Brinker requires two corepressors for maximal and versatile repression in Dpp signalling

Abstract

decapentaplegic (dpp) encodes a Drosophila transforming growth factor-beta homologue that functions as a morphogen in the developing embryo and in adult appendage formation. In the wing imaginal disc, a Dpp gradient governs patterning along the anteroposterior axis by inducing regional expression of diverse genes in a concentration-dependent manner. Recent studies show that responses to graded Dpp activity also require an input from a complementary and opposing gradient of Brinker (Brk), a transcriptional repressor protein encoded by a Dpp target gene. Here we show that Brk harbours a functional and transferable repression domain, through which it recruits the corepressors Groucho and CtBP. By analysing transcriptional outcomes arising from the genetic removal of these corepressors, and by ectopically expressing Brk variants in the embryo, we demonstrate that these corepressors are alternatively used by Brk for repressing some Dpp-responsive genes, whereas for repressing other distinct target genes they are not required. Our results show that Brk utilizes multiple means to repress its endogenous target genes, allowing repression of a multitude of complex Dpp target promoters.

Quantitative contributions of CtBP-dependent and -independent repression activities of Knirps

“…The tolloid gene is repressed by Brinker in the blastoderm embryo in a Groucho-dependent manner, while either CtBP or Groucho are sufficient to mediate brk autoinhibition. Interestingly, neither co-factor appears to be required for repression of omb and sal, suggesting a third pathway for repression, possibly direct competition (Hasson et al, 2001;Rushlow et al, 2001). Similarly, the Even-skipped, Runt and Engrailed proteins repress through Grouchodependent and -independent pathways, again showing genespecificity.…”

“…In Drosophila, the Brinker repressor can interact with both the CtBP and Groucho co-repressors to mediate repression of Dppregulated genes (Hasson et al, 2001;Zhang et al, 2001). For this repressor, distinct co-factors are required at different promoters.…”

Crosstalk between the EGFR and other signalling pathways at the level of the global transcriptional corepressor Groucho/TLE

“…For example, Gro mediates the repressor function of Brinker (Brk) and Tcf/Lef, the nuclear transducers of the Dpp/TGF-b and Wingless (Wg)/Wnt signalling pathways, respectively (Brantjes et al, 2001;Hasson et al, 2001;Zhang et al, 2001). Gro-dependent repressors also act downstream of receptor tyrosine kinase (RTK) pathways, for instance those mediated by the Torso receptor and by EGFR (Paroush et al, 1997;Price et al, 1997).…”

“…It appears that many repressors possess more than one repression domain. Brk and Su(H), for example, rely both on Gro as well as on a second corepressor called CtBP for turning off gene expression (Hasson et al, 2001). Gro and CtBP act qualitatively differently, in that Gro mediates repression over long distances (41 Kb), whereas CtBP functions at short range (100 -150 bp) ( Figure 2B; Zhang and Levine, 1999).…”

Opposing inputs by Hedgehog and Brinker define a stripe ofhairyexpression in theDrosophilaleg imaginal disc

“…Brk can mediate active repression (Kirkpatrick et al, 2001), and binds the co-repressors dCtBP and Groucho (Gro), which mediate short-and long-range repression, respectively (Saller et al, 2002;Zhang et al, 2001). Brk requires Gro and/or dCtBP function for repression of a subset of its target genes, whereas neither is required for repression of others (Hasson et al, 2001). In the D-h enhancer, the CMB is positioned about 1 kb from the HHRE, suggesting that CMB-binding repressor(s) act at long range to repress HHRE-directed expression.…”