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Paracrine Signaling Mediated at Cellcell Contacts

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Paracrine Signaling Mediated at Cellcell Contacts Insights & Perspectives Think again Paracrine signaling mediated at cellÀcell contacts Sougata Roy*,† and Thomas B. Kornberg Recent findings in several organ systems show that cytoneme-mediated systems. However, recent work that we signaling transports signaling proteins along cellular extensions and targets discuss here describes paracrine signal- cell-to-cell exchanges to synaptic contacts. This mechanism of paracrine ing that is instead contact-mediated and signaling may be a general one that is used by many (or all) cell types in many (or dependent on transient synapses that all) organs. We briefly review these findings in this perspective. We also non-neuronal cells make. These synap- describe the properties of several signaling systems that have previously been ses form at sites where specialized signaling filopodia called cytonemes interpreted to support a passive diffusion mechanism of signaling protein extend to contact target cells. dispersion, but can now be understood in the context of the cytoneme mechanism. Keywords: The classical model of .cytonemes; filopodia; morphogen; paracrine signaling; synapse; TGF-b paracrine signaling assumes that signals disperse by passive Introduction so that signals are within only 15À20 nm diffusion of their target receptors when they are Animal cells communicate over long released. Paracrine signaling, the third There are many paracrine signaling distances in various ways. Endocrine general mechanism, may be considered proteins that have been characterized. cells signal systemically by releasing to be a variant of endocrine signaling, They include the Fibroblast Growth hormones that disseminate in the vas- functioning at relatively short range Factors (FGFs) and other proteins that culature. Neurons also release signals, when secreted signals move limited activate Receptor Tyrosine Kinases, but they exchange information at syn- distances by passive diffusion in extra- TGF-b family members, Wnt proteins, apses that form where their axons and cellular fluid. The evidence that has Hedgehog (Hh) proteins, chemokines, dendrites contact target cells. Some supported this mechanism of paracrine as well as cytokines and other ligands axons extend over distances of several signaling has been obtained over many that activate the Jak-STAT pathway. All meters, effectively bridging distant cells years in many different experimental act at a distance, presumably by binding to receptors on target cells after diffus- ing from the producing cells that secrete DOI 10.1002/bies.201400122 them. In many cases, their distributions and patterns of signaling activation Cardiovascular Research Institute, University of extracellular matrix; EGF, epidermal growth indicate that they have spread out from California, San Francisco, CA, USA factor; FGF, fibroblast growth factor; FRAP, source cells, generating concentration fluorescence recovery after photobleaching; *Corresponding author: GAG, glycosaminoglycan; GFP, green fluores- gradients that decline with increasing Sougata Roy cent protein; GRASP, GFP reconstitution across distance, and cells that are the targets of E-mail: [email protected] synaptic partners; Hh, hedgehog; HSPG, heparan the signals respond in a concentration- sulfate proteoglycan; Ihog, interference hedge- dependent manner. The question we †Current Address: Department of Cell Biology and hog; LAP, latency-associated peptide; LTBP, Molecular Genetics, University of Maryland, latent TGF-b binding protein; Ptc, patched; address is not whether developmental College Park, MD, USA RTK, receptor tyrosine kinase; Shh, sonic hedge- fields have concentration gradients of hog; TGF-b, Transforming growth factor-b; Tkv, signaling proteins that regulate growth Abbreviations: thickveins. ASP, air sac primordium; A/P, anterior/posterior; and patterning, but how these proteins Btl, breathless; Dpp, decapentaplegic; ECM, disperse to distant cells. Bioessays 37: 25–33, ß 2014 WILEY Periodicals, Inc. www.bioessays-journal.com 25 S. Roy and T. B. Kornberg Insights & Perspectives..... The first report of non-autonomous reflected in the many names that have on the columnar cells, concentrating instructive signaling described a region been coined (e.g. thick filopodia, thin mostly on the region that produces the of the amphibian gastrula (the blastopore filopodia, growth cone filopodia, den- wing blade. dorsal lip) that induced gastrulation and dritic spines, invadopodia, gliapodia, Columnar cells in the wing blade embryogenesis after transfer to ectopic and myopodia). Cytonemes are the primordium that are outside of the Dpp locationsinrecipientembryos[1].This specialized filopodia that have been signaling center and respond to Dpp inductive capacity was not a general shown to traffic signaling proteins such extend cytonemes that orient toward property of embryo cells, suggesting that as morphogens, growth factors and cell the signaling center (Fig. 1A), and the the cells at the blastopore lip are specially determination factors. They have been properties of these cytonemes are con- endowed to make something (an “induc- observed in both vertebrate and inverte- sistent with the idea that they bridge the Think again er”) that instructs and patterns outlying brate systems and have been character- distance between Dpp producing and cells. This group of cells has been ized most extensively in Drosophila receiving cells, and move Dpp between branded a “developmental organizer”, larval tissues [4]. them [3, 20À22]. The presence and and the simplest mechanism that has In the Drosophila larval wing imagi- orientation of these cytonemes depend been considered is the synthesis and nal disc, cells in several signaling on active Dpp signaling À under con- secretion of an inducer molecule that centers produce signaling proteins that ditions of reduced Dpp expression disseminates by diffusion. The search for activate signal transduction in cells that (dppts at restrictive temperature), their such inducers took many forms and express receptors for these signaling number declines and they appear disor- succeeded only after many decades. proteins. One of the signaling centers dered and lack consistent orientation. Although the inducers were assumed to expresses the TGF-b family member They increase in number and appear to be small organic molecules that diffuse Decapentaplegic (Dpp); its Type 1 and have random orientations under condi- rapidly and pass efficiently from cell to Type 2 receptor subunits, Thickveins tional activation of ubiquitous, uniform cell, the known inducers are proteins (Tkv) and Punt, are expressed by all Dpp over-expression (Heat shock in- such as TGF-b,FGF,WntandHh. wing disc cells (reviewed in [9]). The duced expression of Dpp), and they Mathematical analyses and experimental Dpp signaling center is a 8À10 cell-wide orient toward somatic clones that over- studies show that diffusion may, within row that flanks the anterior side of the express Dpp ectopically. There is also certain parameters of diffusion coeffi- anterior/posterior (A/P) compartment evidence that they make direct contact cient, geometric tortuosity, viscosity, and border (Fig. 1A). The A/P border bisects and synapse with the cells in the Dpp extracellular volume, generate the ob- the wing disc along the entire dorso- signaling center. GFP reconstitution served gradients in the times available ventral axis. Cells in the Dpp signaling across synaptic partners (GRASP) is a during development (reviewed in [2]). center both produce and respond to technique that was developed to identi- The discovery of filopodia that serve as Dpp, although it is not known whether fy stable cellÀcell contacts that juxta- conduits that move signaling proteins their signal transduction responses pose cell membranes at distances between source and target cells adds a are due to autocrine, juxtacrine, or 20 nm, such as the synapses that new dimension and a radically different paracrine signaling. Outside of the neurons make. GRASP employs two mechanism for dissemination ([3] and signaling center and as far away as extracellular, membrane-tethered frag- reviewed in [4]). the disc flanks, cells also respond to ments of GFP that can self-assemble to Dpp, and evidence that Dpp moves generate fluorescent protein. The points from the cells that express it in order to of GRASP fluorescence at the Dpp Cytonemes mediate bind to Tkv on distant cells include signaling center in discs that express both GFP fluorescence and antibody one of the complementing GFP frag- paracrine signaling by staining in discs that overexpress Dpp: ments in the dpp domain and the other bridging signaling cells GFPinthesignalingcenter[10À14]. in the disc flanks (Fig. 1B) indicates that Dpp distributes in concentration gra- cells in these distant locations make Filopodia are thin cellular extensions dients that decline with increasing direct contact despite their separation that have been observed in many cell distance from the signaling center; by as much as 40 mm. The Dpp-depen- types. As described in excellent reviews the question how Dpp moves across dent cytonemes contain Tkv that con- [5À8], they have been assigned different the disc has been studied and dis- centrates in motile puncta and appear to roles to account for their presence in cussed extensively [15À19]. be specific for Dpp. various contexts (e.g. cell migration, cell The wing disc is a flattened sac Although these studies establish a adhesion, force generation, wound heal- composed of two connected epithelial strong correlation between the Dpp- ing, environmental
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