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Results for “developmental biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2026

Euchromatin Peripheral Organization Follows Anterograde Signalling Under Anaesthetic Stress

Anterograde and retrograde signalling establish bidirectional communication between the nucleus and chloroplasts. Retrograde signals from chloroplasts regulate nuclear gene expression while anterograde signals from the nucleus coordinate chloroplast development and maintain cellular homeostasis. How this bidirectional signalling framework extends beyond locus-specific regulation to shape the global spatial organization of nuclear chromatin across tissues remains unclear. Although anaesthesia can alter chromatin organisation, the role of chloroplast dysfunction in these changes remains unclear. Here, we investigate how chloroplast dysfunction and anaesthesia influence euchromatin and heterochromatin organisation in Solanum lycopersicum seedlings across tissues with contrasting photosynthetic competence. Using confocal and super-resolution radial fluctuation (SRRF) imaging with quantitative multiparameter analysis, we identify distinct, tissue-specific chromatin responses to chloroplast disruption and anaesthesia. Notably, anaesthesia induces distinct spatial chromatin changes across tissues that are independent of chloroplast dysfunction, suggesting a direct nuclear response to anaesthesia rather than a chloroplast-mediated retrograde effect. These findings highlight chromatin topology as a potential quantitative biomarker of cellular disruption and provide a framework for investigating anterograde chloroplast-nucleus coordination and stress-responsive nuclear organisation in plants.

plant biology↗

bioRxiv2026

Nuclear Myosin VI stabilises Ku-associated DNA ends during non-homologous end joining

DNA double-strand breaks (DSBs) require rapid signalling and physical stabilisation of broken DNA ends to preserve genome integrity. Here, we identify myosin VI (MVI) as an ATM-regulated component of the DSB response. DNA damage induces rapid nuclear accumulation and nanoscale reorganisation of MVI across multiple cell models, in an ATM-dependent manner. Pharmacological or genetic perturbation of MVI attenuates {gamma}H2AX signalling and disrupts Ku80 organisation, while DNA damage persists. This leads to increased sensitivity to cisplatin and bleomycin. Super-resolution imaging reveals spatial association of MVI with Ku80-containing repair structures, implicating MVI in non-homologous end joining (NHEJ). In a minimal reconstituted system, MVI and actin enhance the proximity of Ku70/80-bound DNA ends. Together, our findings identify MVI as a regulator of DSB repair that links ATM signalling to Ku-associated DNA-end stabilisation and suggest that targeting MVI may sensitise tumour cells to genotoxic therapy.

cancer biology↗

bioRxiv2026

Seed Microbiome Transfer Mitigates Intergenerational Dysbiosis, Modulates Plant Defenses and Suppresses Foliar Disease

Antibiotic-induced disruption of plant-associated microbiomes has the potential to alter host health beyond the directly exposed generation, yet whether the effects of dysbiosis are transmitted through the seed microbiome remains unknown. Here, we investigated the intergenerational impacts of streptomycin-induced dysbiosis in tomato (Solanum lycopersicum), demonstrated that seed microbiome transfer (SMT) restores progeny microbiome function and disease resistance, and characterized the underlying physiological and genetic mechanisms. Parental streptomycin exposure altered the composition of progeny rhizosphere bacterial communities, reduced expression of defense-associated genes, and increased susceptibility to Xanthomonas perforans. Suppression of immune gene expression was strongly associated with increased disease severity, indicating that parental dysbiosis impaired progeny plants ability to mount effective immune responses. Transfer of the seed microbiome from healthy plant donors partially restored rhizosphere community composition, reduced disease severity and recovered defense gene expression of three genes. Together, our findings demonstrated that antibiotic exposure microbiome disturbance generates intergenerational legacy effects that influence plant immunity and disease susceptibility and seed microbiome transfer can counteract this dysbiosis across generations.

plant biology↗

bioRxiv2026

Comparison of evolutionary rescue via biological and cultural evolution

Rapid evolution allows populations to persist in environments where they would otherwise go extinct. This phenomenon, known as evolutionary rescue, is typically studied in the framework of biological evolution, yet adaptive traits can also arise and spread through cultural evolution. The present study developed a stochastic eco-evolutionary model to compare rescue probabilities through biological and cultural evolution. Transmission bias governed the rescue probability under cultural evolution by setting how readily a rare adaptive trait was copied. Conformity bias suppressed population persistence because a rare trait was the least likely to be copied. Content bias toward the adaptive trait enabled evolutionary rescue when social learning was rapid, but it typically yielded a lower rescue probability than biological evolution. Only anticonformity bias, together with a high social learning rate, exceeded the rescue probability of biological evolution by enabling the adaptive trait to be established more rapidly. These results demonstrate that transmission bias alters the demographic consequences of cultural evolution and highlight the importance of transmission processes in evolutionary rescue theory. Understanding how adaptive behaviours are socially transmitted may also improve predictions of animal population persistence and inform conservation efforts in rapidly changing environments.

evolutionary biology↗

bioRxiv2026

Proteolytic Remodeling of Cargo Receptor Networks by RHBDL4 Tunes Secretory Pathway Flux

Cargo receptors are central organizers of the secretory pathway, yet the mechanisms controlling their abundance remain poorly understood. The endoplasmic reticulum (ER)-resident intramembrane protease RHBDL4 promotes substrate turnover via a non-canonical branch of ER-associated degradation and has recently been implicated in regulating secretory pathway components. We previously identified the p24 cargo receptor TMED7 as an RHBDL4 substrate, suggesting that cargo receptor turnover contributes to secretory pathway regulation. Here, quantitative proteomics identify members of the ER-Golgi intermediate compartment (ERGIC) cargo receptor family as endogenous RHBDL4 substrates, demonstrating that RHBDL4 targets multiple cargo receptor families within the early secretory pathway. Accordingly, RHBDL4 modulates multiple ERGIC-dependent transport pathways. In addition, unbiased secretome analysis reveals increased secretion of lysosomal precursor proteins upon RHBDL4 ablation. Mechanistically, we show that this phenotype is mediated, at least in part, by RHBDL4-dependent cleavage of the lysosomal cargo receptor sortilin/SORT1. Together, these findings identify cargo receptors as a major class of RHBDL4 substrates and establish proteolytic remodeling of cargo receptor networks as a mechanism for regulating secretory pathway flux.

cell biology↗

bioRxiv2026

Non-invasive forecasting of skin cancer evolution through longitudinal hair sampling

The ability to longitudinally track clonal evolution non-invasively would transform cancer interception strategies, long before late-stage disease when most cancer genomes are analysed. Here, we demonstrate that repeated hair sampling from the same individual followed by exome sequencing enables tracking of somatic evolution in vivo over several months after chemically induced skin carcinogenesis. We found that hair follicles accumulate a higher mutation burden than spatially-matched skin and harbour mutations that spread into surrounding epidermis and persist throughout tumour progression. DNA-damaged follicles enter sustained quiescence that delays replication and repair, creating a reservoir for long-lived mutations. During premalignant progression, carcinogen-associated mutations become enriched as follicular clones expand into adjacent skin. Mutation tracking identified genes that may govern tumour predisposition and initiation, many of which are mutated at high incidence in human cutaneous squamous cell carcinoma cohorts. Hair follicles therefore provide a non-invasive readout to forecast the early development of skin cancer, enabling patient risk stratification.

cell biology↗

bioRxiv2026

Scalable proxiloids enable human-relevant assessment of kidney proximal tubule toxicity

Drug-induced injury to the human proximal tubule (PT) is a leading cause of acute kidney injury and drug attrition, yet remains difficult to predict preclinically. PT toxicity arises from the coupling of transporter-mediated xenobiotic accumulation and high oxidative metabolic demand. Current models lack key aspects of PT physiology or are difficult to scale for toxicity testing. New Approach Methodologies (NAMs) address this challenge through human-relevant in vitro systems. Here we introduce proxiloids, a scalable suspension-based human induced pluripotent stem cell differentiation strategy. Within 14 days, proxiloids form lumenized, polarized tubular organoids enriched for PT identity, with functional transport and oxidative metabolic competence. Proxiloids are compatible with genetically encoded reporters and standard multiwell assays, enabling detection of defined stress responses. They recapitulate aminoglycoside nephrotoxicity with greater sensitivity than matched two-dimensional cultures and detect adefovir-induced mitochondrial toxicity not predicted in rodents. Together, proxiloids provide a scalable, human-relevant NAM for PT nephrotoxicity assessment.

cell biology↗

bioRxiv2026

The nuclear actin cytoskeleton supports DNA double-strand break repair via VCP-mediated extraction of the KU70/80 complex from damaged chromatin

Double-strand breaks (DSBs) are critical lesions in genomic DNA, and their accurate repair is essential for maintaining genome stability. The nuclear actin cytoskeleton has been implicated in homology-directed repair (HDR) of DSBs. However, the underlying mechanism remains poorly understood. Here, we report that Myosin VI (Myo6), an actin-based motor protein, cooperates with F-actin in end resection and DSB mobilization. Our findings reveal that Myo6 directly interacts with both KU70 and the ubiquitin-dependent segregase VCP to facilitate the extraction of the KU70/80 complex from chromatin. This process is supported by F-actin, revealing an interplay between nuclear actin dynamics and the DSB repair machinery. By elucidating the function of Myo6 and its direct interactions with key repair factors, our study provides mechanistic insight into how repair mechanisms rely on nuclear actin to safeguard genome integrity.

cell biology↗

bioRxiv2026

Predictability failure in glucose-insulin system for ICU patients

Modern medicine implicitly assumes that physiological responses to intervention are predictably determined by administered treatments. However, physiological systems containing intrinsic delays between the detection of a stimulus and the biological response may violate this assumption. We investigate the human glucose-insulin system as described by the Ultradian model and mathematically demonstrate that clinically relevant forcing protocols-such as pulsatile insulin delivery and step-wise glucose infusion, both commonly used in intensive care units (ICUs)-can induce sustained temporal chaos that may hamper accurate prediction of the physiological response. If not accounted for, these chaotic dynamics could create difficulties in achieving optimal dosing and timing when administering glucose and insulin in clinical or home care settings. This phenomenon, termed delay-induced uncertainty (DIU), arises from the interaction between physiological delay, intrinsic shear near a limit cycle, and external forcing. Using the Ultradian glucose-insulin model, we compute top Lyapunov exponents to quantify predictability. Across a range of pulsatile and step-wise forcing regimes, including stochastic amplitudes drawn from Markov processes, we observe positive Lyapunov exponents, indicating sustained chaos. Our results suggest that delayed endocrine regulation may fundamentally limit the predictive value of the models used to develop glycemic management strategies, with implications for clinical protocols in the ICU.

systems biology↗

bioRxiv2026

GDF15 contributes to inflammasome-associated excessive mechanoresponses of hyperlipidemic PdL fibroblasts

Orthodontic tooth movement relies on a tightly regulated pro-inflammatory and pro resorptive mechanoresponse of local periodontal ligament fibroblasts (PdLFs). Dysregulation is linked to complications such as root resorption and tooth loss. Hyperlipidemic conditions promote excessive PdL mechanoresponses, with growth differentiation factor 15 (GDF15) acting as potential regulator. This study examined the contribution of the inflammasome/pyroptosis pathway as underlying mechanism for dysregulated mechanoresponses. Human PdLFs were treated with palmitic acid (PA) or oleic acid (OA) for six days before 24 hours of compressive loading. PA increased CASP1, CASP4, and CASP3 activity, secretion of IL-1{beta}, IL-18, and HMGB1, and LDH release. Pharmacological blockade and siRNA-mediated knockdown of inflammasome- and pyroptosis-related targets revealed that NLRP3, CASP1, CASP4, and GSDMD partially contributed to monocyte and osteoclast overactivation. Silencing PA-increased GDF15, partially normalized the phenotype, at least in part by inflammasome/pyroptosis regulation. GDF15 acted through extracellular, and a nuclear signaling route, each accounting partially to this phenotype. Together, GDF15 partially regulates the PA-induced, pyroptosis-associated overactivated mechanoresponse alongside pyroptosis-independent mechanisms suggesting it as an interesting target for potential clinical interventions.

cell biology↗

bioRxiv2026

The trade-off between parsimony and model complexity for understanding biomedical mechanisms from mathematical models

Mechanistic mathematical models have been used extensively to provide a deeper understanding of biological mechanisms, including unveiling the regulation of tumour growth and its response to various treatments. However, given the breadth of biological regulatory mechanisms, these models are frequently large and thus prone to potential issues with parameter identifiability. Statistical metrics like the Akaike and Bayesian information criteria can help identify a parsimonious model by balancing goodness of fit against model complexity. Yet simple models may fail to provide sufficient biological insight if they do not adequately capture known physiological processes or mechanisms. A modeller must therefore balance hypothesis generation and biological learning with model tractability. Here, we illustrate this balance using models of ovarian cancer growth and treatment response to cisplatin and immune checkpoint blockade in homologous recombination (HR)-deficient and HR-proficient immunocompetent mouse models. We develop a hierarchy of mathematical models of increasing complexity to describe tumour growth, treatment response, and immune dynamics. Our results highlight the limits of relying purely on statistical metrics for model selection, particularly when the goal is to obtain biological insight and underscore the importance of balancing model complexity to avoid overfitting and parameter unidentifiability.

systems biology↗

bioRxiv2026

Critical Fragility Emerges from Chromosomal Instability in Cancer

Genomic instability is a major driver of tumor evolution, promoting diversification and adaptation while simultaneously increasing the accumulation of deleterious alterations. How tumor populations balance these opposing effects remains poorly understood. Here, we introduce a computational framework that explicitly represents diploid genomes, functional gene classes, point mutations, and chromosome-segregation errors in spatially constrained and well-mixed tumor populations. We identify a viability boundary separating sustained tumor expansion from instability-induced population collapse. Within the viable regime, mutation and selection generate a stable distribution of genomic-instability classes that is accurately captured by an analytical replicator--mutator description. Near the viability boundary, tumor dynamics exhibit prolonged extinction transients and strong sensitivity to stochastic fluctuations, with important differences between solid and liquid architectures. Chromosomal alterations further modify growth by creating transient benefits through increased gene dosage and genetic redundancy, while ultimately increasing genomic fragility. Finally, simulated interventions show that eliminating low-instability subpopulations or increasing the global mutational burden can displace tumors beyond their viability boundary and trigger irreversible collapse. These results identify genome instability as both an evolutionary advantage and an intrinsic vulnerability, providing a quantitative framework for developing therapies that exploit the limits of tumor evolution.

cancer biology↗

bioRxiv2026

Heterogeneous and conserved radiation responses reveal FOXM1-dependent regulation of microcephaly genes in glioblastoma

Glioblastoma (GBM) is characterized by marked heterogeneity, glioma stem-like cells (GSCs), and resistance to therapy. Because GSCs share features with neural progenitor cells (NPCs), we investigated whether neurodevelopmental programs contribute to their response to irradiation. Transcriptional profiling of four patient-derived GSC lines revealed cell line-specific responses, with radiosensitivity correlating with the magnitude of p53 activation and basal expression of its negative regulator, MDM2. Despite this heterogeneity, radiation consistently activated p53-dependent pathways and suppressed cell-cycle programs. Among these, genes associated with primary hereditary microcephaly (MCPH) that regulate NPC proliferation were coordinately repressed. Single-cell RNA sequencing localized this response to G2/M-cycling cells. FOXM1 was similarly reduced following irradiation, emerged as a candidate regulator of a subset of MCPH genes, and correlated with their expression in GBM tumors. Pharmacological inhibition of FOXM1 reduced expression of selected MCPH genes and enhanced radiosensitivity in U251 cells. Together, these findings identify coordinated suppression of a FOXM1-associated MCPH program as part of the GBM radiation response, while suggesting that the radiosensitizing effects of pharmacological FOXM1 inhibition extend beyond this transcriptional axis.

cancer biology↗

bioRxiv2026

m1A58 acts as a conformational checkpoint coupling human initiator tRNA maturation to translation initiation

tRNAs are characterized by extensive chemical modifications that influence tRNA fate. N1-methyladenosine at position 58 (m1A58) is a widespread core tRNA modification linked to physiological and pathological processes. However, how m1A58 coordinate tRNA folding and processing to ensure translational efficiency in mammalian cells remains largely unknown. Using acute dTAG-mediated degradation and CRISPR-Cas9 knockout, we identified initiator methionine tRNA (tRNAiMet) as selectively vulnerable to m1A58 loss, lacking the isodecoder buffering observed for most other tRNA isoacceptors. NMR analysis of the tRNAiMet showed that m1A58 stabilizes D/T-loop interactions, consistent with a maturation-competent conformation. In vitro processing assays further demonstrated that m1A58 promotes RNase P-mediated 5'-leader removal and RNase Z-mediated 3'-trailer cleavage, while La/SSB protects accumulated precursors. Disrupting this checkpoint impaired the assembly of the eIF2-containing 43S pre-initiation complex and global protein synthesis, which was substantially rescued by adding m1A58-modified tRNAiMet. Acute TRMT6 degradation elicited temporally coordinated gene-expression responses involving proteostasis, transport and signaling. Together, these findings establish m1A58 as a conformational checkpoint coupling human initiator-tRNA maturation to translation initiation and stress responses.

molecular biology↗

bioRxiv2026

RSV competes with the host for translational machinery without a host shutoff strategy

RNA viruses often enhance ribosome recruitment to their own mRNAs through non-canonical sequence elements or by degrading host mRNA. Respiratory syncytial virus (RSV) produces mRNAs with host-like features, including 5'-cap and poly(A) tail. Therefore, the virus lacks an obvious mechanism to preferentially protect its own mRNAs or recruit ribosomes. Furthermore, it remains unknown how RSV interacts with antiviral defense pathways that would reduce cap-dependent translation. Using spike-in normalized sequencing of total and ribosome-associated RNA, we found that RSV does not appear to evoke any host shutoff mechanisms to limit the expression of host genes. These findings show that RSV manages to make use of available ribosomes by competing effectively with host mRNAs and any translational shutoff mechanism would be detrimental. Consistent with this, we found that following activation of antiviral host pathways that reduce cap-dependent translation, translation of RSV mRNAs is decreased to the same extent as host mRNAs. Furthermore, we found that RSV infection does not trigger the dsRNA-activated kinase PKR (which initiates the ISR) and OAS (activates endonuclease RNase L) pathways. These data support a model in which RSV achieves viral protein production, not though inhibiting the host, but by successfully competing with host mRNAs and avoiding activation of antiviral pathways.

molecular biology↗

bioRxiv2026

Gene duplication of SNAPC1 generates transcription factors for snRNAs and sex-specific piRNAs

Piwi-interacting RNAs (piRNAs) are small non-coding RNAs essential for transposon silencing and germline integrity across metazoans. In many species, piRNA expression is sexually dimorphic, yet the molecular mechanisms underlying this sex specificity remain poorly understood. In Caenorhabditis elegans, sexually dimorphic piRNA expression is regulated at the transcriptional level. We previously identified SNPC-1.3, a paralog of the small nuclear RNA (snRNA) activating protein complex (SNAPc/SNPC) subunit SNAPC1, as a male-specific piRNA transcription factor. However, the factors governing female piRNA expression remained elusive. Here, we identify SNPC-1.2, a second SNPC-1 paralog, as a female-specific piRNA transcription factor. SNPC-1.2 interacts with the core piRNA transcriptional machinery, binds female piRNA loci, is required for female piRNA expression, and promotes hermaphrodite fertility. In contrast, a third paralog, SNPC-1.1, retains the ancestral SNAPc function in snRNA transcription and is dispensable for piRNA biogenesis. Together, these findings reveal how gene duplication and functional specialization within the snpc-1 gene family generate specificity factors that direct the core SNAP complex to distinct genomic targets, providing a molecular mechanism for sexually dimorphic piRNA expression while maintaining canonical snRNA transcription.

molecular biology↗

bioRxiv2026

Initial tumor composition shapes resistance evolution and treatment outcomes in non-small cell lung cancer

Drug resistance is a leading cause of treatment failure in non-small cell lung cancer (NSCLC), yet how resistance evolves during treatment and whether its fitness consequences depend on tumor composition remains poorly understood. Using a game-theoretic mathematical model fitted to longitudinal in-vitro data from alectinib-sensitive and alectinib-resistant H3122 NSCLC cells grown under different treatment and microenvironmental conditions, we found that the fitness effect of evolving resistance depended critically on the initial proportion of resistant cells in the tumor. When resistant cells were initially rare, resistance evolved faster and increasing resistance was associated with a growth advantage. When resistant cells were initially frequent, increasing resistance was associated with a fitness cost. In both cases, increasing resistance eroded treatment efficacy. In the gain-of-resistance regime, stabilization therapy could maintain a stable tumor equilibrium only if resistant cells were excluded. Maximum tolerated dosing was not always optimal for maximizing time to progression; intermediate doses performed better when they kept the initial tumor growth rate close to zero. These results suggest that evolutionary therapy for NSCLC should account not only for the abundance of resistant cells, but also for how resistance is evolving and what fitness consequences it currently carries in individual patients.

cancer biology↗

bioRxiv2026

Lipogenic gene expression and substrate sensitivity in the bovine mammary gland shape milk fat composition

Milk fat is produced by mammary epithelial cells (MEC) through a conserved mechanism shared among all fat-producing cells across biological kingdoms. Although highly conserved, different tissues and organisms produce distinctive fat compositions. Notably, ruminant milk fat is characterized by enrichment in short and medium chain fatty acids. We hypothesized that this unique profile is driven by MEC-specific metabolic characteristics related to their response to lipogenic substrates. To study this, we compared bovine MEC and udder-derived fibroblasts in terms of their lipogenic capacity and fatty acid composition when exposed to lipogenic building blocks. When exposed to acetate, MEC showed coordinated upregulation of acyl-CoA short-chain synthetase 1 (ACSS1) and diacylglycerol transferase (DGAT), while expression of acyl-CoA synthetase long-chain 1 (ACSL1) decreased. Medium chain fatty acids were also elevated in acetate-treated MEC and not in fibroblasts. The role of ACSS1 in the production of medium chain fatty acids in MEC was confirmed by knockdown experiments. Metabolomics analysis showed that in MEC acetate treatment triggered a broad metabolic response, primarily amino acids catabolism, energy and polar lipid metabolism. Collectively, these findings demonstrate effective utilization of acetate for de novo fatty acid synthesis in MEC with preferred tendency to produce medium chain fatty acids.

cell biology↗