title: New negative feedback regulators of Egfr signaling in Drosophila.
abstract: 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 led to the discovery of new components and targets. Here we used microarray analysis of 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 A Disintegrin And Metalloproteinase with ThromboSpondin motifs (ADAMTS) 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). How Drosophila Egfr activity is modulated by CG4096 is unknown, but interestingly vertebrate EGF ligands are regulated by a related ADAMTS protein. We suggest Sulf1 and CG4096 are negative feedback regulators of Egfr signaling that function in the extracellular space to influence ligand activity.
authors.affiliation: Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Butchar
authors.forename: Donna
authors.initials: D
authors.lastname: Cain
authors.forename: Sathiya N
authors.initials: SN
authors.lastname: Manivannan
authors.forename: Andrea D
authors.initials: AD
authors.lastname: McCue
authors.forename: Liana
authors.initials: L
authors.lastname: Bonanno
authors.forename: Sarah
authors.initials: S
authors.lastname: Halula
authors.forename: Sharon
authors.initials: S
authors.lastname: Truesdell
authors.forename: Christina L
authors.initials: CL
authors.lastname: Austin
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Jacobsen
authors.forename: Amanda
authors.initials: A
authors.lastname: Simcox
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D008024:Ligands; D010641:Phenotype; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D013429:Sulfatases / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D014680:Veins / Q000378:metabolism; D014921:Wings, Animal / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D008024:Ligands; D066246:ErbB Receptors; C568065:SULF1 protein, Drosophila; D013429:Sulfatases