TY - JOUR AB - Tension of the actomyosin cell cortex plays a key role in determining cell–cell contact growth and size. The level of cortical tension outside of the cell–cell contact, when pulling at the contact edge, scales with the total size to which a cell–cell contact can grow [J.-L. Maître et al., Science 338, 253–256 (2012)]. Here, we show in zebrafish primary germ-layer progenitor cells that this monotonic relationship only applies to a narrow range of cortical tension increase and that above a critical threshold, contact size inversely scales with cortical tension. This switch from cortical tension increasing to decreasing progenitor cell–cell contact size is caused by cortical tension promoting E-cadherin anchoring to the actomyosin cytoskeleton, thereby increasing clustering and stability of E-cadherin at the contact. After tension-mediated E-cadherin stabilization at the contact exceeds a critical threshold level, the rate by which the contact expands in response to pulling forces from the cortex sharply drops, leading to smaller contacts at physiologically relevant timescales of contact formation. Thus, the activity of cortical tension in expanding cell–cell contact size is limited by tension-stabilizing E-cadherin–actin complexes at the contact. AU - Slovakova, Jana AU - Sikora, Mateusz K AU - Arslan, Feyza N AU - Caballero Mancebo, Silvia AU - Krens, Gabriel AU - Kaufmann, Walter AU - Merrin, Jack AU - Heisenberg, Carl-Philipp J ID - 10766 IS - 8 JF - Proceedings of the National Academy of Sciences of the United States of America TI - Tension-dependent stabilization of E-cadherin limits cell-cell contact expansion in zebrafish germ-layer progenitor cells VL - 119 ER - TY - JOUR AB - The differentiation of cells depends on a precise control of their internal organization, which is the result of a complex dynamic interplay between the cytoskeleton, molecular motors, signaling molecules, and membranes. For example, in the developing neuron, the protein ADAP1 (ADP-ribosylation factor GTPase-activating protein [ArfGAP] with dual pleckstrin homology [PH] domains 1) has been suggested to control dendrite branching by regulating the small GTPase ARF6. Together with the motor protein KIF13B, ADAP1 is also thought to mediate delivery of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to the axon tip, thus contributing to PIP3 polarity. However, what defines the function of ADAP1 and how its different roles are coordinated are still not clear. Here, we studied ADAP1’s functions using in vitro reconstitutions. We found that KIF13B transports ADAP1 along microtubules, but that PIP3 as well as PI(3,4)P2 act as stop signals for this transport instead of being transported. We also demonstrate that these phosphoinositides activate ADAP1’s enzymatic activity to catalyze GTP hydrolysis by ARF6. Together, our results support a model for the cellular function of ADAP1, where KIF13B transports ADAP1 until it encounters high PIP3/PI(3,4)P2 concentrations in the plasma membrane. Here, ADAP1 disassociates from the motor to inactivate ARF6, promoting dendrite branching. AU - Düllberg, Christian F AU - Auer, Albert AU - Canigova, Nikola AU - Loibl, Katrin AU - Loose, Martin ID - 8988 IS - 1 JF - PNAS SN - 00278424 TI - In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1 VL - 118 ER - TY - JOUR AB - N-1-naphthylphthalamic acid (NPA) is a key inhibitor of directional (polar) transport of the hormone auxin in plants. For decades, it has been a pivotal tool in elucidating the unique polar auxin transport-based processes underlying plant growth and development. Its exact mode of action has long been sought after and is still being debated, with prevailing mechanistic schemes describing only indirect connections between NPA and the main transporters responsible for directional transport, namely PIN auxin exporters. Here we present data supporting a model in which NPA associates with PINs in a more direct manner than hitherto postulated. We show that NPA inhibits PIN activity in a heterologous oocyte system and that expression of NPA-sensitive PINs in plant, yeast, and oocyte membranes leads to specific saturable NPA binding. We thus propose that PINs are a bona fide NPA target. This offers a straightforward molecular basis for NPA inhibition of PIN-dependent auxin transport and a logical parsimonious explanation for the known physiological effects of NPA on plant growth, as well as an alternative hypothesis to interpret past and future results. We also introduce PIN dimerization and describe an effect of NPA on this, suggesting that NPA binding could be exploited to gain insights into structural aspects of PINs related to their transport mechanism. AU - Abas, Lindy AU - Kolb, Martina AU - Stadlmann, Johannes AU - Janacek, Dorina P. AU - Lukic, Kristina AU - Schwechheimer, Claus AU - Sazanov, Leonid A AU - Mach, Lukas AU - Friml, Jiří AU - Hammes, Ulrich Z. ID - 8993 IS - 1 JF - PNAS SN - 00278424 TI - Naphthylphthalamic acid associates with and inhibits PIN auxin transporters VL - 118 ER - TY - JOUR AB - Understanding to what extent stem cell potential is a cell-intrinsic property or an emergent behavior coming from global tissue dynamics and geometry is a key outstanding question of systems and stem cell biology. Here, we propose a theory of stem cell dynamics as a stochastic competition for access to a spatially localized niche, giving rise to a stochastic conveyor-belt model. Cell divisions produce a steady cellular stream which advects cells away from the niche, while random rearrangements enable cells away from the niche to be favorably repositioned. Importantly, even when assuming that all cells in a tissue are molecularly equivalent, we predict a common (“universal”) functional dependence of the long-term clonal survival probability on distance from the niche, as well as the emergence of a well-defined number of functional stem cells, dependent only on the rate of random movements vs. mitosis-driven advection. We test the predictions of this theory on datasets of pubertal mammary gland tips and embryonic kidney tips, as well as homeostatic intestinal crypts. Importantly, we find good agreement for the predicted functional dependency of the competition as a function of position, and thus functional stem cell number in each organ. This argues for a key role of positional fluctuations in dictating stem cell number and dynamics, and we discuss the applicability of this theory to other settings. AU - Corominas-Murtra, Bernat AU - Scheele, Colinda L.G.J. AU - Kishi, Kasumi AU - Ellenbroek, Saskia I.J. AU - Simons, Benjamin D. AU - Van Rheenen, Jacco AU - Hannezo, Edouard B ID - 8220 IS - 29 JF - Proceedings of the National Academy of Sciences of the United States of America TI - Stem cell lineage survival as a noisy competition for niche access VL - 117 ER - TY - JOUR AB - The brain represents and reasons probabilistically about complex stimuli and motor actions using a noisy, spike-based neural code. A key building block for such neural computations, as well as the basis for supervised and unsupervised learning, is the ability to estimate the surprise or likelihood of incoming high-dimensional neural activity patterns. Despite progress in statistical modeling of neural responses and deep learning, current approaches either do not scale to large neural populations or cannot be implemented using biologically realistic mechanisms. Inspired by the sparse and random connectivity of real neuronal circuits, we present a model for neural codes that accurately estimates the likelihood of individual spiking patterns and has a straightforward, scalable, efficient, learnable, and realistic neural implementation. This model’s performance on simultaneously recorded spiking activity of >100 neurons in the monkey visual and prefrontal cortices is comparable with or better than that of state-of-the-art models. Importantly, the model can be learned using a small number of samples and using a local learning rule that utilizes noise intrinsic to neural circuits. Slower, structural changes in random connectivity, consistent with rewiring and pruning processes, further improve the efficiency and sparseness of the resulting neural representations. Our results merge insights from neuroanatomy, machine learning, and theoretical neuroscience to suggest random sparse connectivity as a key design principle for neuronal computation. AU - Maoz, Ori AU - Tkačik, Gašper AU - Esteki, Mohamad Saleh AU - Kiani, Roozbeh AU - Schneidman, Elad ID - 8698 IS - 40 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 00278424 TI - Learning probabilistic neural representations with randomly connected circuits VL - 117 ER - TY - JOUR AB - In the high spin–orbit-coupled Sr2IrO4, the high sensitivity of the ground state to the details of the local lattice structure shows a large potential for the manipulation of the functional properties by inducing local lattice distortions. We use epitaxial strain to modify the Ir–O bond geometry in Sr2IrO4 and perform momentum-dependent resonant inelastic X-ray scattering (RIXS) at the metal and at the ligand sites to unveil the response of the low-energy elementary excitations. We observe that the pseudospin-wave dispersion for tensile-strained Sr2IrO4 films displays large softening along the [h,0] direction, while along the [h,h] direction it shows hardening. This evolution reveals a renormalization of the magnetic interactions caused by a strain-driven cross-over from anisotropic to isotropic interactions between the magnetic moments. Moreover, we detect dispersive electron–hole pair excitations which shift to lower (higher) energies upon compressive (tensile) strain, manifesting a reduction (increase) in the size of the charge gap. This behavior shows an intimate coupling between charge excitations and lattice distortions in Sr2IrO4, originating from the modified hopping elements between the t2g orbitals. Our work highlights the central role played by the lattice degrees of freedom in determining both the pseudospin and charge excitations of Sr2IrO4 and provides valuable information toward the control of the ground state of complex oxides in the presence of high spin–orbit coupling. AU - Paris, Eugenio AU - Tseng, Yi AU - Paerschke, Ekaterina AU - Zhang, Wenliang AU - Upton, Mary H AU - Efimenko, Anna AU - Rolfs, Katharina AU - McNally, Daniel E AU - Maurel, Laura AU - Naamneh, Muntaser AU - Caputo, Marco AU - Strocov, Vladimir N AU - Wang, Zhiming AU - Casa, Diego AU - Schneider, Christof W AU - Pomjakushina, Ekaterina AU - Wohlfeld, Krzysztof AU - Radovic, Milan AU - Schmitt, Thorsten ID - 8699 IS - 40 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 00278424 TI - Strain engineering of the charge and spin-orbital interactions in Sr2IrO4 VL - 117 ER - TY - JOUR AB - In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene-expression levels that is compatible with in vivo and in vitro biophysical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In nonequilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal nonequilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity, and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate,” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in nonequilibrium models is in a trade-off with gene-expression noise, predicting bursty dynamics—an experimentally observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space of nonequilibrium enhancer models to a much smaller subspace that optimally realizes biological function, we deliver a rich class of models that could be tractably inferred from data in the near future. AU - Grah, Rok AU - Zoller, Benjamin AU - Tkačik, Gašper ID - 9000 IS - 50 JF - PNAS SN - 00278424 TI - Nonequilibrium models of optimal enhancer function VL - 117 ER - TY - JOUR AB - Pulsating flows through tubular geometries are laminar provided that velocities are moderate. This in particular is also believed to apply to cardiovascular flows where inertial forces are typically too low to sustain turbulence. On the other hand, flow instabilities and fluctuating shear stresses are held responsible for a variety of cardiovascular diseases. Here we report a nonlinear instability mechanism for pulsating pipe flow that gives rise to bursts of turbulence at low flow rates. Geometrical distortions of small, yet finite, amplitude are found to excite a state consisting of helical vortices during flow deceleration. The resulting flow pattern grows rapidly in magnitude, breaks down into turbulence, and eventually returns to laminar when the flow accelerates. This scenario causes shear stress fluctuations and flow reversal during each pulsation cycle. Such unsteady conditions can adversely affect blood vessels and have been shown to promote inflammation and dysfunction of the shear stress-sensitive endothelial cell layer. AU - Xu, Duo AU - Varshney, Atul AU - Ma, Xingyu AU - Song, Baofang AU - Riedl, Michael AU - Avila, Marc AU - Hof, Björn ID - 7932 IS - 21 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 00278424 TI - Nonlinear hydrodynamic instability and turbulence in pulsatile flow VL - 117 ER - TY - JOUR AB - The formation of self-organized patterns is key to the morphogenesis of multicellular organisms, although a comprehensive theory of biological pattern formation is still lacking. Here, we propose a minimal model combining tissue mechanics with morphogen turnover and transport to explore routes to patterning. Our active description couples morphogen reaction and diffusion, which impact cell differentiation and tissue mechanics, to a two-phase poroelastic rheology, where one tissue phase consists of a poroelastic cell network and the other one of a permeating extracellular fluid, which provides a feedback by actively transporting morphogens. While this model encompasses previous theories approximating tissues to inert monophasic media, such as Turing’s reaction–diffusion model, it overcomes some of their key limitations permitting pattern formation via any two-species biochemical kinetics due to mechanically induced cross-diffusion flows. Moreover, we describe a qualitatively different advection-driven Keller–Segel instability which allows for the formation of patterns with a single morphogen and whose fundamental mode pattern robustly scales with tissue size. We discuss the potential relevance of these findings for tissue morphogenesis. AU - Recho, Pierre AU - Hallou, Adrien AU - Hannezo, Edouard B ID - 6191 IS - 12 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 00278424 TI - Theory of mechanochemical patterning in biphasic biological tissues VL - 116 ER -