cytoneme

During development, cells use specialized filopodia called cytonemes to deploy the signaling proteins that coordinate growth and direct morphogenesis. Cytonemes are dynamic structures that can extend long distances across tissues to either deliver or take up signaling proteins. Signaling proteins transfer between cells at the tips of cytonemes where specific contacts termed morphogenetic synapses form. This review summarizes our current understanding of the roles and functions of cytonemes, and it explores some of the conceptual issues relevant to the cytoneme mechanism of contact-dependent cell-cell signaling...

Butterfly wing eyespot patterns are determined in pupal tissues by organisers located at the centre of the prospective eyespots. Nevertheless, organiser cells have not been examined cytochemically in vivo, partly due to technical difficulties. Here, we directly observed organiser cells in pupal forewing epithelium via an in vivo confocal fluorescent imaging technique, using 1-h post-pupation pupae of the blue pansy butterfly, Junonia orithya. The prospective eyespot centre was indented from the plane of the ventral tissue surface...

Drosophila dorsal air sac development depends on Decapentaplegic (Dpp) and Fibroblast growth factor (FGF) proteins produced by the wing imaginal disc and transported by cytonemes to the air sac primordium (ASP). Dpp and FGF signaling in the ASP was dependent on components of the planar cell polarity (PCP) system in the disc, and neither Dpp- nor FGF-receiving cytonemes extended over mutant disc cells that lacked them. ASP cytonemes normally navigate through extracellular matrix (ECM) composed of collagen, laminin, Dally and Dally-like (Dlp) proteins that are stratified in layers over the disc cells...

Wnt proteins act as potent morphogens in various aspects of embryonic development and adult tissue homeostasis. However, in addition to its physiological importance, aberrant Wnt signaling has been linked to the onset and progression of different types of cancer. On the cellular level, the secretion of Wnt proteins involves trafficking of lipid-modified Wnts from the endoplasmic reticulum (ER) to Golgi and further compartments via the Wnt cargo receptor evenness interrupted. Others and we have recently shown that Wnt proteins are secreted on extracellular vesicles (EVs) such as microvesicles and exosomes...

Tunnelling nanotubes and cytonemes function as highways for the transport of organelles, cytosolic and membrane-bound molecules, and pathogens between cells. During viral infection in the model organism Drosophila melanogaster, a systemic RNAi antiviral response is established presumably through the transport of a silencing signal from one cell to another via an unknown mechanism. Because of their role in cell-cell communication, we investigated whether nanotube-like structures could be a mediator of the silencing signal...

Wnt signaling regulates a broad variety of processes during embryonic development and disease. A hallmark of the Wnt signaling pathway is the formation of concentration gradients by Wnt proteins across responsive tissues, which determines cell fate in invertebrates and vertebrates. To fulfill its paracrine function, trafficking of the Wnt morphogen from an origin cell to a recipient cell must be tightly regulated. A variety of models have been proposed to explain the extracellular transport of these lipid-modified signaling proteins in the aqueous extracellular space; however, there is still considerable debate with regard to which mechanisms allow the precise distribution of ligand in order to generate a morphogenetic gradient within growing tissue...

Pattern formation via direct cell to cell contact has received considerable attention over the years. In particular the lateral-inhibition mechanism observed in the Notch signalling pathway can generate a regular periodic pattern of differential cell activity, and has been proposed to explain the emergence of patterns in various tissues and organs. The majority of models of this system have focussed on short-range contacts: a cell signals only to its nearest neighbours and the resulting patterns tend to be of fine-scale "salt and pepper" nature...

Hedgehog (Hh) molecules act as morphogens directing cell fate during development by activating various target genes in a concentration dependent manner. Hitherto, modeling morphogen gradient formation in multicellular systems has employed linear diffusion, which is very far from physical reality and needs to be replaced by a deeper understanding of nonlinearities. We have developed a novel mathematical approach by applying flux-limited spreading (FLS) to Hh morphogenetic actions. In the new model, the characteristic velocity of propagation of each morphogen is a new key biological parameter...

The Hedgehog (Hh) signaling pathway is a regulator of patterning, cell migration and axon guidance during development as well as of homeostatic events in adult organs. It is highly conserved from Drosophila to humans. In many contexts during development, Hh appears to function as a morphogen; it spreads from producing cells to trigger concentration dependent responses in target cells, leading to their specification. During production, Hh undergoes two lipid modifications resulting in a highly hydrophobic molecule...

The flight muscles, dorsal air sacs, wing blades, and thoracic cuticle of the Drosophila adult function in concert, and their progenitor cells develop together in the wing imaginal disc. The wing disc orchestrates dorsal air sac development by producing decapentaplegic and fibroblast growth factor that travel via specific cytonemes in order to signal to the air sac primordium (ASP). Here, we report that cytonemes also link flight muscle progenitors (myoblasts) to disc cells and to the ASP, enabling myoblasts to relay signaling between the disc and the ASP...

BACKGROUND INFORMATION: In a previous study, we demonstrated that human neutrophils can develop membrane tubulovesicular extensions (TVEs) that are 160-250 nm in width and several micrometres long. These extensions, or cytonemes, are capable of establishing long-range contacts with other cells or bacteria. Cytonemes consist of membrane tubules and vesicles of a uniform diameter aligned in a row. The mechanism of membrane tubulation/vesiculation to form cytonemes remains unknown. Upon endocytosis, the GTPase dynamin and an intact actin cytoskeleton are required for endocytic vesicles scission from the plasma membrane...

Embryonic development and adult tissue homeostasis require precise information exchange between cells and their microenvironment to coordinate cell behavior. A specialized class of ultra-long actin-rich filopodia, termed cytonemes, provides one mechanism for this spatiotemporal regulation of extracellular cues. We provide here a mechanism whereby the stem-cell marker Lgr5, and its family member Lgr4, promote the formation of cytonemes. Lgr4- and Lgr5-induced cytonemes exceed lengths of 80 µm, are generated through stabilization of nascent filopodia from an underlying lamellipodial-like network and functionally provide a pipeline for the transit of signaling effectors...

Recent findings in several organ systems show that cytoneme-mediated signaling transports signaling proteins along cellular extensions and targets cell-to-cell exchanges to synaptic contacts. This mechanism of paracrine signaling may be a general one that is used by many (or all) cell types in many (or all) organs. We briefly review these findings in this perspective. We also describe the properties of several signaling systems that have previously been interpreted to support a passive diffusion mechanism of signaling protein dispersion, but can now be understood in the context of the cytoneme mechanism...

The Hedgehog signalling pathway is crucial for development, adult stem cell maintenance, cell migration and axon guidance in a wide range of organisms. During development, the Hh morphogen directs tissue patterning according to a concentration gradient. Lipid modifications on Hh are needed to achieve graded distribution, leading to debate about how Hh is transported to target cells despite being membrane-tethered. Cytonemes in the region of Hh signalling have been shown to be essential for gradient formation, but the carrier of the morphogen is yet to be defined...

Filopodia are cellular protrusions that have been implicated in many types of mechanosensory activities. Morphogens are signaling proteins that regulate the patterned development of embryos and tissues. Both have long histories that date to the beginnings of cell and developmental biology in the early 20th century, but recent findings tie specialized filopodia called cytonemes to morphogen movement and morphogen signaling. This review explores the conceptual and experimental background for a model of paracrine signaling in which the exchange of morphogens between cells is directed to sites where cytonemes directly link cells that produce morphogens to cells that receive and respond to them...

Hedgehog (Hh) is a paracrine signaling protein with major roles in development and disease. In vertebrates and invertebrates, Hh signal transduction is carried out almost entirely by evolutionarily conserved components, and in both, intercellular movement of Hh is mediated by cytonemes - specialized filopodia that serve as bridges that bring distant cells into contact. A significant difference is the role of the primary cilium, a slender, tubulin-based protuberance of many vertebrate cells. Although the primary cilium is essential for Hh signaling in cells that have one, most Drosophila cells lack a primary cilium...

Development creates a vast array of forms and patterns with elegant economy, using a small vocabulary of pattern-generating proteins such as BMPs, FGFs and Hh in similar ways in many different contexts. Despite much theoretical and experimental work, the signaling mechanisms that disperse these morphogen signaling proteins remain controversial. Here, we review the conceptual background and evidence that establishes a fundamental and essential role for cytonemes as specialized filopodia that transport signaling proteins between signaling cells...

Decapentaplegic (Dpp), a Drosophila morphogen signaling protein, transfers directly at synapses made at sites of contact between cells that produce Dpp and cytonemes that extend from recipient cells. The Dpp that cytonemes receive moves together with activated receptors toward the recipient cell body in motile puncta. Genetic loss-of-function conditions for diaphanous, shibire, neuroglian, and capricious perturbed cytonemes by reducing their number or only the synapses they make with cells they target, and reduced cytoneme-mediated transport of Dpp and Dpp signaling...

In vivo time-lapse imaging and functional tests bring fresh evidence that the morphogen Hedgehog is conveyed to target cells via long filopodia extensions, dubbed cytonemes. This study provides the tools and conceptual framework to understand how cytonemes form and carry morphogens.

Hedgehog (Hh) signalling is important in development, stem cell biology and disease. In a variety of tissues, Hh acts as a morphogen to regulate growth and cell fate specification. Several hypotheses have been proposed to explain morphogen movement, one of which is transport along filopodia-like protrusions called cytonemes. Here, we analyse the mechanism underlying Hh movement in the wing disc and the abdominal epidermis of Drosophila melanogaster. We show that, in both epithelia, cells generate cytonemes in regions of Hh signalling...