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Cells of multicellular organisms are in continuous conversation with the neighbouring cells. The sender cells signal the receiver cells to influence their behaviour in transport, metabolism, motility, division, and growth. How cells communicate with each other can be categorized by biochemical signalling processes, which can be characterised by the distance between the sender cell and the receiver cell. Existing classifications describe autocrine signals as those where the sender cell is identical to the receiver cell. Complementary to this scenario, paracrine signalling describes signalling between a sender cell and a different receiver cell. Finally, juxtacrine signalling describes the exchange of information between adjacent cells by direct cell contact, whereas endocrine signalling describes the exchange of information, e.g., by hormones between distant cells or even organs through the bloodstream. In the last two decades, however, an unexpected communication mechanism has been identified which uses cell protrusions to exchange chemical signals by direct contact over long distances. These signalling protrusions can deliver signals in both ways, from sender to receiver and vice versa. We are starting to understand the morphology and function of these signalling protrusions in many tissues and this accumulation of findings forces us to revise our view of contact-dependent cell communication. In this review, we will focus on the two main categories of signalling protrusions, cytonemes and tunnelling nanotubes. These signalling protrusions emerge as essential structural components of a vibrant communication network in the development and tissue homeostasis of any multicellular organism.

Signaling filopodia, termed cytonemes, are dynamic actin-based membrane structures that regulate the exchange of signaling molecules and their receptors within tissues. However, how cytoneme formation is regulated remains unclear. Here, we show that Wnt/planar cell polarity (PCP) autocrine signaling controls the emergence of cytonemes, and that cytonemes subsequently control paracrine Wnt/β-catenin signal activation. Upon binding of the Wnt family member Wnt8a, the receptor tyrosine kinase Ror2 becomes activated. Ror2/PCP signaling leads to the induction of cytonemes, which mediate the transport of Wnt8a to neighboring cells. In the Wnt-receiving cells, Wnt8a on cytonemes triggers Wnt/β-catenin-dependent gene transcription and proliferation. We show that cytoneme-based Wnt transport operates in diverse processes, including zebrafish development, murine intestinal crypt and human cancer organoids, demonstrating that Wnt transport by cytonemes and its control via the Ror2 pathway is highly conserved in vertebrates., eLife digest Communication helps the cells that make up tissues and organs to work together as a team. One way that cells share information with each other as tissues grow and develop is by exchanging signaling proteins. These interact with receptors on the surface of other cells; this causes the cell to change how it behaves. The Wnt family of signaling proteins orchestrate organ development. Wnt proteins influence which types of cells develop, how fast they divide, and how and when they move. Relatively few cells, or small groups of cells, in developing tissues produce Wnt proteins, while larger groups nearby respond to the signals. We do not fully understand how Wnt proteins travel between cells, but recent work revealed an unexpected mechanism – cells seem to hand-deliver their messages. Finger-like structures called cytonemes grow out of the cell membrane and carry Wnt proteins to their destination. If the cytonemes do not form properly the target cells do not behave correctly, which can lead to severe tissue malformation. Mattes et al. have now investigated how cytonemes form using a combination of state-of-the-art genetic and high-resolution imaging techniques. In initial experiments involving zebrafish cells that were grown in the laboratory, Mattes et al. found that the Wnt proteins kick start their own transport; before they travel to their destination, they act on the cells that made them. A Wnt protein called Wnt8a activates the receptor Ror2 on the surface of the signal-producing cell. Ror2 then triggers signals inside the cell that begin the assembly of the cytonemes. The more Ror2 is activated, the more cytonemes the cell makes, and the more Wnt signals it can send out. This mechanism operates in various tissues: Ror2 also controls the cytoneme transport process in living zebrafish embryos, the mouse intestine and human stomach tumors. This knowledge will help researchers to develop new ways to control Wnt signaling, which could help to produce new treatments for diseases ranging from cancers (for example in the stomach and bowel) to degenerative diseases such as Alzheimer’s disease.

During the early stages of embryonic development, various means of cell communication orchestrate tissue development within the highly dynamic environment. Signalling gradients of morphogens determine cell fates, tissue generation, and in the long run organs of the final organism. In our research we focus on the distribution and effects of Wnt8a, a morphogen involved in the development and differentiation of the brain. In a previous work we were able to show experimentally that this protein is distributed by a novel short-range propagation mechanism by means of specialized filopodia[1]. Here we present our results on extending these simulations of a simple flat tissue towards a more accurate description of the embryo in a 3D environment.The simulation models the tissue expansion on a 3D spherical surface and morphogen distribution via filopodia formation. It integrates length and angle distributions as well as growth frequencies of the filopodia, cell migration, and a slight ligand decay consistently with experimental measurements. Additionally it extends our previous model by explicitly considering the movement of the Wnt8a source.[1] Filopodia-based Wnt transport during vertebrate tissue patterning. Stanganello, E., Hagemann, A. I. H., Mattes, B., Sinner, C., Meyen, D., Weber, S., Schug, A., Raz, E. and Scholpp, S., Nature Communications 6, 2015

Paracrine Wnt/β-catenin signalling is important during developmental processes, tissue regeneration and stem cell regulation. Wnt proteins are morphogens, which form concentration gradients across responsive tissues. Little is known about the transport mechanism for these lipid-modified signalling proteins in vertebrates. Here we show that Wnt8a is transported on actin-based filopodia to contact responding cells and activate signalling during neural plate formation in zebrafish. Cdc42/N-Wasp regulates the formation of these Wnt-positive filopodia. Enhanced formation of filopodia increases the effective signalling range of Wnt by facilitating spreading. Consistently, reduction in filopodia leads to a restricted distribution of the ligand and a limited signalling range. Using a simulation, we provide evidence that such a short-range transport system for Wnt has a long-range signalling function. Indeed, we show that a filopodia-based transport system for Wnt8a controls anteroposterior patterning of the neural plate during vertebrate gastrulation.

Tissue development is a key process in living organisms. An essential component for these developmental processes - but also for tissue regeneration and stem cell regulation - is the communication of cells by paracrine signaling. Following the French flag model, these processes are responsive to concentration gradients of signal carrying molecules, so-called morphogens. The highly conserved family of Wnt proteins can act as morphogens and represents important regulators of all these processes. After secretion, specific transport mechanism must ensure proper distribution of the morphogen. Experimental studies in zebrafish embryos and human kidney cells have given first evidence for a novel short-range transport of Wnt morphogens from the Wnt active tissue towards receiving cells using cell protrusions, so-called filopodia, as mediating agent. These specialized filopodia transmit signaling proteins between communicating cells and allow a high degree of control of propagation speed, direction and concentration of the transmitted ligand. The crucial question is how this novel short-range mechanism can result in a long-range gradient of morphogen molecules covering the complete responsive tissue. In order to give an answer to this question and address the theoretical feasibility of the new model we have set up complementary Monte Carlo simulations. The simulation iteratively reproduces ligand production, cell migration, and a slight ligand decay in concordance with experimentally measured boundary conditions. In a filopodia mediated transport system the major parameters are not anymore diffusion rate, cell adhesion, and concentration of the ligand but length, angle distribution, and growth frequency of filopodia. During the simulation we were able to identify key parameters of the underlying mechanism and quantitatively reproduce our experimental data. These results provide evidence that a filopodia based short-range transport system for Wnt has long-range signalling function.