GPI-anchored FGF directs cytoneme-mediated bidirectional signaling to self-regulate tissue-specific dispersion

How signaling proteins generate and distribute a multitude of information to shape tissues is critical to understanding morphogenesis. In Drosophila, FGF produced in wing-disc cells regulates the development of the disc-associated air-sac-primordium/ASP. We discovered that FGF signaling is bidirectional and occurs at a distance between ASP and wing-disc cells through physical contacts of filopodia/cytonemes produced by both cells. FGF is GPI-anchored to the source cytoneme membrane, inhibiting its free secretion but facilitating its contact-dependent binding with FGF-receptors/FGFR on ASP cytonemes, thereby producing cytoneme-cytoneme contacts. Contact-mediated bidirectional FGF-FGFR signaling self-promotes by inducing source and ASP cells to polarize cytonemes toward each other to strengthen inter-cytoneme contacts. Subsequent un-anchoring of FGFR-bound-FGF dissociates contacts and releases FGF target-specifically to ASP cytonemes for paracrine functions. Thus, unlike traditional models of randomly secreted diffusible signals and their one-way directives to recipient cells, GPI-anchored FGF directs both source and recipient cells and self-regulates tissue-specific signaling.