BMP signaling components in embryonic transcriptomes of the hover fly Episyrphus balteatus (Syrphidae)

<p>Abstract</p> <p>Background</p> <p>In animals, signaling of Bone Morphogenetic Proteins (BMPs) is essential for dorsoventral (DV) patterning of the embryo, but how BMP signaling evolved with changes in embryonic DV differentiation is largely unclear. Based on the extensive knowledge of BMP signaling in <it>Drosophila melanogaster</it>, the morphological diversity of extraembryonic tissues in different fly species provides a comparative system to address this question. The closest relatives of <it>D. melanogaster </it>with clearly distinct DV differentiation are hover flies (Diptera: Syrphidae). The syrphid <it>Episyrphus balteatus </it>is a commercial bio-agent against aphids and has been established as a model organism for developmental studies and chemical ecology. The dorsal blastoderm of <it>E. balteatus </it>gives rise to two extraembryonic tissues (serosa and amnion), whereas in <it>D. melanogaster</it>, the dorsal blastoderm differentiates into a single extraembryonic epithelium (amnioserosa). Recent studies indicate that several BMP signaling components of <it>D. melanogaster</it>, including the BMP ligand Screw (Scw) and other extracellular regulators, evolved in the dipteran lineage through gene duplication and functional divergence. These findings raise the question of whether the complement of BMP signaling components changed with the origin of the amnioserosa.</p> <p>Results</p> <p>To search for BMP signaling components in <it>E. balteatus</it>, we generated and analyzed transcriptomes of freshly laid eggs (0-30 minutes) and late blastoderm to early germband extension stages (3-6 hours) using Roche/454 sequencing. We identified putative <it>E. balteatus </it>orthologues of 43% of all annotated <it>D. melanogaster </it>genes, including the genes of all BMP ligands and other BMP signaling components.</p> <p>Conclusion</p> <p>The diversification of several BMP signaling components in the dipteran linage of <it>D. melanogaster </it>preceded the origin of the amnioserosa.</p> <p>[Transcriptome sequence data from this study have been deposited at the NCBI Sequence Read Archive (SRP005289); individually assembled sequences have been deposited at GenBank (<ext-link ext-link-id="JN006969" ext-link-type="gen">JN006969</ext-link>-<ext-link ext-link-id="JN006986" ext-link-type="gen">JN006986</ext-link>).]</p

The Role of Glypicans in Wnt Inhibitory Factor-1 Activity and the Structural Basis of Wif1's Effects on Wnt and Hedgehog Signaling

Proper assignment of cellular fates relies on correct interpretation of Wnt and Hedgehog (Hh) signals. Members of the Wnt Inhibitory Factor-1 (WIF1) family are secreted modulators of these extracellular signaling pathways. Vertebrate WIF1 binds Wnts and inhibits their signaling, but its Drosophila melanogaster ortholog Shifted (Shf) binds Hh and extends the range of Hh activity in the developing D. melanogaster wing. Shf activity is thought to depend on reinforcing interactions between Hh and glypican HSPGs. Using zebrafish embryos and the heterologous system provided by D. melanogaster wing, we report on the contribution of glypican HSPGs to the Wnt-inhibiting activity of zebrafish Wif1 and on the protein domains responsible for the differences in Wif1 and Shf specificity. We show that Wif1 strengthens interactions between Wnt and glypicans, modulating the biphasic action of glypicans towards Wnt inhibition; conversely, glypicans and the glypican-binding “EGF-like” domains of Wif1 are required for Wif1's full Wnt-inhibiting activity. Chimeric constructs between Wif1 and Shf were used to investigate their specificities for Wnt and Hh signaling. Full Wnt inhibition required the “WIF” domain of Wif1, and the HSPG-binding EGF-like domains of either Wif1 or Shf. Full promotion of Hh signaling requires both the EGF-like domains of Shf and the WIF domains of either Wif1 or Shf. That the Wif1 WIF domain can increase the Hh promoting activity of Shf's EGF domains suggests it is capable of interacting with Hh. In fact, full-length Wif1 affected distribution and signaling of Hh in D. melanogaster, albeit weakly, suggesting a possible role for Wif1 as a modulator of vertebrate Hh signaling

Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia

Abstract: Chronic inflammation is one of the main features of cancer cachexia. Experimental and clinical studies showed that cyclooxygenase-2 inhibitors, such as celecoxib, may be beneficial in counteracting major symptoms of this devastating syndrome. We carried out a prospective phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib (300 mg/day for 4 months) on key variables of cachexia (lean body mass, resting energy expenditure, serum levels of proinflammatory cytokines, and fatigue) in patients with advanced cancer at different sites. A sample of 24 patients was enrolled from January to December 2008 and all were deemed assessable. A significant increase of lean body mass and a significant decrease of TNF-alpha were observed. Moreover, an improvement of grip strength, quality of life, performance status, and Glasgow prognostic score was shown. There were no grade 3/4 toxicities. Patient compliance was very good; no patient had to reduce the celecoxib dosage nor interrupt treatment. Our results showed that the COX-2 selective inhibitor celecoxib is an effective single agent for the treatment of cancer cachexia. Although the treatment of cancer cachexia, a multifactorial syndrome, is more likely to yield success with a multitargeted approach; in the present study, we were able to show that a treatment, such as celecoxib, addressing a single target, albeit very important as chronic inflammation, could have positive effects. Therefore, phase III clinical trials are warranted to test the efficacy and safety of celecoxib

Regulation of Drosophila hematopoietic sites by Activin-β from active sensory neurons

An outstanding question in animal development, tissue homeostasis and disease is how cell populations adapt to sensory inputs. During Drosophila larval development, hematopoietic sites are in direct contact with sensory neuron clusters of the peripheral nervous system (PNS), and blood cells (hemocytes) require the PNS for their survival and recruitment to these microenvironments, known as Hematopoietic Pockets. Here we report that Activin-β, a TGF-β family ligand, is expressed by sensory neurons of the PNS and regulates the proliferation and adhesion of hemocytes. These hemocyte responses depend on PNS activity, as shown by agonist treatment and transient silencing of sensory neurons. Activin-β has a key role in this regulation, which is apparent from reporter expression and mutant analyses. This mechanism of local sensory neurons controlling blood cell adaptation invites evolutionary parallels with vertebrate hematopoietic progenitors and the independent myeloid system of tissue macrophages, whose regulation by local microenvironments remain undefined