiments. Another gene with a more complicated regulatory interaction with Dpp is brinker. Brinker is a transcription factor that represses the activation targets of Dpp, so in order to turn on these genes Dpp must repress brinker as well as activate the other targets. In the fly wing, the posterior and anterior halves of the tissue are populated by different kinds of cells that express different genes. Cells in the posterior but not the anterior express the transcription factor Engrailed (En). One of the genes activated by En is hedgehog (hh), a signaling factor. Hedgehog signaling instructs neighboring cells to express Dpp, but Dpp expression is also repressed by En. The result is that Dpp is only produced in a narrow stripe of cells immediately adjacent to but not within the posterior half of the tissue. Dpp produced at this anterior/posterior border then diffuses out to the edges of the tissue, forming a spatial concentration gradient.