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Dll and Sp1 ChIP-seq data from Drosophila third instar leg imaginal discs

ABSTRACT: Animal limb development relies on the establishment of organizing centers, which govern limb outgrowth and patterning by regulating the spatial and temporal expression of secreted signaling molecules. On a molecular level the establishment of organizing centers occurs via cis regulatory modules (CRMs), also known as transcriptional enhancers, that integrate upstream temporal and spatial inputs. We elucidated the mechanism that governs the establishment of an Epidermal Growth Factor Receptor (EGFR) organizing center (EOC) during leg development in Drosophila melanogaster. We find that EGFR activation occurs by sequential activation of the EGFR ligand Vein (Vn) and the EGFR ligand-processing protease Rhomboid (Rho), each through single CRMs. These CRMs integrate in a distinct manner inputs from the Wingless (Wg) and Decapentaplegic (Dpp) signaling pathways, and from the leg selector transcription factors Distal-less (Dll) and Sp1. Elimination of the vn (vnE) and rho (rhoE) EOC enhancers eliminates the expression of these genes in the center of the leg imaginal discs, respectively. A vnE rhoE double deficiency, but not single deletions, demonstrates an absolute requirement of these CRMs for specifying the most distal, but not more proximal, leg fates. In addition, the cis-regulatory logic of vnE and rhoE transcends the leg EOC developmental program, because genomic regions with similar inputs, based on predicted and genome-wide binding by the transcription factors that establish the EOC, faithfully predicts novel CRMs active in the distal leg. The combinatorial input of Wg, Dpp, Dll and Sp1 at these CRMs reveals a molecular signature for coordinating gene expression in the Drosophila leg that might be analogous to many other multi-cellular systems.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE113574 | GEO | 2018/07/11

REPOSITORIES: GEO

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Project description:The highly conserved Epidermal Growth Factor-receptor (Egfr) pathway is required in all animals for normal development and homeostasis; consequently, aberrant Egfr signaling is implicated in a number of diseases. Genetic analysis of Drosophila melanogaster Egfr has contributed significantly to understanding this conserved pathway and has led to the discovery of new components and targets. Here we used microarray analysis of Drosophila third instar wing discs, in which Egfr signaling was perturbed, to identify new Egfr-responsive genes. Upregulated transcripts included five known targets suggesting the approach was valid. We investigated the function of 29 previously uncharacterized genes, which had pronounced responses. The Egfr pathway is important for wing-vein patterning and using reverse genetic analysis we identified five genes that showed venation defects. Three of these genes are expressed in vein primordia and all showed transcriptional changes in response to altered Egfr activity consistent with being targets of the pathway. Genetic interactions with Egfr further linked two of the genes, Sulfated (Sulf1), an endosulfatase gene, and CG4096, an ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) gene, to the pathway. Sulf1 showed a strong genetic interaction with the neuregulin-like ligand vein (vn) and may influence binding of Vn to heparan-sulfated proteoglycans (HSPGs). Genetic evidence also shows that CG4096 functions by modulating activity of the Egfr ligands. The substrate(s) and how ligand activity is affected are unknown, but interestingly vertebrate EGF ligands are regulated by a related ADAMTS protein. We conclude Sulf1 and CG4096 are negative feedback regulators of Egfr signaling that function in the extracellular space to influence ligand activity. 3 replicates each of wing disc samples in which EGFR dominant negative (EGFR-DN) or EGFR activated (EGFR-TOP) transgenes were expressed with the 71B-Gal4 driver.

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Dll and Sp1 ChIP-seq data from Drosophila third instar leg imaginal discs

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