TY - JOUR AB - Embryo morphogenesis relies on highly coordinated movements of different tissues. However, remarkably little is known about how tissues coordinate their movements to shape the embryo. In zebrafish embryogenesis, coordinated tissue movements first become apparent during “doming,” when the blastoderm begins to spread over the yolk sac, a process involving coordinated epithelial surface cell layer expansion and mesenchymal deep cell intercalations. Here, we find that active surface cell expansion represents the key process coordinating tissue movements during doming. By using a combination of theory and experiments, we show that epithelial surface cells not only trigger blastoderm expansion by reducing tissue surface tension, but also drive blastoderm thinning by inducing tissue contraction through radial deep cell intercalations. Thus, coordinated tissue expansion and thinning during doming relies on surface cells simultaneously controlling tissue surface tension and radial tissue contraction. AU - Morita, Hitoshi AU - Grigolon, Silvia AU - Bock, Martin AU - Krens, Gabriel AU - Salbreux, Guillaume AU - Heisenberg, Carl-Philipp J ID - 1067 IS - 4 JF - Developmental Cell SN - 15345807 TI - The physical basis of coordinated tissue spreading in zebrafish gastrulation VL - 40 ER - TY - JOUR AB - Many organ surfaces are covered by a protective epithelial-cell layer. It emerges that such layers are maintained by cell stretching that triggers cell division mediated by the force-sensitive ion-channel protein Piezo1. See Letter p.118 AU - Heisenberg, Carl-Philipp J ID - 1025 IS - 7643 JF - Nature SN - 00280836 TI - Cell biology: Stretched divisions VL - 543 ER - TY - JOUR AB - Eukaryotic cells store their chromosomes in a single nucleus. This is important to maintain genomic integrity, as chromosomes packaged into separate nuclei (micronuclei) are prone to massive DNA damage. During mitosis, higher eukaryotes disassemble their nucleus and release individualized chromosomes for segregation. How numerous chromosomes subsequently reform a single nucleus has remained unclear. Using image-based screening of human cells, we identified barrier-to-autointegration factor (BAF) as a key factor guiding membranes to form a single nucleus. Unexpectedly, nuclear assembly does not require BAF?s association with inner nuclear membrane proteins but instead relies on BAF?s ability to bridge distant DNA sites. Live-cell imaging and in vitro reconstitution showed that BAF enriches around the mitotic chromosome ensemble to induce a densely cross-bridged chromatin layer that is mechanically stiff and limits membranes to the surface. Our study reveals that BAF-mediated changes in chromosome mechanics underlie nuclear assembly with broad implications for proper genome function. AU - Samwer, Matthias AU - Schneider, Maximilian AU - Hoefler, Rudolf AU - Schmalhorst, Philipp S AU - Jude, Julian AU - Zuber, Johannes AU - Gerlic, Daniel ID - 803 IS - 5 JF - Cell SN - 00928674 TI - DNA cross-bridging shapes a single nucleus from a set of mitotic chromosomes VL - 170 ER - TY - JOUR AB - Polysaccharides (carbohydrates) are key regulators of a large number of cell biological processes. However, precise biochemical or genetic manipulation of these often complex structures is laborious and hampers experimental structure–function studies. Molecular Dynamics (MD) simulations provide a valuable alternative tool to generate and test hypotheses on saccharide function. Yet, currently used MD force fields often overestimate the aggregation propensity of polysaccharides, affecting the usability of those simulations. Here we tested MARTINI, a popular coarse-grained (CG) force field for biological macromolecules, for its ability to accurately represent molecular forces between saccharides. To this end, we calculated a thermodynamic solution property, the second virial coefficient of the osmotic pressure (B22). Comparison with light scattering experiments revealed a nonphysical aggregation of a prototypical polysaccharide in MARTINI, pointing at an imbalance of the nonbonded solute–solute, solute–water, and water–water interactions. This finding also applies to smaller oligosaccharides which were all found to aggregate in simulations even at moderate concentrations, well below their solubility limit. Finally, we explored the influence of the Lennard-Jones (LJ) interaction between saccharide molecules and propose a simple scaling of the LJ interaction strength that makes MARTINI more reliable for the simulation of saccharides. AU - Schmalhorst, Philipp S AU - Deluweit, Felix AU - Scherrers, Roger AU - Heisenberg, Carl-Philipp J AU - Sikora, Mateusz K ID - 804 IS - 10 JF - Journal of Chemical Theory and Computation SN - 15499618 TI - Overcoming the limitations of the MARTINI force field in simulations of polysaccharides VL - 13 ER - TY - THES AB - Cell-cell contact formation constitutes the first step in the emergence of multicellularity in evolution, thereby allowing the differentiation of specialized cell types. In metazoan development, cell-cell contact formation is thought to influence cell fate specification, and cell fate specification has been implicated in cell-cell contact formation. However, remarkably little is yet known about whether and how the interaction and feedback between cell-cell contact formation and cell fate specification affect development. Here we identify a positive feedback loop between cell-cell contact duration, morphogen signaling and mesendoderm cell fate specification during zebrafish gastrulation. We show that long lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for proper ppl cell fate specification. We further show that Nodal signalling romotes ppl cell-cell contact duration, thereby generating an effective positive feedback loop between ppl cell-cell contact duration and cell fate specification. Finally, by using a combination of theoretical modeling and experimentation, we show that this feedback loop determines whether anterior axial mesendoderm cells become ppl progenitors or, instead, turn into endoderm progenitors. Our findings reveal that the gene regulatory networks leading to cell fate diversification within the developing embryo are controlled by the interdependent activities of cell-cell signaling and contact formation. AU - Barone, Vanessa ID - 961 SN - 2663-337X TI - Cell adhesion and cell fate: An effective feedback loop during zebrafish gastrulation ER - TY - JOUR AB - During animal development, cell-fate-specific changes in gene expression can modify the material properties of a tissue and drive tissue morphogenesis. While mechanistic insights into the genetic control of tissue-shaping events are beginning to emerge, how tissue morphogenesis and mechanics can reciprocally impact cell-fate specification remains relatively unexplored. Here we review recent findings reporting how multicellular morphogenetic events and their underlying mechanical forces can feed back into gene regulatory pathways to specify cell fate. We further discuss emerging techniques that allow for the direct measurement and manipulation of mechanical signals in vivo, offering unprecedented access to study mechanotransduction during development. Examination of the mechanical control of cell fate during tissue morphogenesis will pave the way to an integrated understanding of the design principles that underlie robust tissue patterning in embryonic development. AU - Chan, Chii AU - Heisenberg, Carl-Philipp J AU - Hiiragi, Takashi ID - 728 IS - 18 JF - Current Biology SN - 09609822 TI - Coordination of morphogenesis and cell fate specification in development VL - 27 ER - TY - JOUR AB - The cellular mechanisms allowing tissues to efficiently regenerate are not fully understood. In this issue of Developmental Cell, Cao et al. (2017)) discover that during zebrafish heart regeneration, epicardial cells at the leading edge of regenerating tissue undergo endoreplication, possibly due to increased tissue tension, thereby boosting their regenerative capacity. AU - Spiro, Zoltan P AU - Heisenberg, Carl-Philipp J ID - 729 IS - 6 JF - Developmental Cell SN - 15345807 TI - Regeneration tensed up polyploidy takes the lead VL - 42 ER - TY - JOUR AB - Roots navigate through soil integrating environmental signals to orient their growth. The Arabidopsis root is a widely used model for developmental, physiological and cell biological studies. Live imaging greatly aids these efforts, but the horizontal sample position and continuous root tip displacement present significant difficulties. Here, we develop a confocal microscope setup for vertical sample mounting and integrated directional illumination. We present TipTracker – a custom software for automatic tracking of diverse moving objects usable on various microscope setups. Combined, this enables observation of root tips growing along the natural gravity vector over prolonged periods of time, as well as the ability to induce rapid gravity or light stimulation. We also track migrating cells in the developing zebrafish embryo, demonstrating the utility of this system in the acquisition of high-resolution data sets of dynamic samples. We provide detailed descriptions of the tools enabling the easy implementation on other microscopes. AU - Von Wangenheim, Daniel AU - Hauschild, Robert AU - Fendrych, Matyas AU - Barone, Vanessa AU - Benková, Eva AU - Friml, Jirí ID - 946 JF - eLife TI - Live tracking of moving samples in confocal microscopy for vertically grown roots VL - 6 ER - TY - JOUR AB - The segregation of different cell types into distinct tissues is a fundamental process in metazoan development. Differences in cell adhesion and cortex tension are commonly thought to drive cell sorting by regulating tissue surface tension (TST). However, the role that differential TST plays in cell segregation within the developing embryo is as yet unclear. Here, we have analyzed the role of differential TST for germ layer progenitor cell segregation during zebrafish gastrulation. Contrary to previous observations that differential TST drives germ layer progenitor cell segregation in vitro, we show that germ layers display indistinguishable TST within the gastrulating embryo, arguing against differential TST driving germ layer progenitor cell segregation in vivo. We further show that the osmolarity of the interstitial fluid (IF) is an important factor that influences germ layer TST in vivo, and that lower osmolarity of the IF compared with standard cell culture medium can explain why germ layers display differential TST in culture but not in vivo. Finally, we show that directed migration of mesendoderm progenitors is required for germ layer progenitor cell segregation and germ layer formation. AU - Krens, Gabriel AU - Veldhuis, Jim AU - Barone, Vanessa AU - Capek, Daniel AU - Maître, Jean-Léon AU - Brodland, Wayne AU - Heisenberg, Carl-Philipp J ID - 676 IS - 10 JF - Development SN - 09501991 TI - Interstitial fluid osmolarity modulates the action of differential tissue surface tension in progenitor cell segregation during gastrulation VL - 144 ER - TY - JOUR AB - During embryonic development, mechanical forces are essential for cellular rearrangements driving tissue morphogenesis. Here, we show that in the early zebrafish embryo, friction forces are generated at the interface between anterior axial mesoderm (prechordal plate, ppl) progenitors migrating towards the animal pole and neurectoderm progenitors moving in the opposite direction towards the vegetal pole of the embryo. These friction forces lead to global rearrangement of cells within the neurectoderm and determine the position of the neural anlage. Using a combination of experiments and simulations, we show that this process depends on hydrodynamic coupling between neurectoderm and ppl as a result of E-cadherin-mediated adhesion between those tissues. Our data thus establish the emergence of friction forces at the interface between moving tissues as a critical force-generating process shaping the embryo. AU - Smutny, Michael AU - Ákos, Zsuzsa AU - Grigolon, Silvia AU - Shamipour, Shayan AU - Ruprecht, Verena AU - Capek, Daniel AU - Behrndt, Martin AU - Papusheva, Ekaterina AU - Tada, Masazumi AU - Hof, Björn AU - Vicsek, Tamás AU - Salbreux, Guillaume AU - Heisenberg, Carl-Philipp J ID - 661 JF - Nature Cell Biology SN - 14657392 TI - Friction forces position the neural anlage VL - 19 ER - TY - JOUR AB - Cell-cell contact formation constitutes an essential step in evolution, leading to the differentiation of specialized cell types. However, remarkably little is known about whether and how the interplay between contact formation and fate specification affects development. Here, we identify a positive feedback loop between cell-cell contact duration, morphogen signaling, and mesendoderm cell-fate specification during zebrafish gastrulation. We show that long-lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for ppl cell-fate specification. We further show that Nodal signaling promotes ppl cell-cell contact duration, generating a positive feedback loop between ppl cell-cell contact duration and cell-fate specification. Finally, by combining mathematical modeling and experimentation, we show that this feedback determines whether anterior axial mesendoderm cells become ppl or, instead, turn into endoderm. Thus, the interdependent activities of cell-cell signaling and contact formation control fate diversification within the developing embryo. AU - Barone, Vanessa AU - Lang, Moritz AU - Krens, Gabriel AU - Pradhan, Saurabh AU - Shamipour, Shayan AU - Sako, Keisuke AU - Sikora, Mateusz K AU - Guet, Calin C AU - Heisenberg, Carl-Philipp J ID - 735 IS - 2 JF - Developmental Cell SN - 15345807 TI - An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate VL - 43 ER - TY - JOUR AB - Nonadherent polarized cells have been observed to have a pearlike, elongated shape. Using a minimal model that describes the cell cortex as a thin layer of contractile active gel, we show that the anisotropy of active stresses, controlled by cortical viscosity and filament ordering, can account for this morphology. The predicted shapes can be determined from the flow pattern only; they prove to be independent of the mechanism at the origin of the cortical flow, and are only weakly sensitive to the cytoplasmic rheology. In the case of actin flows resulting from a contractile instability, we propose a phase diagram of three-dimensional cell shapes that encompasses nonpolarized spherical, elongated, as well as oblate shapes, all of which have been observed in experiment. AU - Callan Jones, Andrew AU - Ruprecht, Verena AU - Wieser, Stefan AU - Heisenberg, Carl-Philipp J AU - Voituriez, Raphaël ID - 1239 IS - 2 JF - Physical Review Letters TI - Cortical flow-driven shapes of nonadherent cells VL - 116 ER - TY - JOUR AB - Actin and myosin assemble into a thin layer of a highly dynamic network underneath the membrane of eukaryotic cells. This network generates the forces that drive cell- and tissue-scale morphogenetic processes. The effective material properties of this active network determine large-scale deformations and other morphogenetic events. For example, the characteristic time of stress relaxation (the Maxwell time τM) in the actomyosin sets the timescale of large-scale deformation of the cortex. Similarly, the characteristic length of stress propagation (the hydrodynamic length λ) sets the length scale of slow deformations, and a large hydrodynamic length is a prerequisite for long-ranged cortical flows. Here we introduce a method to determine physical parameters of the actomyosin cortical layer in vivo directly from laser ablation experiments. For this we investigate the cortical response to laser ablation in the one-cell-stage Caenorhabditis elegans embryo and in the gastrulating zebrafish embryo. These responses can be interpreted using a coarse-grained physical description of the cortex in terms of a two-dimensional thin film of an active viscoelastic gel. To determine the Maxwell time τM, the hydrodynamic length λ, the ratio of active stress ζΔμ, and per-area friction γ, we evaluated the response to laser ablation in two different ways: by quantifying flow and density fields as a function of space and time, and by determining the time evolution of the shape of the ablated region. Importantly, both methods provide best-fit physical parameters that are in close agreement with each other and that are similar to previous estimates in the two systems. Our method provides an accurate and robust means for measuring physical parameters of the actomyosin cortical layer. It can be useful for investigations of actomyosin mechanics at the cellular-scale, but also for providing insights into the active mechanics processes that govern tissue-scale morphogenesis. AU - Saha, Arnab AU - Nishikawa, Masatoshi AU - Behrndt, Martin AU - Heisenberg, Carl-Philipp J AU - Julicher, Frank AU - Grill, Stephan ID - 1249 IS - 6 JF - Biophysical Journal TI - Determining physical properties of the cell cortex VL - 110 ER - TY - JOUR AB - Background: High directional persistence is often assumed to enhance the efficiency of chemotactic migration. Yet, cells in vivo usually display meandering trajectories with relatively low directional persistence, and the control and function of directional persistence during cell migration in three-dimensional environments are poorly understood. Results: Here, we use mesendoderm progenitors migrating during zebrafish gastrulation as a model system to investigate the control of directional persistence during migration in vivo. We show that progenitor cells alternate persistent run phases with tumble phases that result in cell reorientation. Runs are characterized by the formation of directed actin-rich protrusions and tumbles by enhanced blebbing. Increasing the proportion of actin-rich protrusions or blebs leads to longer or shorter run phases, respectively. Importantly, both reducing and increasing run phases result in larger spatial dispersion of the cells, indicative of reduced migration precision. A physical model quantitatively recapitulating the migratory behavior of mesendoderm progenitors indicates that the ratio of tumbling to run times, and thus the specific degree of directional persistence of migration, are critical for optimizing migration precision. Conclusions: Together, our experiments and model provide mechanistic insight into the control of migration directionality for cells moving in three-dimensional environments that combine different protrusion types, whereby the proportion of blebs to actin-rich protrusions determines the directional persistence and precision of movement by regulating the ratio of tumbling to run times. AU - Diz Muñoz, Alba AU - Romanczuk, Pawel AU - Yu, Weimiao AU - Bergert, Martin AU - Ivanovitch, Kenzo AU - Salbreux, Guillame AU - Heisenberg, Carl-Philipp J AU - Paluch, Ewa ID - 1271 IS - 1 JF - BMC Biology TI - Steering cell migration by alternating blebs and actin-rich protrusions VL - 14 ER - TY - JOUR AU - Callan Jones, Andrew AU - Ruprecht, Verena AU - Wieser, Stefan AU - Heisenberg, Carl-Philipp J AU - Voituriez, Raphaël ID - 1275 IS - 13 JF - Physical Review Letters TI - Callan-Jones et al. Reply VL - 117 ER - TY - JOUR AU - Schwayer, Cornelia AU - Sikora, Mateusz K AU - Slovakova, Jana AU - Kardos, Roland AU - Heisenberg, Carl-Philipp J ID - 1096 IS - 6 JF - Developmental Cell TI - Actin rings of power VL - 37 ER - TY - JOUR AB - During metazoan development, the temporal pattern of morphogen signaling is critical for organizing cell fates in space and time. Yet, tools for temporally controlling morphogen signaling within the embryo are still scarce. Here, we developed a photoactivatable Nodal receptor to determine how the temporal pattern of Nodal signaling affects cell fate specification during zebrafish gastrulation. By using this receptor to manipulate the duration of Nodal signaling in vivo by light, we show that extended Nodal signaling within the organizer promotes prechordal plate specification and suppresses endoderm differentiation. Endoderm differentiation is suppressed by extended Nodal signaling inducing expression of the transcriptional repressor goosecoid (gsc) in prechordal plate progenitors, which in turn restrains Nodal signaling from upregulating the endoderm differentiation gene sox17 within these cells. Thus, optogenetic manipulation of Nodal signaling identifies a critical role of Nodal signaling duration for organizer cell fate specification during gastrulation. AU - Sako, Keisuke AU - Pradhan, Saurabh AU - Barone, Vanessa AU - Inglés Prieto, Álvaro AU - Mueller, Patrick AU - Ruprecht, Verena AU - Capek, Daniel AU - Galande, Sanjeev AU - Janovjak, Harald L AU - Heisenberg, Carl-Philipp J ID - 1100 IS - 3 JF - Cell Reports TI - Optogenetic control of nodal signaling reveals a temporal pattern of nodal signaling regulating cell fate specification during gastrulation VL - 16 ER - TY - JOUR AB - Cell movement has essential functions in development, immunity, and cancer. Various cell migration patterns have been reported, but no general rule has emerged so far. Here, we show on the basis of experimental data in vitro and in vivo that cell persistence, which quantifies the straightness of trajectories, is robustly coupled to cell migration speed. We suggest that this universal coupling constitutes a generic law of cell migration, which originates in the advection of polarity cues by an actin cytoskeleton undergoing flows at the cellular scale. Our analysis relies on a theoretical model that we validate by measuring the persistence of cells upon modulation of actin flow speeds and upon optogenetic manipulation of the binding of an actin regulator to actin filaments. Beyond the quantitative prediction of the coupling, the model yields a generic phase diagram of cellular trajectories, which recapitulates the full range of observed migration patterns. AU - Maiuri, Paolo AU - Rupprecht, Jean AU - Wieser, Stefan AU - Ruprecht, Verena AU - Bénichou, Olivier AU - Carpi, Nicolas AU - Coppey, Mathieu AU - De Beco, Simon AU - Gov, Nir AU - Heisenberg, Carl-Philipp J AU - Lage Crespo, Carolina AU - Lautenschlaeger, Franziska AU - Le Berre, Maël AU - Lennon Duménil, Ana AU - Raab, Matthew AU - Thiam, Hawa AU - Piel, Matthieu AU - Sixt, Michael K AU - Voituriez, Raphaël ID - 1553 IS - 2 JF - Cell TI - Actin flows mediate a universal coupling between cell speed and cell persistence VL - 161 ER - TY - JOUR AB - In animal embryos, morphogen gradients determine tissue patterning and morphogenesis. Shyer et al. provide evidence that, during vertebrate gut formation, tissue folding generates graded activity of signals required for subsequent steps of gut growth and differentiation, thereby revealing an intriguing link between tissue morphogenesis and morphogen gradient formation. AU - Bollenbach, Mark Tobias AU - Heisenberg, Carl-Philipp J ID - 1581 IS - 3 JF - Cell TI - Gradients are shaping up VL - 161 ER - TY - JOUR AB - Vertebrates have a unique 3D body shape in which correct tissue and organ shape and alignment are essential for function. For example, vision requires the lens to be centred in the eye cup which must in turn be correctly positioned in the head. Tissue morphogenesis depends on force generation, force transmission through the tissue, and response of tissues and extracellular matrix to force. Although a century ago D'Arcy Thompson postulated that terrestrial animal body shapes are conditioned by gravity, there has been no animal model directly demonstrating how the aforementioned mechano-morphogenetic processes are coordinated to generate a body shape that withstands gravity. Here we report a unique medaka fish (Oryzias latipes) mutant, hirame (hir), which is sensitive to deformation by gravity. hir embryos display a markedly flattened body caused by mutation of YAP, a nuclear executor of Hippo signalling that regulates organ size. We show that actomyosin-mediated tissue tension is reduced in hir embryos, leading to tissue flattening and tissue misalignment, both of which contribute to body flattening. By analysing YAP function in 3D spheroids of human cells, we identify the Rho GTPase activating protein ARHGAP18 as an effector of YAP in controlling tissue tension. Together, these findings reveal a previously unrecognised function of YAP in regulating tissue shape and alignment required for proper 3D body shape. Understanding this morphogenetic function of YAP could facilitate the use of embryonic stem cells to generate complex organs requiring correct alignment of multiple tissues. AU - Porazinski, Sean AU - Wang, Huijia AU - Asaoka, Yoichi AU - Behrndt, Martin AU - Miyamoto, Tatsuo AU - Morita, Hitoshi AU - Hata, Shoji AU - Sasaki, Takashi AU - Krens, Gabriel AU - Osada, Yumi AU - Asaka, Satoshi AU - Momoi, Akihiro AU - Linton, Sarah AU - Miesfeld, Joel AU - Link, Brian AU - Senga, Takeshi AU - Castillo Morales, Atahualpa AU - Urrutia, Araxi AU - Shimizu, Nobuyoshi AU - Nagase, Hideaki AU - Matsuura, Shinya AU - Bagby, Stefan AU - Kondoh, Hisato AU - Nishina, Hiroshi AU - Heisenberg, Carl-Philipp J AU - Furutani Seiki, Makoto ID - 1817 IS - 7551 JF - Nature TI - YAP is essential for tissue tension to ensure vertebrate 3D body shape VL - 521 ER -