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Modes, C. D.

Publications and source records attributed to Modes, C. D..

18 recordsLinked to original sources
bioRxiv2026

Multiple contact sites between cells and the vitelline envelope coordinate tissue flows in Drosophila gastrulation

Gastrulation is thought to be driven primarily by forces generated within individual cells. These cell-intrinsic forces collectively induce tissue-scale flows and transform the monolayered embryo into a multilayered structure. However, as the embryo constitutes a mechanically closed system, these flows must be balanced by regions of resistance or anchoring to enable asymmetric morphogenesis. In the Drosophila embryo, integrin-mediated attachment of the blastoderm to the vitelline envelope has been shown to stabilize germ band extension at the organismal scale. Disrupting such an attachment leads to a characteristic twisting phenotype. Yet, how this attachment shapes concurrent global morphogenetic events remains unclear. We discovered that the integrin -subunit scab, which mediates the attachment, is expressed in three different regions of the cellular blastoderm near prominent invagination events. Through a combination of light-sheet imaging, genetic and mechanical perturbations, we demonstrate that integrin-enhanced friction is essential for unidirectional tissue flows in those regions, with effects including cephalic furrow positioning and epithelial stability. Guided by a minimal physical model, we further show that multiple attachment sites enhance the robustness and reproducibility of global tissue movements. Together, our results indicate that Drosophila gastrulation emerges from a balance between cell-intrinsic force generation and spatially distributed adhesion to the surrounding envelope, which together shape tissue flows at the embryo scale.

developmental biology↗
bioRxiv2025

SpinePy enables automated 3D spatiotemporal quantification of multicellular in vitro systems

Organoids and stem-cell-based embryo models such as gastruloids are powerful systems to quantitatively study morphogenesis and patterning. This requires 3D analysis in reference frames that emerge dynamically over development, but are less stereotypical than in vivo. Meaningful statistical comparison and interpretation of biological and physical quantities in space and time -- such as signaling activity, gene expression or cell flows -- depend on proper quantification in these internal and dynamic coordinate systems, especially in in vitro systems that naturally exhibit larger variation. Here, we present a computational framework, packaged as a modular Python toolkit termed SpinePy, that identifies the emergent primary body axis ("spine") of individual gastruloids and constructs a local, dynamic coordinate system aligned to their morphology. SpinePy enables 3D quantification relative to evolving axes and statistical comparisons of morphodynamics, patterning, and densities across structures with varying geometries. We validate and benchmark SpinePy using both synthetic and experimental gastruloid data, providing practical insights into method performance. Using this framework, we generate 3D patterning maps from gastruloids formed with different initial cell numbers (N0). This reveals distinct patterning classes that are better explained by gastruloid volumes than by N0. While demonstrated in gastruloids, SpinePy is broadly applicable to any multicellular system where analysis relative to evolving internal axes is needed, advancing quantitative and comparative spatial biology.

developmental biology↗
bioRxiv2025

The Optic cup is actively shape programmed by independently patterned apical forces

During morphogenesis, initially flat tissues often must transition into complex 3D shapes, reminiscent of shape-programmable systems in physics and engineering. One key question in developmental biology and physics alike is therefore how distinct mechanical inputs interact to produce the correct shape. To investigate this, we here study the onset of optic cup invagination during vertebrate eye development, combining 3D shape analysis, perturbation experiments, and physical modelling inspired by shape-programmable materials. We find that basal invagination is initiated at the apical surfaces through active, patterned cell behaviours. These behaviours generate in-plane strain patterns reshaping the apical surface and thereby bending the tissue basally. Surprisingly, this means that basal shape initiation is driven by apical dynamics. While retinal pigmented epithelium and neuroepithelium exhibit distinct shape transitions, these are temporally coordinated to jointly shape the optic cup. These findings highlight that 3D shape can emerge from local apical activity of two coordinated patterns.

developmental biology↗
bioRxiv2025

Quantification of lipid sorting during clathrin-mediated endocytosis

Clathrin-mediated endocytosis is a major transport route for proteins from the plasma membrane to the interior of the cell. While the recruitment of cargo proteins to clathrin-coated pits is well understood, it remains an open question if lipids are also sorted by this process. To address this question, we combined super-resolution STED imaging of bifunctional lipid probes with mathematical modeling. Quantification of 10 different lipid species revealed significant differences in pit partitioning, ranging from slight enrichment to moderate exclusion. We find that the lipid asymmetry in the plasma membrane is sufficient to explain the observed trend. Taken together, our findings imply that clathrin-mediated endocytosis has a minor selectivity for cytoplasmic leaflet lipids, but overall does not significantly contribute to lipid sorting compared to non-vesicular trafficking. More broadly, we believe that lipid super-resolution imaging will be a powerful approach to quantify lipid partitioning into membrane structures in cells.

cell biology↗
bioRxiv2024

Timely neurogenesis enables increased nuclear packing order during neuronal lamination

The coordination of cell proliferation, migration, and differentiation is crucial for organogenesis in many tissues, including the central nervous system and other organs that arise from pseudostratified epithelia (PSE). PSE feature densely packed elongated epithelial cells, with nuclei positioned along the apicobasal cell axis in a cell cycle-dependent manner. Also, PSE serve as organ precursors in diverse developmental contexts across evolution. While the role of nuclear movements in PSE has been extensively studied, less is known about whether and how their nuclear packing arrangements and changes of packing state influence tissue morphogenesis. To address this, we analyzed nuclear shapes, sizes and neighborhood statistics by segmenting nuclei in 3D and over development in zebrafish retinal neuroepithelia (RNE). We find that in PSE nuclei exhibit orientational, nematic-like order but remain positionally disordered. This pattern is conserved in other, less packed, neuroepithelia, like the hindbrain, suggesting that nematic-like order is a hallmark of pseudostratification. Our analysis during retinal development also revealed that nuclear packing density increases, approaching theoretical packing limits for disordered monodisperse ellipsoids at stages when the tissue transitions to a laminated neuronal structure. As neurogenesis progresses, nuclear shapes are remodeled, enabling the RNE to shift to a crystalline, ordered structure, while maintaining orientational alignment. Failure to initiate neurogenesis results in severe tissue deformations due to increased buckling instability. Our results thus show an instance where nuclear shape and nuclear positioning and their changes are essential for proper retinal morphogenesis, a phenomenon most likely also found in other tissue arrangements.

developmental biology↗
bioRxiv2024

Anisotropic stretch biases the self-organization of actin fibers in multicellular Hydra aggregates

During development, groups of cells generate shape by coordinating their mechanical properties through an interplay of self-organization and pre-patterning. Hydra displays a striking planar pattern of actin fibers at the organism scale, and mechanics influence the morphogenesis of biological structures during its pre-patterned regeneration. However, how mechanics participate in the formation of an ordered pattern from a totally disordered state remains unknown. To study this, we used cellular aggregates formed from dissociated Hydra cells, which initially lose all actin polarity yet regenerate a long-range actin pattern. We showed quantitatively that the actin meshwork evolves from a disordered symmetric state to an ordered state in which rotational symmetry is broken, and translation symmetry is partially broken, with the nematic and smectic order parameters increasing over days. During the first hours, the actin meshwork displayed spatial heterogeneity in the nematic order parameter, and ordered domains separated by lines of defects progressively grew and fused. This suggests that local cell-cell interactions drive the transition from disorder to order. To understand the mechanism of ordering, we perturbed the tissues physical constraints. We showed that while topology and geometry do not have a direct effect, anisotropic stretch biases the emerging orientation of the actin meshwork within hours. Surprisingly, although a Wnt protein gradient is expected to play a role in the actin ordering, the stretch-associated alignment happened without a Wnt enrichment. This demonstrates the role of tissue mechanics in the alignment of the actin fibers during the disorder-to-order transition.

developmental biology↗
bioRxiv2023

The everting Drosophila wing disc is a shape-programmed material

How complex 3D tissue shape emerges during animal development remains an important open question in biology and biophysics. In this work, we study eversion of the Drosophila wing disc pouch, a 3D morphogenesis step when the epithelium transforms from a radially symmetric dome into a curved fold shape via an unknown mechanism. To explain this morphogenesis, we take inspiration from inanimate "shape-programmable" materials, which are capable of undergoing blueprinted 3D shape transformations arising from in-plane gradients of spontaneous strains. Here, we show that active, in-plane cellular behaviors can similarly create spontaneous strains that drive 3D tissue shape change and that the wing disc pouch is shaped in this way. We map cellular behaviors in the wing disc pouch by developing a method for quantifying spatial patterns of cell behaviors on arbitrary 3D tissue surfaces using cellular topology. We use a physical shape-programmability model to show that spontaneous strains arising from measured active cell behaviors create the tissue shape changes observed during eversion. We validate our findings using a knockdown of the mechanosensitive molecular motor MyoVI, which we find to reduce active cell rearrangements and disrupt wing pouch eversion. This work shows that shape programming is a mechanism for animal tissue morphogenesis and suggests that there exist intricate patterns in nature that could present novel designs for shape-programmable materials.

biophysics↗
bioRxiv2023

Impossible ecologies: Interaction networks and stability of coexistence in ecological communities

Does an ecological community allow stable coexistence? Identifying the general principles that determine the answer to this question is a central problem of theoretical ecology. Random matrix theory approaches have uncovered the general trends of the effect of competitive, mutualistic, and predator-prey interactions between species on stability of coexistence. However, an ecological community is determined not only by the counts of these different interaction types, but also by their network arrangement. This cannot be accounted for in a direct statistical description that would enable random matrix theory approaches. Here, we therefore develop a different approach, of exhaustive analysis of small ecological communities, to show that this arrangement of interactions can influence stability of coexistence more than these general trends. We analyse all interaction networks of N [<=] 5 species with Lotka-Volterra dynamics by combining exact results for N [<=] 3 species and numerical exploration. Surprisingly, we find that a very small subset of these networks are "impossible ecologies", in which stable coexistence is non-trivially impossible. We prove that the possibility of stable coexistence in general ecologies is determined by similarly rare "irreducible ecologies". By random sampling of interaction strengths, we then show that the probability of stable coexistence varies over many orders of magnitude even in ecologies that differ only in the network arrangement of identical ecological interactions. Finally, we demonstrate that our approach can reveal the effect of evolutionary or environmental perturbations of the interaction network. Overall, this work reveals the importance of the full structure of the network of interactions for stability of coexistence in ecological communities.

ecology↗
bioRxiv2023

Multifractal signatures in ossification reveal a disordered-to-ordered transition in mineral pattern

Developing biological systems can exhibit both dynamic pattern formation and cross-scale interactions. Multiscale relationships are critical in the establishment of these patterns but remain poorly understood. Classification of mineral pattern in bone is a quintessential example. One approach to quantifying these patterns relies upon statistical self-similarity and, in particular, monofractal analysis. However, simple monofractal characterisations fail to capture the complexity of multiscale interactions in developing biological systems. Here we show that multifractal techniques, effectively capture the complex patterns of self-similarity in a dimensionally reduced, usable way. Further, we show that a simple generative model of ossification in the mouse skull, coupled with multifractal methods indicates a primary role of collagen density in pattern establishment and predicts the existence of a sharp boundary in pattern complexity.

biophysics↗
bioRxiv2023

Pre-patterned epithelial invagination prevents mechanical instability during fly gastrulation

Mechanical forces are crucial for driving and shaping tissue morphogenesis during embryonic development, but their relevance for the evolution of development remains poorly understood. Here, we show that a morphogenetic innovation present in fly embryos--a deep epithelial fold known as the cephalic furrow--plays a mechanical role during Drosophila gastrulation. By integrating in vivo experiments and in silico simulations, we find that the formation of the cephalic furrow prevents mechanical instabilities at the head-trunk epithelium by absorbing the compressive stresses generated by concurrent morphogenetic movements of gastrulation, the expansion of mitotic domains and the germ band extension. Furthermore, by comparing the expression of known and novel genes involved in cephalic furrow formation between fly species, we find that the presence of the cephalic furrow is linked to changes in the expression of buttonhead transcription factor at the head-trunk boundary. These data suggest that the genetic control of cephalic furrow formation was established through the integration of a new player into the ancestral head-trunk patterning system, and that mechanical instability may have been the selective pressure associated with the evolution of the cephalic furrow. Our findings uncover empirical evidence for how mechanical forces can influence the evolution of morphogenetic innovations in early development.

developmental biology↗
bioRxiv2022

Core PCP mutations affect short time mechanical properties but not tissue morphogenesis in the Drosophila pupal wing

How morphogenetic movements are robustly coordinated in space and time is a fundamental open question in biology. We study this question using the wing of Drosophila melanogaster, an epithelial tissue that undergoes large-scale tissue flows during pupal stages. We showed previously (Etournay et al., 2015) that pupal wing morphogenesis involves both cellular behaviors that allow relaxation of mechanical tissue stress, as well as cellular behaviors that appear to be actively patterned. The core planar cell polarity (PCP) pathway influences morphogenetic cell movements in many other contexts, which suggests that it could globally pattern active cellular behaviors during pupal wing morphogenesis. We show here, however, that this is not the case: there is no significant phenotype on the cellular dynamics underlying pupal morphogenesis in mutants of core PCP. Furthermore, using laser ablation experiments, coupled with a rheological model to describe the dynamics of the response to laser ablation, we conclude that while core PCP mutations affect the fast timescale response to laser ablation, they do not affect overall tissue mechanics. In conclusion, our work shows that cellular dynamics and tissue shape changes during Drosophila pupal wing morphogenesis are independent of one potential chemical guiding cue, core PCP.

developmental biology↗
bioRxiv2022

Matrix topology guides collective cell migration in vivo

Diverse modes of cell migration shape organisms in health and disease and much research has focused on the role of intracellular and extracellular components in different cell migration phenomena. What is less explored, however, is how the arrangement of the underlying extracellular matrix that many cells move upon in vivo influences migration. Combining novel transgenic lines and image analysis pipelines, reveals that during zebrafish optic cup formation cells use cryptopodia-like protrusions to migrate collectively and actively over a topologically changing matrix. These changing topologies correspond to different cell-matrix interactions. Interference with matrix topology results in loss of cryptopodia and inefficient migration. Thus, matrix topology influences the efficiency of directed collective cell migration during eye morphogenesis, a concept likely conserved in other developmental and disease contexts. One-Sentence SummaryDynamic cell-matrix interactions, crucial for successful collective rim cell migration, rely on extracellular matrix topologies during optic cup development in vivo.

developmental biology↗
bioRxiv2021

On biological flow networks: Antagonism between hydrodynamic and metabolic stimuli as driver of topological transitions.

A plethora of computational models have been developed in recent decades to account for the morphogenesis of complex biological fluid networks, such as capillary beds. Contemporary adaptation models are based on optimization schemes where networks react and adapt toward given flow patterns. Doing so, a system reduces dissipation and network volume, thereby altering its final form. Yet, recent numeric studies on network morphogenesis, incorporating uptake of metabolites by the embedding tissue, have indicated the conventional approach to be insufficient. Here, we systematically study a hybrid-model which combines the network adaptation schemes intended to generate space-filling perfusion as well as optimal filtration of metabolites. As a result, we find hydrodynamic stimuli (wall-shear stress) and filtration based stimuli (uptake of metabolites) to be antagonistic as hydrodynamically optimized systems have suboptimal uptake qualities and vice versa. We show that a switch between different optimization regimes is typically accompanied with a complex transition between topologically redundant meshes and spanning trees. Depending on the metabolite demand and uptake capabilities of the adaptating networks, we are further able to demonstrate the existence of nullity re-entrant behavior and the development of compromised phenotypes such as dangling non-perfused vessels and bottlenecks. Author summaryBiological flow networks, such as capillaries, do not grow fully developed and matured in their final and functional form. Instead they grow a rudimentary network which self-organizes bit by bit in the context of their surrounding tissue, perfusion and other stimuli. Interestingly, it has been repeatedly shown that this development is mechano-transductional in nature, coupling complex bio-chemical signaling to mechanical cues such as wall-shear stress. In accordance with previous studies we propose a minimal hybrid model that takes into account stimuli in the form of the actual metabolite uptake of the surrounding tissue and the conventional wall-shear stress approach, and incorporate these into the metabolic cost function scheme. We present a numeric evaluation of our model, displaying the antagonistic interplay of uptake and shear stress driven morphogenesis as well as the topological ramifications and frustrated network formations, i.e. dangling branches, bottlenecks and re-entrant behavior in terms of redundancy transitions.

physiology↗
bioRxiv2021

Tissue scale properties of the extracellular matrix regulates nuclear shape, organisation and fate in the embryonic midline sutures

Balancing self-renewal and differentiation is a key feature of every stem cell niche and one that is tuned by mechanical interactions of cells with their neighbors and surrounding extracellular matrix. The fibrous stem cell niches that develop as sutures between skull bones must balance the complex extracellular environment that emerges to define them with self-renewal and bone production. Here, we address the role for physical stimuli in suture development by probing the relationship between nuclear shape, organization and gene expression in response to a developing collagen network in embryonic midline sutures. This work complements genetic approaches used to study sutures and provides the first quantitative analyses of physical structure in these sutures. By combining multiple imaging modalities with novel shape description, in addition to network analysis methods, we find the early emergence of a complex extracellular collagen network to have an important role in regulating morphogenesis and cell fate. We show that disrupted collagen crosslinking can alter ECM organization of midline sutures as well as stimulate expression of bone differentiation markers. Further, our findings suggest that in vivo, skeletal tissues can uncouple the response of the nuclear lamina from collagen mediated tissue stiffening seen in vitro. Our findings highlight a crucial relationship between the cellular microenvironment, tissue stiffness and geometry with gene expression in normal development and maintenance of progenitor fate in embryonic sutures.

developmental biology↗
bioRxiv2021

ANDOR and beyond: dynamically switchable logic gates as modules for flexible information processing

Understanding how complex (bio-)chemical pathways and regulatory networks may be capable of processing information in efficient, flexible, and robust ways is a key question with implications touching fields across biology, systems biology, biochemistry, synthetic biology, dynamical systems theory, and network science. Considerable effort has been focused on the identification and characterization of structural motifs in these signaling networks, and companion efforts have instead sought to cast their operation as controlled by dynamical modules that appear out of dynamical correlations during information processing. While both these approaches have been successful in many examples of biological information processing, cases in which the signaling or regulatory network exhibits multi-functionality or context dependence remain problematic. We here propose a small set of higher-order effective modules that simultaneously incorporate both network structure and the attendant dynamical landscape. In so doing, we render effective computational units that can perform different logical operations based purely on the basin of attraction in which the network dynamics resides or is steered to. These dynamically switchable biochemical logic gates require fewer chemical components or gene products overall than their traditional analogs where static, separate gates are used for each desired function. We demonstrate the applicability and limits of these flexible gates by determining a robust range of parameters over which they correctly operate and further characterize the resilience of their function against intrinsic noise of the constituent reactions using the theory of large deviations. We also show the capability of this framework for general computations by designing a binary adder/subtractor circuit composed of only six components.

biophysics↗
bioRxiv2019

How to Pare a Pair: Topology Control and Pruning in Intertwined Complex Networks.

Recent work on self-organized remodeling of vasculature in slime-mold, leaf venation systems and vessel systems in vertebrates has put forward a plethora of potential adaptation mechanisms. All these share the underlying hypothesis of a flow-driven machinery, meant to alter rudimentary vessel networks in order to optimize the systems dissipation, flow uniformity, or more, with different versions of constraints. Nevertheless, the influence of environmental factors on the long-term adaptation dynamics as well as the networks structure and function have not been fully understood. Therefore, interwoven capillary systems such as found in the liver, kidney and pancreas, present a novel challenge and key opportunity regarding the field of coupled distribution networks. We here present an advanced version of the discrete Hu-Cai model, coupling two spatial networks in 3D. We show that spatial coupling of two flow-adapting networks can control the onset of topological complexity in concert with short-term flow fluctuations. We find that both fluctuation-induced and spatial coupling induced topology transitions undergo curve collapse obeying simple functional rescaling. Further, our approach results in an alternative form of Murrays law, which incorporates local vessel interactions and flow interactions. This geometric law allows for the estimation of the model parameters in ideal Kirchhoff networks and respective experimentally acquired network skeletons.

biophysics↗
bioRxiv2019

Tissue shape determines actin-dependent nuclear migration mechanisms in neuroepithelia

Correct nuclear position is crucial for cellular function. Depending on cell context however, cytoskeletal elements and force generation mechanisms vary. While these mechanisms have been intensely studied in single cells, how nuclear positioning is linked to tissue morphology is less clear. Here, we compare apical nuclear positioning in developing straight and curved neuroepithelia of zebrafish. Interestingly, in differently shaped neuroepithelia the kinetics of nuclear positioning differ and we find that distinct actin-dependent mechanisms are employed. In straight neuroepithelia nuclear positioning is controlled by Rho-ROCK-dependent myosin contractility. Curved neuroepithelia use a formin-dependent pushing mechanism for which we propose a force generation theory. We suggest that cytoskeleton adaptability to tissue shape ensures correct nuclear positioning and robust epithelial maturation across different geometries. We further speculate that different mechanisms arise due to differences in actin arrangements during development, a theme highlighting the importance of developmental context for the execution of intracellular processes.

cell biology↗
bioRxiv2018

Multi-sample SPIM image acquisition, processing and analysis of vascular growth in zebrafish

To quantitatively understand biological processes that occur over many hours or days, it is desirable to image multiple samples simultaneously and automatically process and analyze the resulting datasets. Here, we present a complete multi-sample preparation, imaging, processing, and analysis workflow to determine the development of the vascular volume in zebrafish. Up to five live embryos were mounted and imaged simultaneously over several days using selective plane illumination microscopy (SPIM). The resulting large imagery dataset of several terabytes was processed in an automated manner on a high-performance computer cluster and segmented with a novel segmentation approach that uses images of red blood cells as training data. This analysis yielded a precise quantification of growth characteristics of the whole vascular network, head vasculature, and tail vasculature over development. Our multi-sample platform demonstrates effective upgrades to conventional single-sample imaging platforms and paves the way for diverse quantitative long-term imaging studies.\n\nSummary statementWe present a dedicated multi-sample light sheet imaging, processing and analysis platform and demonstrate its value for studies of vascular growth in zebrafish.

developmental biology↗