Disease relevance of dpp

• A screen for modifiers of decapentaplegic mutant phenotypes identifies lilliputian, the only member of the Fragile-X/Burkitt's Lymphoma family of transcription factors in Drosophila melanogaster [1].
• The vertebrate orthologs of dpp, BMP-2 and -4, are crucial for gastrulation and neural induction, and aberrant signaling by BMPs and other TGF-beta family members results in developmental defects including holoprosencephaly (HPE) [2].
• Melanoma cells escape transforming growth factor-beta (TGFbeta)-mediated growth inhibition by expressing the Smad (mothers against decapentaplegic homolog, Drosophila) inhibitors Ski and Sno [3].
• These data identify a novel mechanism placing PTEN as a key regulator of diabetic mesangial hypertrophy involving TGF-beta signaling [4].
• In diabetic nephropathy, the hypertrophic effect of hyperglycemia is thought to be mediated by transforming growth factor-beta (TGF-beta) [4].

Psychiatry related information on dpp

• We find that this competitive behavior correlates with, and can be corrected by, the activation of the BMP/Dpp survival signaling pathway [5].

High impact information on dpp

• We propose that the use of broadly distributed Dpp homodimers and spatially restricted Dpp/Scw heterodimers produces the biphasic signal that is responsible for specifying the two dorsal tissue types [6].
• Signaling by these ligands is regulated at the extracellular level by the BMP binding proteins Sog and Tsg [6].
• By employing a method for spatial, temporal, and quantitative control over gene expression, we show that the juxtaposition of cells perceiving different levels of DPP signaling is essential for medial-wing-cell proliferation and can be sufficient to promote the proliferation of cells throughout the wing [7].
• Conversely, uniform activation of the DPP pathway inhibits cell proliferation in medial wing cells [7].
• Furthermore, we show that Dpp fails to move across cells mutant for dally and dally-like (dly), two Drosophila glypican members of heparin sulfate proteoglycan (HSPG) [8].

Biological context of dpp

• Defects in Brk25D receptor function combined with reduced expression of dpp ligand produce mutant phenotypes in the embryo and adult [9].
• Here we show that the misexpression of sog using the even-skipped stripe-2 enhancer redistributes Dpp signalling in a mutant background in which dpp is expressed throughout the embryo [10].
• A gene complex acting downstream of dpp in Drosophila wing morphogenesis [11].
• These findings suggest that cyclic AMP-dependent protein kinase A is a component of the signal transduction pathway through which Hh and Ptc direct localized expression of dpp (or wg) and establish the compartment boundary organizer [12].
• The divergence in dpp expression is surprising given that all other comparative data on gene expression during insect leg development indicate that the molecular pathways regulating this process are conserved [13].

Anatomical context of dpp

• These data strongly support the view that the primary phylogenetically conserved function of the Drosophila sog and dpp genes and the homologous Xenopus chordin and BMP-4 genes is to subdivide the primitive embryonic ectoderm into neural versus non-neural domains [14].
• In addition, abd-A function is required for the expression of wg in the visceral mesoderm posterior to the dpp-expressing cells [15].
• One consequence of dpp expression is the induction of labial (lab) in the underlying endoderm cells [15].
• In this report we provide the first direct evidence that sog plays a local role in the lateral region of the blastoderm embryo to oppose Dpp activity in the neuroectoderm [14].
• Regulatory genes that are required for eye/optic lobe fate, including sine oculis (so) and eyes absent (eya), are turned on in their respective domains by Dpp [16].

Associations of dpp with chemical compounds

• Drosophila Dpp morphogen movement is independent of dynamin-mediated endocytosis but regulated by the glypican members of heparan sulfate proteoglycans [8].
• The Transforming Growth Factor-beta superfamily member decapentaplegic (dpp) acts as an extracellular morphogen to pattern the embryonic ectoderm of the Drosophila embryo [17].
• Receptor serine/threonine kinases implicated in the control of Drosophila body pattern by decapentaplegic [18].
• Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic [19].
• Fmrf expression is controlled by a combinatorial code of intrinsic factors and an extrinsic BMP signal [20].

Physical interactions of dpp

• Repression of dpp targets by binding of brinker to mad sites [21].
• Cell binding and co-immunoprecipitation studies suggest that non-HS-modified Dally retains some ability to bind Dpp or BMP4 [22].
• Brk25D binds dpp protein and bone morphogenetic protein 2 with high affinity [9].
• Interestingly, we found that the activity of the enhancer is only stimulated by DPP signaling significantly upon binding of LAB and EXD [23].
• We have identified a single essential Labial (LAB)/EXD-binding site in a Decapentaplegic (DPP)-responsive enhancer of the homeotic gene lab which drives expression in the developing midgut [23].
• We show that the transcriptional co-regulator dNAB is a Dpp target in the developing wing that interacts with Brk to eliminate cells with reduced Dpp signaling through the JNK pathway [24].

Enzymatic interactions of dpp

• We conclude that dSmurf specifically targets phosphorylated MAD to proteasome-dependent degradation and regulates DPP signaling during development [25].
• Holy Tolloido: Tolloid cleaves SOG/Chordin to free DPP/BMPs [26].

Regulatory relationships of dpp

• In wild-type embryos, the ability of Dpp to induce expression of dorsal markers including itself (autoactivation) in the neuroectoderm is blocked by sog [14].
• For target genes to be activated, Dpp signalling must suppress transcription of a repressor encoded by the brinker (brk) gene [27].
• In early larval development, a short-range Hedgehog signal originating from the posterior compartment of the imaginal wing disc activates expression of genes including decapentaplegic (dpp) in a stripe running along the anterior-posterior compartment boundary [28].
• We show that restoring expression of eya in loss-of-function dpp mutant backgrounds is sufficient to induce so and dac expression and to rescue eye development [29].
• However, a direct role for Shn in regulating the transcriptional response to Dpp has not been demonstrated [30].
• First, Dpp appears to directly enhance the levels of EGF pathway activity within the follicular epithelium [31].
• Our results demonstrate that, as is the case for patterning, Dpp controls wing growth entirely via repression of the target gene brinker (brk) [32].

Other interactions of dpp

• Hh is secreted by posterior cells; it acts at short range to induce dorsal anterior cells to secrete Dpp and ventral anterior cells to secrete Wg [33].
• Both planar transcytosis initiated by Dynamin-mediated endocytosis and extracellular diffusion have been proposed for Dpp movement across cells [8].
• Local inhibition and long-range enhancement of Dpp signal transduction by Sog [10].
• We propose that slow-proliferating cells upregulate Brk levels owing to a disadvantage in competing for, or in transducing, the Dpp survival signal [34].
• Here we show that exd function and Dpp/Wg signalling are antagonistic and divide the leg into two mutually exclusive domains [35].
• We then determined experimentally in the wing epithelium: (1) the precision of the Dpp concentration gradient; (2) the precision of the Dpp signaling activity profile; and (3) the precision of activation of the Dpp target gene spalt [36].

Analytical, diagnostic and therapeutic context of dpp

• The patterns of gene expression and the formation of the second midgut constriction in the presence of ectopic dpp are most consistent with a dpp-induced transformation of virtually the entire midgut to cell fates normally seen only in the parasegment (ps)7 and ps8 regions of the midgut [37].
• Dissection of Dpp-response elements from genes expressed during embryonic mesoderm patterning and midgut morphogenesis provides important insights into the contributions of Smad proteins and tissue-specific transcription factors to spatial regulation of gene expression [38].
• To examine the relative contribution of the two proteins in the regulation of endogenous Dpp target genes we developed a cell culture assay and show that Shn and Mad act synergistically to induce transcription [30].
• We also show that the activation of this round of dpp expression is dependent upon prior Dpp signals, the signal transducer Medea, and possibly release from dTCF-mediated repression [39].
• To test whether this promoter specificity accounts for the regulatory autonomy normally found for the three genes, we used in vivo gene targeting to replace the oaf promoter with a dpp-compatible one in an otherwise normal chromosome [40].

References