Activin receptor inhibition by Smad2 regulates Drosophila wing disc patterning through BMP-response elements

Abstract

SUMMARYImaginal disc development in Drosophila requires coordinated cellular proliferation and tissue patterning. In our studies of TGF superfamily signaling components, we found that a protein null mutation of Smad2, the only Activin subfamily R-Smad in the fruit fly, produces overgrown wing discs that resemble gain of function for BMP subfamily signaling. The wing discs are expanded specifically along the anterior-posterior axis, with increased proliferation in lateral regions. The morphological defect is not observed in mutants for the TGF receptor baboon, and epistasis tests showed that baboon is epistatic to Smad2 for disc overgrowth. Rescue experiments indicate that Baboon binding, but not canonical transcription factor activity, of Smad2 is required for normal disc growth. Smad2 mutant discs generate a P-Mad stripe that is narrower and sharper than the normal gradient, and activation targets are correspondingly expressed in narrowed domains. Repression targets of P-Mad are profoundly mis-regulated, with brinker and pentagone reporter expression eliminated in Smad2 mutants. Loss of expression requires a silencer element previously shown to be controlled by BMP signaling. Epistasis experiments show that Baboon, Mad and Schnurri are required to mediate the ectopic silencer output in the absence of Smad2. Taken together, our results show that loss of Smad2 permits promiscuous Baboon activity, which represses genes subject to control by Mad-dependent silencer elements. The absence of Brinker and Pentagone in Smad2 mutants explains the compound wing disc phenotype. Our results highlight the physiological relevance of substrate inhibition of a kinase, and reveal a novel interplay between the Activin and BMP pathways.

TGF-β signaling in insects regulates metamorphosis via juvenile hormone biosynthesis

“…Regulation of dad also has been reported to be affected by the function of Mad and Smox (29). To understand how Gb'Myo signaling prevents Gb'Dpp/Gbb signaling, we investigated whether the Gb'Dpp/Gbb and Gb'Myo signaling pathways are associated with expression of Gb'dad.…”

CTCF-dependent co-localization of canonical Smad signaling factors at architectural protein binding sites in D. melanogaster

“…In support of this observation, recent studies have shown complex formation between TGF-b and BMP Smad proteins at BMP response elements in human epithelial cells, 56 suggesting cross-talk between TGF-b and BMP signaling factors may be a conserved phenomenon. Ligand stimulation of the TGF-b receptor Baboon can also induce phosphorylation of the BMP R-Smad Mad, 27 and mutation of the Activin R-Smad dSmad2 leads to altered BMP pathway signaling, 57 suggesting a potentially strong degree of interaction between TGF-b and BMP signaling pathways both upstream and downstream of nuclear translocation. Surprisingly, numerous Medea and Schnurri binding sites are present independently of either Mad or dSmad2, though a majority of Schnurri binding sites overlap with Medea (Fig.…”

Targeting TGF-β Signaling for Therapeutic Gain

“…1) (Derynck and Zhang 2003;Sorrentino et al 2008). There can be considerable cross talk between intracellular signaling pathways of the different TGF-b subfamilies, both downstream from and upstream of their respective receptors (Ray et al 2010;Grönroos et al 2012;Peterson and O'Connor 2013). In disease states, ablation of signaling from one ligand subtype may interfere with the signaling output from others in either a positive or negative manner, with one of the finest examples being found through human genetics (Hatsell et al 2015).…”