Biology subjects

Keren, K.

Publications and source records attributed to Keren, K..

9 recordsLinked to original sources

bioRxiv2026

β-catenin Dynamics in Regenerating Hydra

Body axis specification is essential for morphogenesis, yet how axial patterning is dynamically coordinated remains unclear. In Hydra, Wnt/{beta}-catenin signaling is central to axial patterning, but its spatiotemporal dynamics are not well understood. Since nuclear {beta}-catenin mediates Wnt-dependent transcription, its localization provides a relevant readout for pathway dynamics. Here, we track {beta}-catenin abundance and nuclear localization in vivo during regeneration from bisected Hydra, tissue rings, and small tissue fragments. Following bisection, nuclear {beta}-catenin is detected exclusively at the regenerating oral end, where a broad signal appears and then declines before focusing at the future head. Tissue rings, lacking both head and foot, exhibit similar oral-aboral asymmetry. In regenerating fragments, the initial response often spans nearly the entire tissue, including the future foot region, followed by an additional peak before stabilizing at the future head. Overall, our results show that the spatial restriction of nuclear {beta}-catenin correlates with the divergence of regenerative dynamics toward head or foot formation, while the trajectories leading to these outcomes vary across different initial tissue configurations.

biophysics↗

bioRxiv2026

Body-Axis Reorientation in Regenerating Hydra under Geometric Confinement

Defining a body axis is a central aspect of animal morphogenesis. During regeneration from excised Hydra tissue pieces, the newly formed body axis typically preserves the orientation of the parent body axis and aligns with the inherited nematic organization of the supracellular actomyosin fibers. Here we show that this inherited orientation can be overridden by geometric confinement. Tissue spheroids confined in narrow cylindrical channels in a frustrating configuration, with the inherited axis initially perpendicular to the channel, regenerate with their body axis aligned along the channel. Using high-resolution live imaging we show that this reorientation is accompanied by remodeling of the nematic fiber organization. New fibers form parallel to the channel axis in the initially disordered closure regions, creating sharp domain boundaries with the inherited transverse fibers. These domain boundaries subsequently propagate, with perpendicular fibers dissolving and new fibers forming along the channel axis. The confined tissue behaves as a solid-like active nematic material, storing anisotropic strain over long timescales while allowing nematic reorganization relative to the material frame. Our results suggest that coupling between tissue strain and nematic alignment contributes to fiber reorientation and body-axis patterning, highlighting how external mechanical constraints can redirect the body axis during morphogenesis.

biophysics↗

bioRxiv2024

Confinement modulates axial patterning in regenerating Hydra

The establishment of the body plan is a major step in animal morphogenesis. The role of mechanical forces and feedback in patterning the body plan remains unclear. Here we explore this question, by studying regenerating Hydra tissues confined in narrow cylindrical channels which constrain their morphology. We find that frustration between the orientation of the channel and the inherited axis in the regenerating tissues can lead to the formation of a multiaxial body plan. The morphological outcome is directly related to the pattern of nematic topological defects that emerges in the organization of the supracellular actomyosin fibers. When the inherited axis, which can be read out from the initial alignment of the supracellular fibers in the confined spheroid, is parallel to the channels axis, the tissue regenerates normally into animals with a single body axis aligned with the channel. However, regenerating spheroids that are confined in a frustrated perpendicular configuration often develop excess defects (including negatively-charged -[1/2] defects) and regenerate into multiaxial morphologies. The influence of mechanical constraints on the regenerated body plan argues against an axial patterning mechanism that is based solely on inherited gradients of biochemical morphogens. We further show that the dependence of the regeneration outcomes on the initial tissue orientation can be recapitulated by a biophysical model which considers the coupled dynamics of the nematic organization of the actomyosin fibers and a morphogen concentration field, incorporating a mechanochemical feedback loop involving strain-dependent morphogen production at defect sites.

biophysics↗

bioRxiv2024

Mechanical strain focusing at topological defect sites in regenerating Hydra

The formation of a new head during Hydra regeneration involves the establishment of a head organizer that functions as a signaling center and contains an aster-shaped topological defect in the organization of the supracellular actomyosin fibers. Here we show that the future head region in regenerating tissue fragments undergoes multiple instances of extensive stretching and rupture events from the onset of regeneration. These recurring localized tissue deformations arise due to transient contractions of the supracellular ectodermal actomyosin fibers that focus mechanical strain at defect sites. We further show that stabilization of aster-shaped defects is disrupted by perturbations of the Wnt signaling pathway. We propose a closed-loop feedback mechanism promoting head organizer formation, and develop a biophysical model of regenerating Hydra tissues that incorporates a morphogen source activated by mechanical strain and an alignment interaction directing fibers along morphogen gradients. We suggest that this positive feedback loop leads to mechanical strain focusing at defect sites, enhancing local morphogen production and promoting robust organizer formation.

biophysics↗

bioRxiv2022

Size-dependent transition from steady contraction to waves in actomyosin networks with turnover

Actomyosin networks play essential roles in many cellular processes including intracellular transport, cell division, and cell motility, exhibiting a myriad of spatiotemporal patterns. Despite extensive research, how the interplay between network mechanics, turnover and geometry leads to these different patterns is not well understood. We focus on the size-dependent behavior of contracting actomyosin networks in the presence of turnover, using a reconstituted system based on cell extracts encapsulated in water-in-oil droplets. We find that the system can self-organize into different global contraction patterns, exhibiting persistent contractile flows in smaller droplets and periodic contractions in the form of waves or spirals in larger droplets. The transition between continuous and periodic contraction occurs at a characteristic length scale that is inversely dependent on the network contraction rate. These dynamics are recapitulated by a theoretical model, which considers the coexistence of different local density-dependent mechanical states with distinct rheological properties. The model shows how large-scale contractile behaviors emerge from the interplay between network percolation essential for long-range force transmission and rearrangements due to advection and turnover. Our findings thus demonstrate how varied contraction patterns can arise from the same microscopic constituents, without invoking specific biochemical regulation, merely by changing the systems geometry.

biophysics↗

bioRxiv2021

Canalized morphogenesis driven by inherited tissue asymmetries in Hydra regeneration

The emergence and stabilization of a body axis is a major step in animal morphogenesis, determining the symmetry of the body plan as well as its polarity. To advance our understanding of the emergence of body-axis polarity we study regenerating Hydra. Axis polarity is strongly memorized in Hydra regeneration even in small tissue segments. What type of processes confer this memory? To gain insight into the emerging polarity, we utilize frustrating initial conditions by studying regenerating tissue strips which fold into hollow spheroids by adhering their distal ends, of opposite original polarities. Despite the convoluted folding process and the tissue rearrangements during regeneration, these tissue strips develop a new organizer in a reproducible location preserving the original polarity and yielding an ordered body plan. These observations suggest that the integration of mechanical and biochemical processes supported by their mutual feedback attracts the tissue dynamics towards a well-defined developmental trajectory biased by weak inherited cues from the parent animal. Hydra thus provide an example of dynamic canalization in which the dynamic rules themselves are inherited, in contrast to the classical picture where a detailed developmental trajectory is pre-determined.

biophysics↗

bioRxiv2021

Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer

Understanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in cancer. SignificanceWe provide a comprehensive systems medicine strategy to unveil oncogenic circuitries and inform novel precision therapy decisions against CNA in cancer. This first clinical multi-omic analysis of chr1q-amp in MM identifies a central PBX1-FOXM1 regulatory axis driving high-risk prognosis, as a novel therapeutic target against chr1q-amp in cancer.

cancer biology↗

bioRxiv2021

Plasticity of body axis polarity in Hydra regeneration under constraints

One of the major events in animal morphogenesis is the emergence of a polar body axis. Here, we combine classic grafting techniques with live imaging to study the emergence of body axis polarity during whole body regeneration in Hydra. Composite tissues are made by fusing two rings, excised from separate animals, in different configurations that vary in the polarity and original positions of the rings along the body axes of the parent animals. Under frustrating initial configurations, body axis polarity that is otherwise stably inherited from the parent animal, can become labile and even be reversed. Importantly, the site of head regeneration exhibits a strong bias toward the edges of the tissue, even when this involves polarity reversal. In particular, we observe head formation at an originally aboral tissue edge, which is not compatible with models of Hydra regeneration based only on preexisting morphogen gradients or an injury response. Rather, we suggest that the structural bias toward head formation at the doublets edge is reinforced by the presence of a defect in the organization of the supra-cellular actin fibers, which invariably forms at the edge as the tissue heals. In this scenario, the defect supports head formation at the edge, even though a defect is neither required nor sufficient for head formation. Altogether, our results suggest that body axis determination is an integrated process that arises from the dynamic interplay between mechanical feedback and signaling processes.

biophysics↗

bioRxiv2020

Topological defects in the nematic order of actin fibers as organization centers of Hydra morphogenesis

Animal morphogenesis arises from the complex interplay between multiple mechanical and biochemical processes with mutual feedback. Developing an effective, coarse-grained description of morphogenesis is essential for understanding how these processes are coordinated across scales to form robust, functional outcomes. Here we show that the nematic order of the supra-cellular actin fibers in regenerating Hydra defines a slowly-varying field, whose dynamics provide an effective description of the morphogenesis process. We show that topological defects in this field, which are long-lived yet display rich dynamics, act as organization centers with morphological features developing at defect sites. These observations suggest that the nematic orientation field can be considered a "mechanical morphogen" whose dynamics, in conjugation with various biochemical and mechanical signaling processes, result in the robust emergence of functional patterns during morphogenesis.

biophysics↗