Nuclear interpretation of Dpp signaling in Drosophila

Abstract

Signaling by Decapentaplegic (Dpp), a member of the TGFbeta superfamily of signaling molecules similar to vertebrate BMP2 and BMP4, has been implicated in many developmental processes in Drosophila melanogaster. Notably, Dpp acts as a long-range morphogen during imaginal disc growth and patterning. Genetic approaches led to the identification of a number of gene products that constitute the core signaling pathway. In addition to the ligand-activated heteromeric receptor complex and the signal-transducing intracellular Smad proteins, Dpp signaling requires two nuclear proteins, Schnurri (Shn) and Brinker (Brk), to prime cells for Dpp responsiveness. A complex interplay between the nuclear factors involved in Dpp signaling appears to control the transcriptional readout of the Dpp morphogen gradient. It remains to be seen whether similar molecular mechanisms operate in the nucleus in vertebrate systems.

Fig. 1. The Dpp signaling pathway in Drosophila melanogaster. The Mad–Medea complex is essential for gene activation and gene repression. Shn is essential for Mad/Medea-mediated repression of brk transcription, but is dispensable for Dpp-mediated transcriptional activation of most target genes. The question mark indicates the possibility that Shn has additional functions since the brk, shn double mutant embryos are not identical to the brk single mutant embryos (T.Marty and M.Affolter, data not shown but see Torres-Vazquez et al., 2001). Evidence suggesting that Shn also acts as an activator of transcription together with Mad has been provided (Dai et al., 2000); it remains to be investigated in vivo whether Shn is required for gene activation in certain cases. Arrows denote upregulation; bars denote downregulation.

Fig. 2. Schematic model for Dpp-dependent patterning of the wing imaginal disc (A) and the embryonic dorsal–ventral axis (B). (A) In the imaginal wing disc, Dpp is secreted from a narrow stripe of cells anterior to the A/P compartment boundary and forms a long-range gradient. Dpp signaling represses the transcription of brk, which encodes a repressor of Dpp target genes. Different target genes are expressed in nested domains; sal is expressed in a less broad domain than omb, and vg is expressed in the entire wing blade primordia. A model for the regulation of expression of these genes is illustrated in Figure 3. (B) In the early Drosophila embryo, dpp is expressed in the dorsal ectoderm and amnioserosa primordium and its activity is graded due to the action of a number of components (see text). brk RNA is expressed under the control of the Dorsal morphogen in the ventral ectoderm abutting the dpp expression domain, and the Brk protein appears to diffuse dorsally during the syncytial blastoderm stages. brk-dependent repression leads to the establishment of different expression borders for early zen and pnr. zen is activated in a dorsal stripe under the control of dpp and screw.

Fig. 3. Schematic model for the patterning of a field of cells by a Dpp morphogen gradient. In the absence of Dpp signaling (a situation that might not occur in the primordia of the wing blade, but in the primordia of the wing hinge in the imaginal disc), high levels of Brk protein repress Dpp target genes (far-left panel). At the periphery of the Dpp gradient, high levels of Brk are present; the low levels of phosphorylated Mad/Med in the nucleus are sufficient to activate the vg^Q enhancer, but too low to repress brk transcription. In the medial region of the gradient, brk is partially repressed under the control of Mad/Med and Shn; the reduced levels of Brk protein are insufficient to repress omb, but still sufficient to repress sal. Towards the center of the gradient, high levels of Dpp signaling strongly repress brk transcription. sal is derepressed and activated to high levels under the control of Mad/Med. Proteins for which evidence for a direct regulation of the corresponding enhancer has been provided experimentally are drawn on the DNA line; other proteins are drawn above the DNA line. For more details on the possible architecture of the enhancers controlling expression of vg, omb and sal, please refer to the text.