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Results for “developmental biology”

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At least 199 records · Page 11Linked to original sources

bioRxiv2018

Morphological, cellular and molecular characterization of posterior regeneration in the marine annelid Platynereis dumerilii

Regeneration, the ability to restore body parts after an injury or an amputation, is a widespread but highly variable and complex phenomenon in animals. While having fascinating scientists for centuries, fundamental questions about the cellular basis of animal regeneration as well as its evolutionary history remain largely unanswered. We study regeneration of the marine annelid Platynereis dumerilii, an emerging comparative developmental biology model, which, like many other annelids, displays important regenerative abilities. If the posterior part of the body is amputated, P. dumerilii worms are able to regenerate the posteriormost differentiated part of the body and stem cell-rich growth zone that allows to make new segments which replace the amputated ones. We show that posterior regeneration is a rapid process that follows a well reproducible paths and timeline, going through specific stages that we thoroughly defined. Wound healing is achieved by one day post-amputation and a regeneration blastema forms one day later. At this time point, some tissue specification already occurs, and a functional posterior growth zone is re-established as early as three days after amputation. Regeneration is only influenced in a minor manner by worm size and position of the amputation site along the antero-posterior axis of the worm and regenerative abilities persist upon repeated amputations without important alterations of the process. We also show that intense cell proliferation occurs during regeneration and that cell divisions are strictly required for regeneration to normally proceed. Finally, through several 5-ethynyl-2-deoxyuridine (EdU) pulse and chase experiments, we provide evidence in favor of a local origin of the blastema, whose constituting cells mostly derive from the segment immediately abutting the amputation plane. The detailed characterization of P. dumerilii posterior body regeneration presented in this article provides the foundation for future mechanistic and comparative studies of regeneration in this species.

developmental biology↗

bioRxiv2019

Self-organised symmetry breaking in zebrafish reveals feedback from morphogenesis to pattern formation

A fundamental question in developmental biology is how the early embryo breaks initial symmetry to establish the spatial coordinate system later important for the organisation of the embryonic body plan. In zebrafish, this is thought to depend on the inheritance of maternal mRNAs [1-3], cortical rotation to generate a dorsal pole of beta-catenin activity [4-8] and the release of Nodal signals from the yolk syncytial layer (YSL) [9-12]. Recent work aggregating mouse embryonic stem cells has shown that symmetry breaking can occur in the absence of extra-embryonic tissue [19,20]. To test whether this is also true in zebrafish, we separated embryonic cells from the yolk and allowed them to develop as aggregates. These aggregates break symmetry autonomously to form elongated structures with an anterior-posterior pattern. Extensive cell mixing shows that any pre-existing asymmetry is lost prior to the breaking morphological symmetry, revealing that the maternal pre-pattern is not strictly required for early embryo patterning. Following early signalling events after isolation of embryonic cells reveals that a pole of Nodal activity precedes and is required for elongation. The blocking of PCP-dependent convergence and extension movements disrupts the establishment of opposing poles of BMP and Wnt/TCF activity and the patterning of anterior-posterior neural tissue. These results lead us to suggest that convergence and extension plays a causal role in the establishment of morphogen gradients and pattern formation during zebrafish gastrulation.

developmental biology↗

bioRxiv2021

Visceral organ morphogenesis via calcium-patterned muscle contractions

How organs achieve their final shape is a problem at the interface between physics and developmental biology. Organs often involve multiple interacting tissue layers that must be coordinated to orchestrate the complex shape changes of development. Intense study uncovered genetic, and physical ingredients driving the form of mono layer tissue. Yet, tracing dynamics across tissue layers, and scales - from cell to tissue, to entire organs - remains an outstanding challenge. Here, we study the midgut of Drosophila embryos as a model visceral organ, to reconstruct in toto the dynamics of multi-layer organ formation in vivo. Using light-sheet microscopy, genetics, computer vision, and tissue cartography, we extract individual tissue layers to map the time course of shape across scales from cells to organ. We identify the kinematic mechanism driving the shape change due to tissue layer interactions by linking out-of-plane motion to active contraction patterns, revealing a convergent extension process in which cells deform as they flow into deepening folds. Acute perturbations of contractility in the muscle layer using non-neuronal optogenetics reveals that these contraction patterns are due to muscle activity, which induces cell shape changes in the adjacent endoderm layer. This induction cascade relies on high frequency calcium pulses in the muscle layer, under the control of hox genes. Inhibition of targets of calcium involved in myosin phosphorylation abolishes constrictions. Our study of multi-layer organogenesis reveals how genetic patterning in one layer triggers a dynamic molecular mechanism to control a physical process in the adjacent layer, to orchestrate whole-organ shape change.

developmental biology↗

bioRxiv2018

A Fasciclin 2 functional switch controls organ size in Drosophila

How cell to cell interactions control local tissue growth to attain a species-specific pattern and organ size is a central question in developmental biology. The Drosophila Neural Cell Adhesion Molecule, Fasciclin 2 (Drosophila NCAM), is expressed during the development of neural and epithelial organs. Genetic mosaic analysis of Fasciclin 2 reveals two complementary and opposing functions during imaginal disc growth, a cell autonomous requirement to promote growth and an opposite non-cell autonomous function to restrain growth at high expression levels. This non-cell autonomous function is mediated by the Fasciclin 2 heterophilic-binding partners CG15630 and CG33543. We show that EGFR physically interacts with Fasciclin 2 and mediates both the cell autonomous and the non-cell autonomous function. We further show that EGFR activity in turn promotes the cell autonomous expression of Fasciclin 2. We suggest that the auto-stimulatory loop between EGFR and Fasciclin 2 operates until reaching a threshold where the Fasciclin 2 non-cell autonomous function counteracts the growth-promoting activity of the homophilic interaction to terminate imaginal disc growth. Accordingly, we have found that Fasciclin 2 limits imaginal disc growth by the end of larval development. Cellular integration of Fasciclin 2 autonomous and non-cell autonomous signaling from neighbor cells may be a key regulator component to orchestrate the rate of intercalary cell proliferation and the final size of an organ.\n\nAuthor SummaryOne of the key unsolved problems in Biology is how a species-specific size is attained during animal development. During development cells should compute the amount of intercalary tissue growth to stop cell proliferation when reaching a correct pattern and size. Classic studies demonstrated that local cell interactions are key in controlling organ growth to reach a correct size and pattern in vertebrates and invertebrates. We present evidence strongly suggesting that Fasciclin 2 (the ortholog of NCAM in Drosophila) functions as a growth level switch to control pattern and organ size. First, we use genetic mosaic analyses to show that Fasciclin 2 promotes organ growth in a cell autonomous manner. Then we show that Fasciclin 2 restrains growth at high expression levels in a non-cell autonomous manner, and that there is a requirement for Fasciclin 2 to limit growth by the end of larval development. This function is dependent on Fasciclin 2 heterophilic binding partners CG15630 and CG33543. The Epidermal Growth Factor receptor mediates both functional facets of Fasciclin 2 and its activity in turn increases Fasciclin 2 cell autonomous expression, suggesting the existence of a functional auto-stimulatory loop. We also show that the Epidermal Growth Factor receptor and Fasciclin 2 physically interact. Our results show that the amount of Fasciclin 2 between cells determines organ size by acting as an expression level switch for EGFR function, and suggest that other specific CAM interactions may integrate similar expression level switches acting as a code for cells to compute local growth in attaining a species-specific organ size and shape.

developmental biology↗

bioRxiv2018

Asymmetric histone incorporation during DNA replication in Drosophila male germline stem cells

One Sentence SummaryDNA replication establishes asymmetric epigenomes SummaryOne of the most fundamental questions in developmental biology concerns how cells with identical genomes differentiate into distinct cell types. One important context for understanding cell fate specification is asymmetric cell division, where the two daughter cells establish different cell fates following a single division. Many stem cells undergo asymmetric division to produce both a self-renewing stem cell and a differentiating daughter cell1-5. Here we show that histone H4 is inherited asymmetrically in asymmetrically dividing Drosophila male germline stem cells, similar to H36. In contrast, both H2A and H2B are inherited symmetrically. By combining superresolution microscopy with the chromatin fiber method, we are able to study histone inheritance patterns on newly replicated chromatin fibers. Using this technique, we find asymmetric inheritance patterns for old and new H3, but symmetric inheritance patterns for old and new H2A on replicating sister chromatids. Furthermore, co-localization studies on isolated chromatin fibers and proximity ligation assays on intact nuclei reveal that old H3 are preferentially incorporated by the leading strand while newly synthesized H3 are enriched on the lagging strand. Finally, using a sequential nucleoside analog incorporation assay, we detect a high incidence of unidirectional DNA replication on germline-derived chromatin fibers and DNA fibers. The unidirectional fork movement coupled with the strand preference of histone incorporation could explain how old and new H3 are asymmetrically incorporated by replicating sister chromatids. In summary, our work demonstrates that the intrinsic asymmetries in DNA replication may help construct sister chromatids enriched with distinct populations of histones. Therefore, these results suggest unappreciated roles for DNA replication in asymmetrically dividing cells in multicellular organisms.

developmental biology↗

bioRxiv2026

High efficiency gene editing and phenotype generation in avian embryos using lipid nanoparticles as a vector delivery platform

Birds are a longstanding developmental biology model because easy access to their fertilized eggs allows for direct observation and experimental manipulation during any stage of embryonic growth prior to hatching. However, functional genetics studies in avian embryos continue to rely primarily on in ovo electroporation and viral transduction, each of which is limited by variable efficiency, procedure-induced embryonic defects, substantial embryo mortality, and ineffective delivery of gene editing reagents such as CRISPR/Cas9. Here we establish lipid nanoparticle (LNP)-mediated delivery as a reproducible alternative for manipulating gene expression in avian embryos with high viability. Using the chicken embryo (Gallus gallus), we targeted migrating cranial NCCs, which contribute extensively to the craniofacial skeleton. We optimized LNP formulation and injection timing and frequency to build a robust and adaptable pipeline that offers efficient delivery of plasmid DNA and RNA cargos. We show that LNP delivery can support the piggyBac transposon system, enabling persistent reporter expression and long-term labeling of cranial NCC derivatives. To test if LNP-mediated delivery of RNA-based CRISPR/Cas9 components can achieve efficient somatic genome editing in ovo, we targeted Runt-related transcription factor 2 (RUNX2), which is required for osteogenesis. Embryos with RUNX2 edits in their cranial NCCs show a severe loss and disruption of craniofacial ossification on the targeted side of their craniofacial skeletons, demonstrating the potential of this approach for rapid functional interrogation of gene function in vivo. We also show that LNPs can mediate transfection in domestic pigeon (Columba livia) and Pekin duck (Anas platyrhynchos) embryos, indicating this method can be deployed across avians as a vector delivery platform for studying development, disease, and evolution.

developmental biology↗

bioRxiv2022

Transcriptional profiling from whole embryos to single neuroblast lineages in Drosophila

Embryonic development results in the production of distinct tissue types, and different cell types within each tissue. A major goal of developmental biology is to uncover the "parts list" of cell types that comprise each organ. Here we perform single cell RNA sequencing (scRNA-seq) of the Drosophila embryo to identify the genes that characterize different cell and tissue types during development. We assay three different timepoints, revealing a coordinated change in gene expression within each tissue. Interestingly, we find that the elav and mhc genes, whose protein products are widely used as markers for neurons and muscles, respectively, show broad pan-embryonic expression, indicating the importance of post-transcriptional regulation. We next focus on the central nervous system (CNS), where we identify genes characterizing each stage of neuronal differentiation: from neural progenitors, called neuroblasts, to their immediate progeny ganglion mother cells (GMCs), followed by new-born neurons, young neurons, and the most mature neurons. Finally, we ask whether the clonal progeny of a single neuroblast (NB7-1) share a similar transcriptional identity. Surprisingly, we find that clonal identity does not lead to transcriptional clustering, showing that neurons within a lineage are diverse, and that neurons with a similar transcriptional profile (e.g. motor neurons, glia) are distributed among multiple neuroblast lineages. Although each lineage consists of diverse progeny, we were able to identify a previously uncharacterized gene, Fer3, as an excellent marker for the NB7-1 lineage. Within the NB7-1 lineage, transcriptional clusters are identifiable in neuroblasts and neurons, and each cluster is composed of current temporal transcription factor (e.g. Hunchback, Kruppel, Pdm, and Castor), novel temporal factors, and/or targets of the temporal transcription factors. In conclusion, we have characterized the embryonic transcriptome for all major tissue types and for three stages of development, as well as the first transcriptomic analysis of a single, identified neuroblast lineage, finding a lineage-enriched transcription factor.

developmental biology↗

bioRxiv2022

Organoid-based single-cell spatiotemporal gene expression landscape of human embryonic development and hematopoiesis

Single-cell level characterization of embryonic development is a major benchmark of human developmental biology. Spatiotemporal analysis of stem-cell-derived embryos offers conceptual and technical advances in the field. Here, we defined the single-cell spatiotemporal gene expression landscape of human embryonic development with stem-cell-derived organoids. We established the human embryonic organoid (HEMO) from expanded potential stem cells and achieved both embryonic and extraembryonic tissues in the same organoid. Time-series single-cell RNA sequencing paired with single-cell resolution spatial revealed human embryonic development signatures such as extraembryonic placenta, yolk sac hematopoiesis neural crest, blood vessels, and cardiac mesoderm. Hematopoietic tissues eventually predominated HEMO with erythropoiesis, mekagaryopiesis, and myelopoiesis. Cell-cell communication network analysis demonstrated that trophoblast-like tissues supplied WNT signaling in neural crest cells to facilitate maturation and migration. Single-cell resolution spatial transcriptomics defined the yolk sac erythro-megakaryopoietic niche. Vitronectin-integrin signaling, a major contributor to megakaryocyte maturation, was predominant in the yolk sac niche in HEMO and to human fetal samples. Overall, our study advances the spatiotemporal analysis of human embryonic development in stem-cell-derived organoids. HighlightsO_LIModeling human embryonic development from stem cells C_LIO_LIUsed of both 10X Chromium and 10X Visium to define the gene expression landscape of embryonic development and hematopoiesis C_LIO_LIWNT signaling as a regulator of neural crest maturation and EMT C_LIO_LIVTN-ITGA2B as the main contributor to Mk maturation within the yolk sac erythro-megakaryopoietic niche C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/505700v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1710d00org.highwire.dtl.DTLVardef@10ca8e0org.highwire.dtl.DTLVardef@2310d1org.highwire.dtl.DTLVardef@252728_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2017

High-throughput live-imaging of embryos in microwell arrays using a modular, inexpensive specimen mounting system

Live-imaging embryos in a high-throughput manner is essential for shedding light on a wide range of questions in developmental biology, but it is difficult and costly to mount and image embryos in consistent conditions. Here, we present OMMAwell, a simple, reusable device that makes it easy to mount up to hundreds of embryos in arrays of agarose microwells with customizable dimensions and spacing. OMMAwell can be configured to mount specimens for upright or inverted microscopes, and includes a reservoir to hold live-imaging medium to maintain constant moisture and osmolarity of specimens during time-lapse imaging. All device components can be cut from a sheet of acrylic using a laser cutter. Even a novice user will be able to cut the pieces and assemble the device in less than an hour. At the time of writing, the total materials cost is less than five US dollars. We include all device design files in a commonly used format, as well as complete instructions for its fabrication and use. We demonstrate a detailed workflow for designing a custom mold and employing it to simultaneously live-image dozens of embryos at a time for more than five days, using embryos of the cricket Gryllus bimaculatus as an example. Further, we include descriptions, schematics, and design files for molds that can be used with 14 additional vertebrate and invertebrate species, including most major traditional laboratory models and a number of emerging model systems. Molds have been user-tested for embryos including zebrafish (Danio rerio), fruit fly (Drosophila melanogaster), coqui frog (Eleutherodactylus coqui), annelid worm (Capitella teleta), amphipod crustacean (Parhyale hawaiensis), red flour beetle (Tribolium castaneum), and three-banded panther worm (Hofstenia miamia), as well mouse organoids (Mus musculus). Finally, we provide instructions for researchers to customize OMMAwell inserts for embryos or tissues not described herein.\n\nSummary StatementThis Techniques and Resources article describes an inexpensive, customizable device for mounting and live-imaging a wide range of tissues and species; complete design files and instructions for assembly are included.

developmental biology↗

bioRxiv2025

In toto imaging of germ plasm dynamics reveals an essential role for early distribution of germ granules in germline development

A fundamental question in developmental biology is how the fertilized egg gives rise to all the different cell types of an organism. The traditional view is that the different cell types are specified either by intrinsic factors such as cell fate determinants or via intercellular signaling. In some animals a cytoplasmic determinant-like substance called germplasm specifies the germline. In zebrafish eggs, germplasm is dispersed in form of mRNP complexes called germ granules, which are enriched at the animal pole. After fertilization the distribution of germ granules changes dramatically. The germ granules accumulate in the corners of the first two cleavage furrows of the embryo, to form four large masses that are essential for germline development. Although germ granule movement has been linked to the network dynamics of the microtubular and actin cytoskeleton, a clear mechanistic understanding of the process is currently lacking. Fundamental questions about germplasm dynamics, including "What is the main driving force?" have not been answered yet. To address this gap, we performed careful quantitative analysis of germ granule dynamics relative to dynamic cytoskeletal reorganization in early zebrafish embryos by live-imaging. We identified stereotypic signatures of germ granule dynamics across different regions of the early embryo. Interestingly, we find that the timing of large-scale germ granule movements contrasts prevailing models for the mechanism of germ granule aggregation during cleavage divisions, and rather points to cytokinetic apparatus itself. Using zebrafish mutants affecting the RNA-binding protein Ybx1 (Y-box binding-protein 1), we show that the timing and dynamics of germ granule accumulation in the blastodisc is a crucial factor for appropriate later aggregation into cleavage furrows and eventual distribution to PGCs. Germplasm accumulation in the cleavage furrows is reduced and ectopic aggregates form at the blastoderm margin of ybx1 mutant embryos. Our work establishes Ybx1 as a novel factor with crucial functions in germplasm distribution and suggests that additional factors drive normal germplasm dynamics.

developmental biology↗

bioRxiv2025

Cell jamming transitions shape regulatory protein gradients and prime evolutionary divergence

A long-standing goal of evolutionary developmental biology is to identify the mechanisms underlying criticality of developmental transitions that allow processes governing individual cells scale up to the organism-level patterning. The viscoelastic properties of embryonic tissues imply collective cell behaviors, leading to the expectation that signaling networks should capitalize on the material properties of tissues, structuring morphogenesis around the spatial and temporal transitions that they induce. Here, we show that this interaction is evident even prior to tissue differentiation and is traceable to behavior of individual cells. In avian beak primordia, we find that fields of mesenchymal cells undergo cycles of local jamming dynamically modulating coordination of cell shape and movement. These cycles progressively alter the spatial reach of regulatory proteins, strongly expanding or restricting their gradients based on tissue mechanical state. Tissue-level gradients of proteins most sensitive to local cell jamming transitions also diverge the most across populations, priming tissue compartmentalization. These findings suggest that the material state transition is an effective interface for integration of stochastic physical processes and genetic regulation and is well placed to underlie criticality of developmental systems allowing local rules governing cell-state transitions scale up to tissue-level patterning. More broadly, our findings reveal how transient material transitions reset developmental trajectories and promote diversification while preserving robustness.

evolutionary biology↗

bioRxiv2025

Inferring Cell Differentiation Dynamics with Unobserved Progenitors

A cell differentiation map describes the transitions between cell types during a developmental process, and determining this map is a key challenge in developmental biology. Recent single-cell lineage tracing technologies generate lineage trees that describe the history of cell divisions during a developmental process but do not directly measure differentiation events between cell types. Current approaches to infer cell differentiation maps from cell lineage trees make unrealistic assumptions about the developmental process, do not allow for unobserved progenitor cell types, or do not infer cell-type specific rates of growth and transitions. To address these issues, we introduce TROUPE, a likelihood-based framework that infers differentiation and growth dynamics directly from leaf-labeled cell lineage trees while allowing for unobserved progenitor types via biologically motivated potency constraints. We provide an efficient algorithm for computing the maximum likelihood transition and growth rates, as well as a simple model-selection scheme to choose the number of unobserved types. On simulations, TROUPE recovers transition and growth rates better than previous approaches even when there are unobserved types. We apply TROUPE to a model of mammalian development, Trunk-Like Structures (TLS), and show that TROUPE computes reasonable rates of self-renewal and differentiation in both standard and perturbed conditions.

developmental biology↗

bioRxiv2026

SCOPE: Localizing fate-decision states and their regulatory drivers in single-cell differentiation

Identifying the precise transcriptomic states at which cells commit to a lineage (branchpoints) and the temporal lag in which chromatin accessibility foreshadows gene expression (epigenetic priming) remain fundamental challenges in developmental biology. While current methods for single-cell sequencing data effectively capture developmental flow, they often lack a principled mechanism for delineating the discrete boundaries, a crucial aspect required to map the molecular logic of lineage commitment. We present SCOPE (Semi-supervised Conformal Prediction), a framework that transforms high-dimensional single-cell measurements into rigorous, discrete prediction sets of all plausible future fates. By formalizing fate uncertainty via conformal inference, SCOPE localizes the precise biological windows during which multipotent progenitors specify their fate. In multi-omic data, SCOPE uncovers epigenetic priming and identifies its driving transcription factors by detecting regimes where chromatin-derived prediction sets resolve toward terminal fates significantly before their transcriptomic counterparts. We apply SCOPE across simulations, lineage-traced mouse hematopoiesis, multiple human hematopoietic datasets, and human retinogenesis to demonstrate its broad applicability and ability to recapitulate known fate specification drivers. Ultimately, SCOPE provides a statistically grounded foundation for localizing fate decisions across biological replicates and modalities, offering a robust tool for identifying the onset of lineage specification in complex developmental systems.

cell biology↗

bioRxiv2022

Sagittarius: Extrapolating Heterogeneous Time-Series Gene Expression Data

Understanding the temporal dynamics of gene expression is crucial for developmental biology, tumor biology, and biogerontology. However, some timepoints remain challenging to measure in the lab, particularly during very early or very late stages of a biological process. Here we propose Sagittarius, a transformer-based model that can accurately simulate gene expression profiles at timepoints outside of the range of times measured in the lab. The key idea behind Sagittarius is to learn a shared reference space for time series measurements, thereby explicitly modeling unaligned timepoints and conditional batch effects between time series, and making the model widely applicable to diverse biological settings. We show Sagittariuss promising performance when extrapolating mammalian developmental gene expression, simulating drug-induced expression at unmeasured dose and treatment times, and augmenting datasets to accurately predict drug sensitivity. We also used Sagittarius to extrapolate mutation profiles for early-stage cancer patients, which enabled us to discover a gene set connected to the Hedgehog signaling pathway that may be related to tumorigenesis in sarcoma patients, including PTCH1, ARID2, and MYCBP2. By augmenting experimental temporal datasets with crucial but difficult-to-measure extrapolated datapoints, Sagittarius enables deeper insights into the temporal dynamics of heterogeneous transcriptomic processes and can be broadly applied to biological time series extrapolation.

genomics↗

bioRxiv2018

A comprehensive reference transcriptome resource for the Iberian ribbed newt Pleurodeles waltl, an emerging model for developmental and regeneration biology

Urodele amphibian newts have unique biological properties, notably including prominent regeneration ability. Iberian ribbed newt, Pleurodeles waltl, is a promising model newt along with the successful development of the easy breeding system and efficient transgenic and genome editing methods. However, genetic information of P. waltl was limited. In the present study, we conducted an intensive transcriptome analysis of P. waltl using RNA-sequencing to build gene models and annotate them. We generated 1.2 billion Illumina reads from a wide variety of samples across 11 different tissues and 9 time points during embryogenesis. They were assembled into 202,788 non-redundant contigs that appear to cover nearly complete (~98%) P. waltl protein-coding genes. Using the gene set as a reference, our gene network analysis identified regeneration-, developmental-stage-, and tissue-specific co-expressed gene modules. Ortholog analyses with other vertebrates revealed the gene repertoire evolution of amphibians which includes urodele-specific loss of bmp4 and duplications of wnt11b. Our transcriptome resource will enhance future research employing this emerging model animal for regeneration research as well as other areas such as developmental biology, stem cell biology, cancer research, ethology and toxico-genomics. These data are available via our portal website, iNewt (http://www.nibb.ac.jp/imori/main/).

genomics↗

bioRxiv2025

Learning Latent Trajectories in Developmental Time Series with Hidden-Markov Optimal Transport

Deriving the sequence of transitions between cell types, or differentiation events, that occur during organismal development is one of the fundamental challenges in developmental biology. Single-cell and spatial sequencing of samples from different developmental timepoints provide data to investigate differentiation but inferring a sequence of differentiation events requires: (1) finding trajectories, or ancestor:descendant relationships, between cells from consecutive timepoints; (2) coarse-graining these trajectories into a differentiation map, or collection of transitions between cell types, rather than individual cells. We introduce Hidden-Markov Optimal Transport (HM -OT), an algorithm that simultaneously groups cells into cell types and learns transitions between these cell types from developmental transcriptomics time series. HM -OT uses low-rank optimal transport to simultaneously align samples in a time series and learn a sequence of clusterings and a differentiation map with minimal total transport cost. We assume that the law governing cell-type trajectories is characterized by the joint law on consecutive time points, tantamount to a Markov assumption on these latent trajectories. HM -OT can learn these clusterings in a fully unsupervised manner or can generate the least-cost cell type differentiation map consistent with a given set of cell type labels. We validate the unsupervised clusters and cell type differentiation map output by HM -OT on a Stereo-seq dataset of zebrafish development, and we demonstrate the scalability of HM -OT to a massive Stereo-seq dataset of mouse embryonic development. Code availabilitySoftware is available at https://github.com/raphael-group/HM-OT

bioinformatics↗

bioRxiv2026

Co-option of a mouse-specific retrotransposon rewires Ash2l isoform usage to prime developmental promoters

How pluripotent stem cells pre-configure the chromatin landscape to enable timely activation of developmental gene programs remains a central question in developmental biology. Here we demonstrate that the core chromatin regulator ASH2L undergoes a developmentally regulated transcription start site (TSS) switch that generates two protein isoforms with distinct developmental functions: a full-length ASH2L containing an N-terminal intrinsically disordered region (IDR), and a conserved, truncated protein isoform lacking this region. In mouse pluripotent stem cells, a lineage-specific ERV-K retrotransposon drives the upstream TSS, which suppresses the downstream TSS through transcription-coupled SETD2-mediated histone H3 lysine 36 methylation. The resulting stem cell-specific truncated ASH2L assembles into COMPASS complexes and enhances histone H3 lysine 4 trimethylation at promoters governing early development. Despite being restricted to pluripotent stem cells, truncated ASH2L is required for proper axial patterning in gastruloids and for the transition of neural progenitors to motor neurons. This temporal decoupling, wherein a chromatin state established during pluripotency executes its function only after the establishing isoform disappears, defines an epigenetic priming mechanism for developmental timing. Thus, lineage-specific retrotransposon co-option reveals how a dedicated protein isoform configures the pluripotent epigenome for developmental transitions after its own expression has ceased.

molecular biology↗

bioRxiv2024

Rapid speciation in the holopelagic ctenophore Mnemiopsis following glacial recession

BackgroundUnderstanding how populations diverge is one of the most compelling questions in evolutionary biology but our grasp on the genomic mechanisms underpinning divergence is limited to a handful of species. Indeed, we know even less about divergence in the pelagic zone, where barriers to gene flow are seemingly absent. The holopelagic ctenophore Mnemiopsis leidyi is the most widely used ctenophore in experimental biology and has become an important model system in studies ranging from developmental biology to neurobiology. In addition, its relatively small and tractable genome provides a powerful foundation for genomic and evolutionary analyses. However, we still lack a clear understanding of species boundaries, population structure, and the evolutionary forces shaping divergence within Mnemiopsis, limiting both evolutionary and ecological interpretations. To expand our general understanding of divergence across novel environments as well as resolve a long-standing taxonomic debate, we generated the most comprehensive genomic study to date of the holopelagic ctenophore Mnemiopsis across a large expanse of its native range. ResultsBy leveraging multiple analytical approaches and generating two near-chromosome level genomes, we identify two distinct species of Mnemiopsis with high levels of genome-wide divergence along the US Atlantic coast, which correspond to M. leidyi and M. gardeni. Our demographic analyses suggest that M. leidyi and M. gardeni began to diverge during the mid-to-late Pleistocene climate transitions and were later shaped by post-glacial oceanographic changes. We highlight substantial genomic rearrangements and copy number variation between species as well as uncover key genes under selection that are likely important for environmental adaptation. ConclusionsTogether, these findings provide compelling evidence that the ctenophore currently recognized as M. leidyi represents more than one species. Recognizing cryptic species boundaries is critical for future study designs, environmental monitoring, and developing targeted management strategies. Altogether, we connect microevolutionary processes with macroevolutionary patterns and provide new insights into how ocean dynamics drive speciation and adaptation in pelagic ecosystems.

evolutionary biology↗