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The notochord defines the axial structure of all vertebrates during development. Notogenesis is a result of major cell reorganization in the mesoderm, the convergence and the extension of the axial cells. However, it is currently not fully understood how these processes act together in a coordinated way during notochord formation. The prechordal plate is an actively migrating cell population in the central mesoderm anterior to the trailing notochordal plate cells. We show that prechordal plate cells express Protocadherin 18a (Pcdh18a), a member of the cadherin superfamily. We find that Pcdh18a-mediated recycling of E-cadherin adhesion complexes transforms prechordal plate cells into a cohesive and fast migrating cell group. In turn, the prechordal plate cells subsequently instruct the trailing mesoderm. We simulated cell migration during early mesoderm formation using a lattice-based mathematical framework and predicted that the requirement for an anterior, local motile cell cluster could guide the intercalation and extension of the posterior, axial cells. Indeed, a grafting experiment validated the prediction and local Pcdh18a expression induced an ectopic prechordal plate-like cell group migrating towards the animal pole. Our findings indicate that the Pcdh18a is important for prechordal plate formation, which influences the trailing mesodermal cell sheet by orchestrating the morphogenesis of the notochord. Electronic supplementary material The online version of this article (10.1007/s00418-020-01887-5) contains supplementary material, which is available to authorized users.

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.

The notochord defines the axial structure of all vertebrates during development. Notogenesis is a result of major cell reorganization in the mesoderm, the convergence and the extension of the axial cells. However, it is currently not known how these processes act together in a coordinated way during notochord formation. Analysing the tissue flow, we determined the displacement of the axial mesoderm and identified, relative to the ectoderm, an actively-migrating notochord tip cell population and a group of trailing notochordal plate cells. Molecularly, these tip cells express Protocadherin18a, a member of the cadherin superfamily. We show that Pcdh18a-mediated recycling of E-cadherin adhesion complexes transforms these tip cells into a cohesive and fast migrating cell group. In turn, these tip cells subsequently instruct the trailing mesoderm. We simulated cell migration during early mesoderm formation using a lattice-based mathematical framework, and predicted that the requirement for an anterior, local motile cell cluster could guide the intercalation of the posterior, axial cells. Indeed, grafting experiments validated the predictions and induced ectopic notochord-like rods. Our findings indicate that the tip cells influence the trailing mesodermal cell sheet by inducing the formation of the notochord.

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.

Concentrated solutions of ultra-high molecular weight (HMW) emeraldine base (EB) are obtained when near stoichiometric quantities of 2-methyl-aziridine (2MA) per polymer repeat unit are co-dissolved in N-methyl-2-pyrrolidinone (NMP). Hydrogen bonds are formed between the secondary and tertiary EB nitrogen atoms found in the polymer repeat unit, and both the 2MA additive and the NMP solvent molecules. The rheological behavior of such solutions is quite different from that of EB/NMP solutions without 2MA. The principals of rheokinetic analysis are used to investigate the mechanism of the EB·2MA complex formation in the concentrated EB/NMP/2MA solution systems. The reaction rate, equilibrium constant and activation energy associated with the complexation are determined. Further, the stability of variable 2MA/EB molar composition and the kinetic effects due to variable temperature are reported for 20% (w/w) EB solutions.