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Results for “developmental biology”

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bioRxiv2025

Regulated development of cannibalistic supergiant cells

Virtually all paradigms in developmental biology apply to differentiating cells and tissues within multicellular animals and plants. However, unicellular eukaryotes, which must simultaneously perform all roles necessary for organismal function, also form complex and specialized structures, using processes that take place exclusively within the confines of a single cell. Here, we describe a ciliate (Euplotes gigatrox sp. nov.) undergoing drastic morphological transformations within a genetically uniform population, the most spectacular being the appearance of "supergiants" that increase in size, change shape, and modify their locomotion and feeding behaviour to cannibalize clonal relatives. We explore supergiant formation from the perspective of life cycle, ecological strategy, and gene expression, demonstrating that supergiants are distinct, regulated, transcriptionally unique stages. These reversibly differentiated cells require both external and internal triggers to develop and have evolved regulatory loops to ensure coupling between environmental and physiological conditions. This system provides a blueprint for approaching both cell differentiation and functional ecology in unicellular organisms, which might open new avenues for the generalization and contextualization of known morphogenetic mechanisms, as well as the discovery of new ones.

cell biology↗

bioRxiv2025

Characterizing the Genome of the Bumblebee Bombus haematurus: A Range-Expanding Pollinator

Over the past two decades, the blood-tailed bumblebee Bombus haematurus has expanded its range from Western Asia into Central Europe. It is among several members of the Pyrobombus subgenus of bumblebees to have undergone recent population expansions. A number of studies have investigated these other species for genomic signatures that might be associated with expansions. Currently there are no published studies describing whole genome resources for B. haematurus and no whole genome data from regions near the edge of the expanding front. Here, we sequenced samples of B. haematurus from part of its recently expanded range in Northern Italy to generate the first whole genome data for this species. The genome size of B. haematurus is in a similar range to that reported for closely related Pyrobombus species ([~]300 mega base pairs), with a predicted [~] 13,500 genes. At the location sampled, there was a comparatively low nucleotide diversity, low inbreeding evidenced through a negative inbreeding coefficient, FIS (-0.14), and low percentage of genome covered by long runs of homozygosity, LROH ([~]0.03%), compatible with a recent history of population expansion. Using nucleotide diversity and Tajimas D, we also detected evidence of positive and balancing selection in developmental biology and signalling genes. Comparison with other members of the Bombus genus and Pyrobombus subgenus revealed similar biological processes to be associated with signatures of selection across the genus. Our comparison also identified similar trends of FIS and LROH between B. haematurus and other Pyrobombus species.

genomics↗

bioRxiv2025

3DTubularVoronoi: a Voronoi-Based Framework for Estimating Equilibrium Cellular Packing in 3D Tubular Epithelia

Epithelial tube morphogenesis is fundamental to organ development and functioning, yet accurately modeling its intricate 3D organization and dynamics remains a challenge. In particular, current computational tools fail to capture the spontaneous emergence of non-transient scutoids, a geometric feature essential for accommodating curvature in epithelia. Here, we introduce 3DTubularVoronoi, a novel simulation framework for modeling epithelial tube morphogenesis and determining their stable cell packing organization depending on mechanical parameters. The model employs a Voronoi tessellation strategy combined with an energy minimization approach using the Metropolis-Hasting algorithm. 3DTubularVoronoi enables realistic epithelial tube simulations, accounting for scutoid formation and dynamic rearrangements. This tool provides an open-source, user-friendly solution for exploring gland morphogenesis and offering insights into developmental biology and tissue engineering. Availabilityhttps://github.com/TheSiMBioSysI2SysBio/3DTubularVoronoi

bioinformatics↗

bioRxiv2025

A steady state pool of calcium-dependent actin is maintained by Homer and controls epithelial mechanosensation

Epithelial cells are inherently contractile and in homeostasis, tissue integrity is maintained by balancing the uneven contractile forces in neighboring cells at the cell-cell interface. By contrast, epithelial cells can utilize an imbalance in contractile force to communicate various information to induce tissue-wide response as in wound healing. Contractility is generated and processed at the apical junctional complex (AJC) by the dynamic behavior of the actin cytoskeleton. Calcium signaling can pattern cellular responses based on its reach and amplitude and the actin cytoskeleton is supported by its wide ranging effects on actin regulators. Calcium transients regulate various cell behaviors associated with actin remodeling, such as in damage response and developmental morphogenesis. Here we report that calcium maintains an adaptive pool of AJC-associated actin that is sensitive to tension and encoded by calcium dynamics. For this, the recently identified epithelial polarity module Homer-MUPP1/PatJ is required. Homer regulates calcium signaling in various tissue contexts through interaction with numerous components of the endoplasmic reticulum (ER) and plasma membrane (PM) calcium signal toolkit. Knockout of either Homer or MUPP1/PatJ attenuated tension-induced calcium response and severely disrupted wound healing migration, which is dependent on guidance input through AJC tension. We also show that Homer is integral to early embryonic neurodevelopment as its suppression causes failure of neural tube closure. Our findings highlight the critical role of localized calcium dynamics on AJC actin remodeling and cellular behavior, elucidating the means of tissue coordination through intercellular tension. Significance statementThis study uncovers a novel mechanism by which localized calcium dynamics at the apical junctional complex maintain an adaptive, tension sensitive pool of actin, regulated by the epithelial polarity scaffolds Homer and MUPP1/PatJ. Importantly, this mechanism operates without perturbing epithelial polarity, indicating a specific means to modulate tissue mechanics. By linking mechanical forces to localized calcium amplification, this module enables precise mechanosensation, coordinating collective behaviors such as epithelial wound healing and neural tube closure in Xenopus. These findings redefine our understanding of intercellular tension sensing in epithelial tissues and highlight the Homer-calcium signaling axis as a key driver of tissue morphogenesis and homeostasis, with far reaching implications for developmental biology, regenerative medicine, and neural tube defect pathogenesis.

cell biology↗

bioRxiv2025

Caenorhabditis diversity on Pohnpei, Micronesia, provides evidence that the Elegans Supergroup has its roots in the Americas and diversified in the Pacific en route to Asia

The microscopic nematode Caenorhabditis elegans stands unrivaled as a model for developmental biology, neurobiology, and genetics, but fundamental aspects of its ecology, biogeography, and natural history remain unknown. Leveraging recent findings that place its center of diversity in the cool, high-elevation forests of Hawaii, we performed an intensive survey of the Caenorhabditis fauna of Pohnpei, a high island in Micronesia that is home to the largest patch of high-elevation forest between Hawaii and East Asia. We found nine species of Caenorhabditis, five of them new, but not C. elegans. Most species were limited to the hot lowlands but three spanned the elevational range and one was found only in the cloudforest. Using the distribution of Caenorhabditis nematodes among habitat patches - individual rotting fruits or flowers - we parameterized simple models that capture key aspects of the population biology of these animals. We generated transcriptomes for the new species and inferred a phylogeny for 70 species of Caenorhabditis, based on 2955 genes. This phylogeny allowed us to perform the first quantitative biogeographic analysis for the group. Our analysis suggests that the deep ancestors of the Elegans Supergroup of species lived in the Americas, and that the Supergroups subsequent diversification occurred in Remote Oceania. The ancestors of the Supergroup gave rise to a diverse Oceanian fauna and ultimately to multiple lineages that moved into Asia, Africa, Australasia, and back into the Americas. Though biogeographic inferences are limited by the lack of information from key regions of the southwest Pacific, the data are consistent with a model of trans-Pacific migration, with the islands of Oceania serving as sources rather than sinks for biodiversity.

evolutionary biology↗

bioRxiv2025

Cooperative short- and long-range interactions enable robust symmetry breaking and axis formation

Establishing the anterior-posterior (A-P) axis is a key symmetry-breaking event in mammalian development. Gastruloids, aggregates of embryonic stem cells, undergo a similar process, forming a single posterior pole from an initially spherical aggregate. This requires the aggregate to convert an inside-outside difference in cell state into one A-P axis. We asked what cell-cell interactions can make this transition robust. We built an agent-based coarse-grained model with an outer cell population and an inner cell population. Cells interacted through short-range adhesion and, in some simulations, through an effective long-range attraction. Adhesion alone rarely produced a single stable axis, often leaving weakly separated or unstable clusters. Adding long-range attraction between outer cells changed this behavior. The outer cells collected into one pole, the inner cells remained in the opposite domain, and most cells stayed in one aggregate. This occurred across a broad range of adhesion strengths. The model also made a simple prediction. If two polarized gastruloids merge in opposite orientations, the two posterior poles should move around the fused aggregate and join into one pole. Human gastruloid merging experiments showed this behavior. Same-orientation pairs fused rapidly. Opposite-orientation pairs fused more slowly as their posterior poles moved around the aggregate and converged. Finally, we built a minimal gene-regulatory model that generated inner and outer states and turned on the same mechanical interactions. In this model, an initially uniform cell population formed one polarized axis. Together, these results suggest that short-range adhesion and long-range attraction can work together to convert radial patterning into one body axis. They also suggest a design principle for synthetic developmental biology: adhesion can sort cells locally, but building one reproducible axis may require interactions that act beyond direct cell-cell contact.

systems biology↗

bioRxiv2025

Splicing Isoforms Associated to TGFb-Induced Myofibroblast Activation

Myofibroblast differentiation is a key process in developmental biology and involved in numerous physiopathology. The gene expression program orchestrating fibroblast to myofibroblast differentiation, as well as its recapitulation by TGF{beta} stimulation in vitro, is relatively well characterized. Intriguingly, it is known that the splicing isoform EDA+FN1 is a marker and driver of myofibroblast differentiation, but the alternative splicing landscape of myofibroblast is unknown. Here, we performed a high-throughput transcriptomic approach by RNA-Seq in a primary skin fibroblast line and uncover more than 250 splicing isoforms associated with TGF{beta}-induced myofibroblasts using two different bioinformatic pipelines. This splicing profile highlights a distinct layer of regulation when compared to the global gene expression profile of myofibroblasts. A 5 alternative splicing event (ASE) signature [ACTN1-19A/19B; COL5A1-64A/64B; COL6A3 exon 4; FLNA exon 30 and TPM1-6a/6b] was further validated by ddPCR and AS-PCR and retrieved in publicly available RNA-Seq datasets describing other TGF{beta}-stimulated lung and skin fibroblasts. Surprisingly, TGF{beta} does not induce an EDA+FN1 splicing shift, although it stimulates global fibronectin expression. Thus, we conclude that the 5 ASEs signature may be used as putative universal myofibroblast markers and be of functional significance to myofibroblast formation and biology.

genomics↗

bioRxiv2025

A nanobody-based degron system for targeted protein knockdown in Dictyostelium discoideum

BackgroundsThe cellular slime mold Dictyostelium discoideum is a widely used model system for studying basic processes in cell and developmental biology. While genetic tools, such as targeted gene disruption by homologous recombination and genome editing using CRISPR/Cas9, are well-established in D. discoideum, efficient methods for conditional loss-of-function studies are limited. Here, we developed a nanobody-based degron system for D. discoideum based on ALFA-tagged protein recruitment to the Skp1-Cullin-F-box (SCF) complex. ResultsALFA-tagged Histone H1 was efficiently degraded by expressing anti-ALFA nanobody (NbALFA) fused to the D. discoideum FbxD F-box domain ( dictyGrad-ALFA). Cell type-specific targeting was achieved by expressing dictyGrad-ALFA under prestalk- and prespore-specific gene promoters. Furthermore, targeting of adenylyl cyclase A (ACA) resulted in the expected aggregation-deficient phenotype, validating the efficacy of dictyGrad-ALFA-mediated protein depletion. Cell type-specific ACA degradation delayed development but eventually resulted in normal fruiting bodies. Our ALFA-tag approach was further used for conditional knockdown in combination with the auxin-inducible degron 2 (AID2) system, which relies on indole-3-acetic acid (IAA)-dependent binding between NbALFA-mAID and a OsTIR-F-box-Skp1A fusion protein. We obtained efficient IAA-induced degradation in prestalk cells; however, efficiency was low in other cell types. ConclusionsTogether, these systems pave the way for conditional and cell type-specific protein degradation in D. discoideum, enabling functional analyses of essential genes for development and survival.

cell biology↗

bioRxiv2025

Transcriptomic profile of embryoid bodies under hypoxia at single cell level

Oxygen availability is a key regulator of cellular physiology and hypoxia plays a central role driving vasculogenesis and angiogenesis during development. While bulk transcriptomics has revealed important oxygen-regulated gene networks, such approaches cannot resolve the cellular heterogeneity and lineage dynamics characteristic of early differentiation. To address this, we generated a single-cell transcriptomic dataset from murine embryoid bodies, a widely used in vitro model of early embryonic development, cultured 8 or 10 days under hypoxic (1% O2) or normoxic (21% O2) conditions for the final 16 or 48 hours of differentiation. This resource enables detailed exploration of how oxygen availability influences lineage specification, vascular and hematopoietic development, and cellular heterogeneity during early differentiation. Beyond developmental biology, the dataset provides a valuable reference for comparative studies of hypoxia responses, benchmarking of single-cell analysis methods, and integrative investigations into oxygen signaling across diverse biological systems.

cell biology↗

bioRxiv2025

Clair-Mosaic: A deep-learning method for long-read mosaic small variant calling

Mosaic variants, defined as postzygotic mutations occurring during an organisms development from zygote to adult, play critical roles in developmental biology, aging, and diseases such as cancer and neurological disorders. However, their accurate detection remains challenging due to low abundance in the genome and low variant allelic fractions (VAF). While current mosaic variant callers are primarily designed for short-read sequencing, no method is available for long-read sequencing, which can generate tens of kilobase-long reads to cover complex genomic regions inaccessible to short reads. To fill the gap, we present Clair-Mosaic, a deep-learning-based method for detecting mosaic small variants from long-read data. Clair-Mosaic was trained on hundreds of millions synthetic variants encompassing diverse read coverages and allelic fractions, enabling it to detect low-VAF mosaic variants with high sensitivity in paired-sample and single-sample modes. In addition to neural network prediction, Clair-Mosaic distinguishes genuine mosaic variants from sequencing artifacts by leveraging their inherent haplotype relationship in phased long reads. Furthermore, a Bayesian mosaic-germline discriminator is introduced to distinguish mosaic variants from germline variants. It also employs multiple post-calling filters, including a mosaic variant database and multiple germline population resources, to tag common germline and mosaic variants. Comprehensive benchmarking on synthetic datasets and real samples demonstrated Clair-Mosaics outstanding performance in ONT and PacBio. Clair-Mosaic is also applicable to short-read data and outperforms methods like MosaicHunter, MosaicForecast, DeepMosaic, and DeepSomatic. Clair-Mosaic is open-source and available at https://github.com/HKU-BAL/Clair-Mosaic.

bioinformatics↗

bioRxiv2025

Chromosome-scale genome assembly and annotation of the two-spotted cricket Gryllus bimaculatus (Orthoptera: Gryllidae)

The two-spotted cricket, Gryllus bimaculatus, is a key hemimetabolous model organism for developmental biology, neuroscience, and regeneration. The existing reference genome is, however, highly fragmented into 47,877 scaffolds, hampering chromosome-scale analyses for these fields. Here, we report a high-quality, chromosome-scale genome assembly for the white-eyed mutant strain of this cricket, generated using a combination of Nanopore and PacBio HiFi long reads, integrated with Hi-C data. The final 1.62 Gbp assembly achieves a scaffold N50 of 107.4 Mbp, a significant improvement in contiguity over the previous 6.3 Mbp N50. We anchored 94.45% of the assembly into 15 pseudomolecules, consistent with the known karyotype (n = 15). The genome completeness (BUSCO v6.0.0 insecta_odb12) reached 98.1%. We also updated the annotation, identifying 14,964 protein-coding genes. This gene set shows markedly improved completeness (BUSCO v6.0.0 insecta_odb12: 95.7%) compared with the previous annotation (81.2%) and successfully recovers all nine essential neuropeptide genes previously reported as missing from the draft assembly. This chromosome-scale genomic resource provides an essential foundation for comparative and functional genomics in G. bimaculatus.

genomics↗

bioRxiv2025

Epithelial convergent extension as a tuning process

Self-tuning--the ability of disordered systems to develop desired collective behaviors by tuning internal couplings in response to feedback--has recently emerged as a powerful framework for understanding adaptation in amorphous solids, mechanical metamaterials, and electrical networks. These systems can learn desired responses, encode memory, and robustly reorganize under repeated stimuli, much like artificial neural networks but without requiring processors to adjust their weights. Here, we extend this paradigm to morphogenesis and show that the epithelium can be viewed as tunable matter and that epithelial convergent extension (CE) can be understood as a self-tuning process. Using a vertex model with active interfacial tensions, we systematically compare distinct tension-update strategies, including externally imposed shear, global gradient descent optimization, and decentralized local feedback rules. We find that while all methods can generate tissue elongation, only local orientation- and length-sensitive rules reproduce key experimental features of CE, such as supracellular actomyosin pattern formation, cell shape changes, and junctional alignment. In contrast, global optimization produces homogeneous tension patterns and mechanically fragile states. By interpreting CE through the lens of tuning, our framework bridges the physics of tunable matter with developmental biology, revealing how simple, local rules enable tissues to efficiently orchestrate complex morphogenetic outcomes through decentralized mechanical adaptation.

biophysics↗

bioRxiv2025

Distinct Programs Drive Organ Development and Regeneration

A prevailing paradigm in stem cell and developmental biology posits that regeneration is a recapitulation of embryonic programs, yet the molecular logic underlying these processes remains unclear. Here, using the mammary gland as a model, we identified a novel intermediate cell state essential for basal-to-luminal differentiation during regeneration. The transcription factor Pou2f3 is a master regulator of this state, critical for regeneration but dispensable for organ physiology. Mechanistically, we found that POU2F3 functions as a transcriptional repressor that drives lineage conversion by restricting chromatin accessibility of basal genes rather than by directly activating luminal programs. Furthermore, we uncovered a POU2F3-TNF feedback loop that maintains epithelial homeostasis, where TNF signaling suppresses Pou2f3 to inhibit differentiation, and loss of luminal cells relieves this repression to trigger regeneration. Strikingly, cell fate is governed by signaling pathways essential for cell-cell communication during development, but by Pou2f3-dependent chromatin remodeling for rapid response and injury repair. We validate the regeneration-specific requirement for Pou2f3 in mammary gland and further demonstrate analogous regeneration defects in prostate and pancreas. These findings challenge the long-held assumption that regeneration recapitulates development and establish a framework for understanding context-specific mechanisms of tissue plasticity, with implications for regenerative medicine and epithelial biology.

cell biology↗

bioRxiv2025

Deep-Pose-Tracker: a unified model for behavioural studies of Caenorhabditis elegans

Tracking and analyzing animal behaviour is a crucial step in fields such as neuroscience and developmental biology. Behavioural studies in the nematode C. elegans, for example, help in understanding how organisms respond to external cues and how the specific physiological responses link to either instantaneous or learned behaviours. Although tracking behaviour through locomotion patterns and postural dynamics is routine, it becomes laborious and time-consuming when performed manually. Automation of this process is therefore crucial for accurate and fast detection and analysis. To this end, we report Deep-Pose-Tracker (DPT), a YOLO (You Only Look Once)-based model for automated pose detection of C. elegans from videos and images. The module is further utilized for several downstream analysis algorithms to quantify essential behavioural features, including locomotion speed, orientation, forward or reverse locomotion, and complex body bends such as omega turns. In addition, it includes eigenworms decomposition to represent complex posture dynamics in a low-dimensional space. The model shows reliable performance on the validation and test datasets, with high inference speed, while being user-friendly. DPT, therefore, can be a valuable toolkit for automated behavioural quantification of C. elegans under varying experimental stimuli.

animal behavior and cognition↗

bioRxiv2017

Medaka population genome structure and demographic history unveiled via Genotyping-by-Sequencing

Medaka is a model organism in medicine, genetics, developmental biology and population genetics. Lab stocks composed of more than 100 local wild populations are available for research in these fields. Thus, medaka represents a potentially excellent bioresource for screening disease-risk- and adaptation-related genes in genome-wide association studies. Although the genetic population structure should be known before performing such an analysis, a comprehensive study on the genome-wide diversity of wild medaka populations has not been performed. Here, we performed genotyping-by-sequencing (GBS) for 81 and 12 medakas captured from a bioresource and the wild, respectively. Based on the GBS data, we evaluated the genetic population structure and estimated the demographic parameters using an approximate Bayesian computation (ABC) framework. The autosomal data confirmed that there were substantial differences between local populations and supported our previously proposed hypothesis on medaka dispersal based on mitochondrial genome (mtDNA) data. A new finding was that a local group that was thought to be a hybrid between the northern and the southern Japanese groups was actually a sister group of the northern Japanese group. Thus, this paper presents the first population-genomic study of medaka and reveals its population structure and history based on autosomal diversity.

evolutionary biology↗

bioRxiv2018

Enhanced Waddington Landscape Model with Cell-CellCommunication Can Explain Molecular Mechanisms ofSelf-Organization

The molecular mechanisms of self-organization that orchestrate embryonic cells to create astonishing patterns have been among major questions of developmental biology. It is recently shown that embryonic stem cells (ESCs), when cultured on particular micropatterns, can self-organize and mimic early steps of pre-implantation embryogenesis. A systems-biology model to address this observation from a dynamical systems perspective is essential. Here, we propose a multicellular mathematical model for pattern formation during in vitro gastrulation of human ESCs. This model enhances the basic principles of Waddington epigenetic landscape with cell-cell communication, in order to enable pattern and tissue formation. To prevent overfitting of the model, there is a minimal number of parameters in the model, which are sufficient to address different experimental observations such as the formation of three germ layers and trophectoderm, responses to altered culture conditions and micropattern diameters, and unexpected spotted forms of the germ layers under certain conditions. This model provides a basis for in-silico modeling of self-organization.

systems biology↗

bioRxiv2018

Experimentally Induced Metamorphosis in Axolotl (Ambystoma mexicanum) Under Constant Diet Restructures Microbiota Accompanied by Reduced Limb Regenerative Capacity

Axolotl (Ambystoma mexicanum) is a critically endangered salamander species and a model organism for regenerative and developmental biology. Despite life-long neoteny in nature and in captive-bred colonies, metamorphosis of these animals can be experimentally induced by administering Thyroid hormones (THs). However, biological consequences of this experimental procedure, such as host microbiota response and implications for regenerative capacity, remain largely unknown. Here, we systematically compared host bacterial microbiota associated with skin, stomach, gut tissues and fecal samples based on 16S rRNA gene sequences, along with limb regenerative capacity, between neotenic and metamorphic Axolotls. Our results show that distinct bacterial communities inhabit individual organs of Axolotl and undergo substantial restructuring through metamorphosis. Drastic restructuring was observed for skin microbiota, highlighted by a major transition from Firmicutes-enriched to Proteobacteria-enriched relative abundance and precipitously decreased diversity. Remarkably, shifts in microbiota was accompanied by a steep reduction in limb regenerative capacity. Fecal microbiota of neotenic and metamorphic Axolotl shared relatively higher similarity, suggesting that diet continues to shape microbiota despite fundamental transformations in the host digestive organs. The results provide novel insights into microbiological and regenerative aspects of Axolotl metamorphosis and will establish a baseline for future in-depth studies.

microbiology↗

bioRxiv2018

Optimal feedback mechanisms for regulating cell numbers

How living cells employ counting mechanisms to regulate their numbers or density is a long-standing problem in developmental biology that ties directly with organism or tissue size. Diverse cells types have been shown to regulate their numbers via secretion of factors in the extracellular space. These factors act as a proxy for the number of cells and function to reduce cellular proliferation rates creating a negative feedback. It is desirable that the production rate of such factors be kept as low as possible to minimize energy costs and detection by predators. Here we formulate a stochastic model of cell proliferation with feedback control via a secreted extracellular factor. Our results show that while low levels of feedback minimizes random fluctuations in cell numbers around a given set point, high levels of feedback amplify Poisson fluctuations in secreted-factor copy numbers. This trade-off results in an optimal feedback strength, and sets a fundamental limit to noise suppression in cell numbers. Intriguingly, this fundamental limit depends additively on two variables: relative half-life of the secreted factor with respect to the cell proliferation rate, and the average number of factors secreted in a cells lifespan. We further expand the model to consider external disturbances in key physiological parameters, such as, proliferation and factor synthesis rates. Intriguingly, while negative feedback effectively mitigates disturbances in the proliferation rate, it amplifies disturbances in the synthesis rate. In summary, these results provide unique insights into the functioning of feedback-based counting mechanisms, and apply to organisms ranging from unicellular prokaryotes and eukaryotes to human cells.

systems biology↗