Fringe modulates Notch–ligand interactions

Abstract

The Notch family of transmembrane receptor proteins mediate developmental cell-fate decisions¹, and mutations in mammalian Notch genes have been implicated in leukaemia, breast cancer, stroke and dementia^2,3,4. During wing development in Drosophila, the Notch receptor is activated along the border between dorsal and ventral cells^5,6,7, leading to the specification of specialized cells that express Wingless (Wg) and organize wing growth and patterning⁶,⁸,⁹. Three genes, fringe (fng), Serrate (Ser) and Delta (Dl), are involved in the cellular interactions leading to Notch activation^{7,9,10,11,12,13,14,15}. Ser and Dl encode transmembrane ligands for Notch¹⁶,¹⁷, whereas fng encodes a pioneer protein¹⁰. We have investigated the relationship between these genes by a combination of expression and coexpression studies in the Drosophila wing. We found that Ser and Dl maintain each other's expression by a positive feedback loop. fng is expressed specifically by dorsal cells and functions to position and restrict this feedback loop to the developing dorsal–ventral boundary. This is achieved by fng through a cell-autonomous mechanism that inhibits a cell's ability to respond to Serrate protein and potentiates its ability to respond to Delta protein.