Glypicans define unique roles for the Hedgehog co-receptors boi and ihog in cytoneme-mediated gradient formation

Simon, Eléanor; Jiménez-Jiménez, Carlos; Seijo-Barandiarán, Irene; Aguilar, Gustavo; Sánchez‐Hernández, D.; Aguirre-Tamaral, Adrián; González-Méndez, Laura; Ripóll, Pedro; Guerrero, Isabel

doi:10.7554/elife.64581

Cited by 18 publications

(36 citation statements)

References 66 publications

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“…Moreover, all signals, including those that are not known to be lipidated (e.g., BMPs and many FGFs), can interact with membrane-anchored proteoglycans, which can restrict free signal dispersion and induce biphasic signaling activation and inhibition [61][62][63] . Glypicans also can control cytoneme stability [64][65][66] . Therefore, our findings showing how GPI anchoring enables Bnl to direct source and recipient cells to reciprocally coordinate with each other by cytonemes provide important new insights into how other signal retention strategies might control signaling and morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

Du¹,

Sohr²,

Li³

et al. 2021

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Du¹,

Sohr²,

Li³

et al. 2021

Preprint

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“…The following fly strains were used in this study: HA-dpp (Matsuda et al, 2021), OLLAS-dpp (this study), OLLAS:HA-dpp (Matsuda et al, 2021 ) HA-gbb (this study), OLLAS-gbb (this study), OLLAS:HA-gbb (this study), gbb 1 /CyO (Wharton et al, 1999), gbb -lacZ (as described in (Akiyama et al, 2012), constructed by replacing the gbb coding sequence with lacZ open reading frame), ptc -Gal4 (Bloomington stock center (BL)207), hh -Gal4, nub -Gal4 Gift from Dr Manolo Calleja, hh -lexA (Simon et al, 2021), UAS- gbb RNAi (BL34898), UAS- dpp RNAi (BL33618), UAS- dpp (BL1486), ap -Gal4 (BL3041), tubulin -Gal80ts (BL7016, BL7019, BL7017), UAS/LexAop-HATrap, lexAop-HATrap, UAS- sax RNAi (VDRC 46350), UAS- put RNAi (BL39025), UAS- wit RNAi (BL25949).…”

Section: Methodsmentioning

confidence: 99%

Heterodimerization-dependent secretion of BMPs in Drosophila

Bauer

Aguilar

Wharton

et al. 2022

Preprint

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Combinatorial signaling is key to instruct context-dependent cell behaviors. During embryonic development, adult homeostasis and disease, Bone Morphogenetic Proteins (BMPs) act as dimers to instruct specific cellular responses. BMP ligands can form both homo- or heterodimers; however, obtaining direct evidence of the endogenous localization and function of each form has proven challenging. Here, we make use of precise genome editing and direct protein manipulation via protein binders to dissect the existence and functional relevance of BMP homo- and heterodimers in the Drosophila wing imaginal disc. This approach revealed in situ the existence of Dpp (BMP2/4)/Gbb (BMP5/6/7/8) heterodimers. We found that Gbb, despite being produced by all the cells of the wing imaginal disc, is only secreted by the cells in which Dpp is expressed. Dpp and Gbb form a gradient of heterodimers whereas neither Dpp nor Gbb homodimers are evident under endogenous physiological conditions. We find that the formation of heterodimers is critical for obtaining optimal signaling and long-range BMP distribution in the developing wing. These results indicate that Dpp/Gbb heterodimers are the active signal required for epithelial patterning and growth.

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“…The HSPGs Dally and Dlp cluster on the cell surface of cultured Drosophila cells and Dlp clusters on Hh-transporting cytonemes [142]. In the Drosophila wing disc, Dally and Dlp interact with and stabilize ectopically expressed Ihog on cytoneme membranes by slowing cytoneme elongation and retraction velocities [143]. Similarly, BOC and CDON enrich in microdomains along portions of chick limb bud cytonemes that remain static, suggesting that they bind to extracellular components to stabilize the structures as they extend [62].…”

Section: Cytoneme Extension and Stabilizationmentioning

confidence: 99%

Regulatory mechanisms of cytoneme-based morphogen transport

Daly

Hall

Ogden

2022

Cell. Mol. Life Sci.

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During development and tissue homeostasis, cells must communicate with their neighbors to ensure coordinated responses to instructional cues. Cues such as morphogens and growth factors signal at both short and long ranges in temporal- and tissue-specific manners to guide cell fate determination, provide positional information, and to activate growth and survival responses. The precise mechanisms by which such signals traverse the extracellular environment to ensure reliable delivery to their intended cellular targets are not yet clear. One model for how this occurs suggests that specialized filopodia called cytonemes extend between signal-producing and -receiving cells to function as membrane-bound highways along which information flows. A growing body of evidence supports a crucial role for cytonemes in cell-to-cell communication. Despite this, the molecular mechanisms by which cytonemes are initiated, how they grow, and how they deliver specific signals are only starting to be revealed. Herein, we discuss recent advances toward improved understanding of cytoneme biology. We discuss similarities and differences between cytonemes and other types of cellular extensions, summarize what is known about how they originate, and discuss molecular mechanisms by which their activity may be controlled in development and tissue homeostasis. We conclude by highlighting important open questions regarding cytoneme biology, and comment on how a clear understanding of their function may provide opportunities for treating or preventing disease.

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Glypicans define unique roles for the Hedgehog co-receptors boi and ihog in cytoneme-mediated gradient formation

Cited by 18 publications

References 66 publications

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

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

Heterodimerization-dependent secretion of BMPs in Drosophila

Regulatory mechanisms of cytoneme-based morphogen transport

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