ABSTRACT
Wingless (Wg) is a member of the Wnt family of growth factors, secreted proteins that control proliferation and differentiation during development. Studies in Drosophila have shown that responses to Wg require cell-surface heparan sulphate, a glycosaminoglycan component of proteoglycans. These findings suggest that a cell-surface proteoglycan is a component of a Wg/Wnt receptor complex. We demonstrate here that the protein encoded by the division abnormally delayed (dally) gene is a cell-surface, heparan-sulphate-modified proteoglycan. dally partial loss-of-function mutations compromise Wg-directed events, and disruption of dally function with RNA interference produces phenotypes comparable to those found with RNA interference of wg or frizzled (fz)/Dfz2. Ectopic expression of Dally potentiates Wg signalling without altering levels of Wg and can rescue a wg partial loss-of-function mutant. We also show that dally, a regulator of Decapentaplegic (Dpp) signalling during post-embryonic development, has tissue-specific effects on Wg and Dpp signalling. Dally can therefore differentially influence signalling mediated by two growth factors, and may form a regulatory component of both Wg and Dpp receptor complexes.
Subject(s)
Drosophila Proteins , Drosophila/physiology , Membrane Glycoproteins/physiology , Proteoglycans/physiology , Proto-Oncogene Proteins/physiology , Signal Transduction , Animals , Animals, Genetically Modified , Cloning, Molecular , Drosophila/genetics , Epidermis/embryology , Epidermis/physiology , Female , Genes, Insect , Genetic Techniques , Genitalia/embryology , Glycosylphosphatidylinositols/chemistry , Glycosylphosphatidylinositols/physiology , Heparan Sulfate Proteoglycans/chemistry , Heparan Sulfate Proteoglycans/physiology , Homeodomain Proteins/physiology , Insect Proteins/physiology , Larva/chemistry , Male , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/genetics , Mutation , Proteoglycans/chemistry , Proteoglycans/genetics , RNA/metabolism , Transcription Factors/physiology , Wnt1 ProteinABSTRACT
Decapentaplegic (Dpp) is a Drosophila member of the Transforming Growth Factor-beta (TGF-beta)/Bone Morphogenetic Protein (BMP) superfamily of growth factors. Dpp serves as a classical morphogen, where concentration gradients of this secreted factor control patterning over many cell dimensions. Regulating the level of Dpp signaling is therefore critical to its function during development. One type of molecule proposed to modulate growth factor signaling at the cell surface are integral membrane proteoglycans. We show here that division abnormally delayed (dally), a Drosophila member of the glypican family of integral membrane proteoglycans is required for normal Dpp signaling during development, affecting cellular responses to this morphogen. Ectopic expression of dally+ can alter the patterning activity of Dpp, suggesting a role for dally+ in modulating Dpp signaling strength. These findings support a role for members of the glypican family in controlling TGF-beta/BMP activity in vivo by affecting signaling at the cell surface.
