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

Abstract

During development, a handful of signals sculpt diverse tissue architectures. How the same signal produces different tissue/context-specific information and outcomes is poorly understood. We explored the basis that programs tissue-specific FGF dispersion and interpretation by cytoneme-mediated contact-dependent communication. Although a Drosophila FGF was thought to be freely secreted, we discovered that it is glypiated and GPI-anchored on the source cell surface, which inhibits non-specific secretion but facilitates tissue-specific cytoneme contact formation and contact-dependent release. For long-distance signaling, source and recipient cells extend FGF-containing and FGFR-containing cytonemes that contact and recognize each other by CAM-like receptor-ligand binding. FGF-FGFR binding reciprocally induces forward and reverse signaling in recipient and source cells, responses of which polarize their cytonemes toward each other to mutually self-sustain contacts. FGFR-bound FGF is then unanchored to hand-deliver FGF to receiving cytonemes, and cytoneme contacts dissociate. Thus, while cytonemes spatiotemporally control FGF dispersion/interpretation, FGF self-regulates its tissue-specific signaling by controlling cytonemes.

Cytonemes coordinate asymmetric signaling and organization in the Drosophila muscle progenitor niche

“…Moreover, Pyr is apically enriched within the source cell 50 . We predict that the membrane tethering is critical to control cytoneme-mediated Pyr signaling, similar to what was observed for a GPI-anchored FGF, Branchless that controls Drosophila ASP development 21 . Similarly, apical enrichment of Ths:GFP suggests a spatial asymmetry in the Ths release.…”

“…Cytoneme-deficiency in AMPs caused pupal lethality, which might suggest that the contact-dependent signaling via cytonemes plays an important role in muscle development/homeostasis. Moreover, a recent study showed that cytonemedependent FGF-FGFR interactions between the ASP and wing disc induces bidirectional responses 21 . It is likely that similar cytoneme-dependent bidirectional receptor-ligand interactions can simultaneously control both wing disc and AMP organization.…”

“…Niche occupancy or cytoneme density (Fig 2I ) was measured by counting the number of cytonemes at every 5 min interval from a 1400 m 2 ROI in YZ sections obtained using Imaris. Cytoneme dynamics were measured following 21 . Average extension and retraction rates represent the averaged extension and retraction rates of the observed cytoneme during its respective lifetime.…”

“…An in vivo mechanism for localized and directed distribution of signals during animal development came from the discovery of specialized signaling filopodia, called cytonemes [14][15][16] . Studies in developing Drosophila and vertebrate embryos demonstrated that signal-exchanging cells extend cytonemes to contact each other and exchange signaling proteins at their contact sites 14,15,[17][18][19][20][21][22] . Cytonemes have been implicated in all major signaling pathways [23][24][25] .…”

Regulatory mechanisms of cytoneme-based morphogen transport

“…HH family members are modified by both cholesterol and long-chain fatty acid modifications [46][47][48] and WNT family members harbor a palmitoylation modification [49,50]. A recent study on FGF transport in the Drosophila wing imaginal disc revealed that the Bnl/ FGF is GPI-anchored to the producing-cell membrane, requiring direct contact with receiving cells to activate signaling through its receptor Breathless (Btl) [51]. These observations, along with the inability of passive diffusion models to fully account for the stringency and robustness observed across physiological morphogen gradients, suggest a requirement for a mode of direct, contact-mediated morphogen delivery to target cells [52][53][54].…”