Fringe signaling and making boundaries: A structure-function study of fringe proteins in Drosophila

Communication between cells is essential for pattern formation, differentiation, and proliferation of tissues. This study investigates the role of a novel gene called fringe (fng), which can induce boundaries at its expression borders. In this study I use the Drosophila wing imaginal disc to understand how fringe mediates interactions between dorsal and ventral cells. The results of this study show that the Notch ligands Serrate and Delta induce each other's expression and this induction is dorsal-ventral asymmetric. fringe functions in the wing imaginal disc by modulating the Notch ligands Serrate and Delta differentially. fringe inhibits the Serrate response and potentiates the Delta response positioning and restricting the Notch feedback loop. This results in the symmetric activation of the wing margin genes. I also describe the localization of epitope tagged FNG protein in wing imaginal discs and find that it has an intriguing pattern of expression. FNG protein exists as both a cell-associated and diffusible form.;I describe the cloning and characterization of three new fringe family members, the mouse Fringe genes ( Manic Fringe, Radical Fringe and Lunatic Fringe). I show that the mouse Fringe genes may be regulated at the level of processing, and their misexpression in the Drosophila wing reveals that Manic Fringe and Radical Fringe have partial activity while Lunatic Fringe is completely inactive. The activity of Lunatic Fringe in Drosophila can be restored by substitution of its pro region with that of Drosophila fringe. I also show that the difference between Drosophila fringe and Lunatic Fringe is not at the level of processing but due to differences in the pro region.;I show by structure function analysis and expression of altered proteins in Schneider cells and wing imaginal discs that there are multiple forms of FNG protein present, both cell-associated and diffusible. I find that diffusible FNG comprises mostly of unprocessed FNG protein and this diffusible FNG is not essential for fringe function. I have examined the significance of processing and determined that processing is not essential for Drosophila fringe function but may modify its activity. Most importantly, I provide evidence that fringe could be a putative secreted glycosyltransferase.