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bioRxiv2026

Gene-metabolite networks reveal physiological trade-offs but not transcriptional co-regulation between carotenoids and dry matter in cassava (Manihot esculenta) roots

Provitamin A biofortification of cassava (Manihot esculenta) is constrained by a negative genetic correlation between total carotenoid (TC) and dry matter (DM) contents, but its underlying biological mechanism remains unclear. We examined this relationship in 24 African, Latin American, and hybrid cassava genotypes by measuring gene expression and metabolites in inner and outer storage root layers that varied spatially in carotenoid accumulation, enabling comparisons across and within genotypes. TC, and particularly upstream cis-carotenes, were negatively associated with DM after accounting for genotype, and this relationship strengthened across developmental timepoints, consistent with a physiological component of the trade-off. Gene-metabolite co-expression networks constructed from genetic, non-genetic, and overall phenotypic trait components showed no significant topological overlap between carotenoid- and starch-related gene sets, indicating that the TC/DM relationship is not driven by transcriptional co-regulation of the main pathways, although individual associations between carotenoids and carbohydrate-related genes suggested possible indirect metabolic links. Instead, TC accumulation was most strongly associated with regulatory, stress-, redox-, and plastid-related genes, enriched for heme-binding and oxidoreductase functions. These findings suggest that the TC/DM trade-off is not a fixed constraint, and identify candidate regulators of carotenoid content for future functional validation to support cassava provitamin A biofortification. HighlightGenetic, spatial, and developmental variation in cassava storage roots implicate cis-carotenes, but not direct transcriptional regulation of the carotenoid and starch pathways, in the trade-off between carotenoids and dry matter.

plant biology↗

bioRxiv2026

Binding to Albumin and Off-Target Toxicity Confound the Use of LRRC8/VRAC Channel Blockers in Cell Physiology Assays

Volume-regulated anion channels (VRACs), formed by leucine-rich repeat-containing 8 (LRRC8) proteins, are ubiquitously expressed chloride channels essential for cell volume regulation and implicated in diverse physiological and pathological processes. Small-molecule VRAC inhibitors have been reported to modulate paracrine signaling, proliferation, differentiation, migration, and apoptosis, and have been patented for potential therapeutic applications in stroke, cardiovascular and metabolic diseases, and cancer. However, growing evidence indicates that many commonly used VRAC blockers exert substantial off-target effects and frequently fail to reproduce phenotypes observed after deletion of the essential VRAC subunit LRRC8A. Here, we systematically compared effects of several widely used pharmacological VRAC inhibitors with outcomes of molecular downregulation of LRRC8A in limiting proliferation of malignant glioblastoma cells derived from surgical specimens. NIH/3T3 fibroblasts served as a non-malignant control. In serum-containing media, structurally diverse VRAC blockers (DCPIB, DIDS, carbenoxolone, phloretin, and bromadiolone) reduced proliferation in a non-uniform manner, with potencies that did not correlate with reported VRAC affinities and varied markedly among cell lines. Radiotracer-based measurements of VRAC activity indicated that these discrepancies were largely attributable to binding of inhibitors to serum albumin. When experiments were repeated under serum-free conditions, all inhibitors except DIDS and phloretin induced extensive death of both malignant and non-malignant cells, confirmed by microscopy and LDH release assays. This cytotoxicity was accompanied by a marked reduction in intracellular ATP levels, consistent with previously reported mitochondrial uncoupling effects. In contrast, LRRC8A knockdown reduced proliferation without substantial cell death. Together, these findings demonstrate that most commercially available VRAC blockers limit proliferation and viability predominantly through VRAC-independent mechanisms. Under standard culture conditions, serum albumin masks much of their intrinsic cytotoxicity. These results underscore the need for rigorous molecular controls in pharmacological studies and provide basis for developing more selective and less toxic VRAC-targeting agents.

pharmacology and toxicology↗

bioRxiv2026

Effects of different shading levels on growth, physiology and leaf surface micromorphology of Sorbus sibirica "Dong Hong" seedlings

BackgroundSorbus sibirica Dong Hong is a promising ornamental cultivar, but its optimal light conditions remain unclear. AimsThis study evaluated the effects of shading on seedling growth, physiology, root morphology, and leaf surface micromorphology. MethodsOne-year-old seedlings were grown under full sunlight (CK) and 30%, 50%, or 70% shade for 100 days. Growth, biomass, root traits, chlorophyll, invertase, soluble protein, stomatal characteristics, and epicuticular wax morphology were determined. ResultsShading significantly affected all measured traits. The 30% shade treatment produced the greatest seedling height, which increased by 118.18% compared with CK, and the highest chlorophyll content, which increased by 120.21%. Soluble protein content was slightly increased, whereas invertase activity decreased under moderate shading. Although total biomass decreased by 18.63%, root development remained relatively stable under 30% shade, with slight increases in total root length and average root diameter. Stomatal density was highest under this treatment, and the epicuticular wax structure remained relatively regular. In contrast, 70% shade markedly inhibited biomass accumulation and root development. ConclusionsModerate shading, particularly 30%, provided the most favorable light environment for Sorbus sibirica Dong Hong seedlings and is recommended for summer nursery cultivation in Northeast China.

plant biology↗

bioRxiv2026

High-level ciprofloxacin resistance in Pseudomonas aeruginosa is associated with genomic adaptation, collateral antibiotic susceptibility, and physiological trade-offs

Antimicrobial resistance in Pseudomonas aeruginosa has emerged as a major clinical concern. Ciprofloxacin has potent intrinsic activity against P. aeruginosa, but resistance to this antibiotic is increasingly reported in clinical settings. In this study, P. aeruginosa ATCC 27853 strain was exposed to gradually increasing ciprofloxacin concentrations for 50 passages ([~]100 days). The final selected resistant strain (CIP-R) with 256-fold of minimum inhibitory concentration was studied further. Whole-genome sequencing revealed 12 genomic alterations, including known mutations in the quinolone resistance-determining genes gyrA (Thr83Ile), parC (Thr177Asn), parE (Glu459Lys). A duplication mutation in nfxB (Tyr153_Gly154dup) was also observed. In addition to these genes, we observed mutations in pilA, tadB, psdR, NP446_RS32055 (TRAP transporter permease), multiple dppA3 variants, and a prophage-associated hypothetical gene (NP446_RS24255), which have not been reported previously. The gyrA Thr83Ile substitution was conserved in 86.38% of ciprofloxacin-resistant clinical isolates retrieved from the NCBI database. Resistance acquisition was accompanied by slower growth, impaired swimming and swarming motility, diminished surface attachment, reduced biofilm formation. The resistant strain has enhanced {beta}-lactamase activity, and resistance to levofloxacin, cefepime, and meropenem together with sensitivity to piperacillin-tazobactam and aztreonam. This study highlights the gyrA Thr83Ile mutation as a key genomic marker for molecular screening of ciprofloxacin resistance and reveals secondary adaptive trade-offs that can be targeted for clinical diagnostic and therapeutic decision-making. In conclusion, achieving high-level ciprofloxacin resistance in P. aeruginosa involves non-target-site genomic adaptations and physiological trade-offs beyond classical target mutations.

microbiology↗

bioRxiv2026

Cumulative effects of nylon microplastic fibres and warming temperature on the behavior and physiology of marine threespine stickleback (Gasterosteus aculeatus)

Populations are exposed to multiple anthropogenic stressors simultaneously; however, the combined effects are poorly understood. Climate change is starkly impacting marine ecosystems and consequently fishes, with warming temperatures and increases in frequencies and durations of extreme climate events. Concurrently, plastics, such as nylon used in fishing industries, are contaminating marine waters at unprecedented levels, with detrimental effects on fishes. Here we studied the cumulative effects of warming and nylon microplastic fibres on the behavior and physiology of threespine stickleback (Gasterosteus aculeatus) by exposing fish to conditions of 15{degrees}C and 20{degrees}C and nylon concentrations of 0, 1, 10, and 100 mg/g (mg nylon/g food) for 4 weeks. Feeding rates responded complexly to multiple stressors, as increasing concentrations of plastic reduced feeding rates, with warming having an antagonistic effect. Furthermore, we observed "coughing" behaviors in response to ingestion of microfibres and a unique reselection tendency of food items previously selected by conspecifics. Under warming conditions, critical thermal maximum (CTmax) increased; however, exposure to plastics led to reductions in CTmax and thermal safety margins. Given these results, we anticipate reduced acclimation capacities, greater anxiety, and reductions in foraging efficiencies with increasing concentrations of plastic. Cumulatively, these stressors will yield greater energetic trade-offs and decreased accuracy in food selection with stark implications for marine ecosystem dynamics.

ecology↗

bioRxiv2026

Unraveling emotional signatures: comparing physiological methods and algorithm-based recognition of spontaneous emotional facial expressions

Recognizing others emotions is central to social interaction. Traditional biological psychology infers emotional responding via laboratory measures, whereas contemporary computer vision algorithms claim to identify emotions unobtrusively from facial video. However, the validity of such algorithms for classifying spontaneous emotional responses occurring without explicit communicative intent remains debated. We compared established psychophysiological measures (EEG, facial EMG, EDA activity) with the open-source facial behavior toolkit OpenFace for classifying participants spontaneous responses during free viewing of happiness-inducing, disgust-inducing, and neutral pictures. Participants provided valence and arousal ratings and later selected the basic emotion that best matched their reaction which served as the classification criterion. Using within-participants single-trial support vector machine (SVM) classification, EEG achieved the highest accuracy (40%), followed by facial EMG (37%); OpenFace reached 36%. All methods except EDA exceeded chance performance (33.3%) and were lower compared to human raters (48%). Predictions declined slightly for across-participants SVMs, being at chance for OpenFace and EDA. The results indicate that in principle both, psychophysiological measures and video-derived facial action units, can capture diagnostically relevant aspects of emotional responding during picture viewing, but that their performance is limited when expressions are spontaneous and not produced for communicative purposes. Inter-individual variability in expressivity and physiological responding likely contributes to these limitations and should be considered when deploying automatic emotion recognition in research or applied settings.

neuroscience↗

bioRxiv2026

Optogenetic Control of cAMP Levels and HCN Channels: Implications in Cardiac Physiology and Parkinsons Disease

Cyclic adenosine monophosphate (cAMP) is a second messenger that regulates various cellular processes, including the activity of hyperpolarization-activated channels (HCN), which are implicated in cardiac physiology and neurodegenerative diseases such as Parkinsons disease (PD). In this study, we used a photoactivated adenylyl cyclase (PAC) S27A mutant to optogenetically control intracellular cAMP levels. We demonstrated that light-induced elevation of cAMP activated HCN4 channels, leading to increased beating rates in cardiomyocytes. Unilateral expression of PAC(S27A) in the substantia nigra pars compacta of mice induced rotation behavior upon light stimulation, which could be attenuated by HCN inhibitors. Furthermore, PAC(S27A) activation partially recovered motor deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, accompanied by increased HCN2 channel expression in ipsilateral basal ganglia. Our findings highlight the potential of using optogenetics to modulate cAMP and HCN channel activity for the treatment of cardiac and neurological disorders.

cell biology↗

bioRxiv2026

Role of Early-Life Microbiome Colonization in Physiological Development of Drosophila melanogaster

The influences of the gut microbiome on animal physiology are well-documented, yet the developmental timing of microbial colonization and its long-term consequences remain poorly understood. In this study, we investigated how the timing of bacterial colonization during development affects transcriptional programming and phenotypic outcomes in adult Drosophila melanogaster reared on a common, rich diet. Using RNA-seq analysis on whole flies colonized either as newly hatched larvae or as newly eclosed adults, we observed minor but distinct transcriptional responses dependent on when flies were colonized. Both embryonic and adult colonization were associated with ~ 25 to ~ 200 differentially expressed genes compared to axenic controls, with the majority upregulated and enriched for immune-response genes, suggesting that colonization establishes a broader immune competence. However, only 10 genes showed persistent differential expression that was not normalized by introducing bacteria to adult axenic flies, including mitochondrial genes, the adipokinetic hormone (Adh), and a putative secreted neuropeptide. Overall, these findings suggest that Drosophila development on a rich diet is largely robust to the timing of bacterial colonization but that certain metabolic effects may occur.

developmental biology↗

bioRxiv2026

Differential physiological, behavioral, and medial prefrontal cortex transcriptomic responses to chronic restraint stress between BALB/c and C57BL/6J mice

Chronic stress is a major risk factor for psychiatric disorders such as depression and anxiety, yet the biological basis of individual differences in stress susceptibility and resilience remains poorly understood. Here, we examined physiological, behavioral, and medial prefrontal cortex (mPFC) transcriptomic responses to chronic restraint stress (CRS) in male BALB/c and C57BL/6J mice. After 21 days of CRS, BALB/c mice exhibited greater stress-related changes than C57BL/6J mice, including greater body weight loss, elevated serum corticosterone, reduced serum antioxidant capacity, and more pronounced depression-like behaviors. RNA sequencing showed largely strain-specific transcriptional changes in the mPFC. Strain x stress interaction analysis, followed by canonical pathway analysis using Ingenuity Pathway Analysis (IPA), identified strain-dependent molecular signatures. The most prominent differences involved extracellular matrix (ECM) organization and remodeling and neuroinflammatory signaling pathways, with greater predicted activation in BALB/c mice. IPA upstream regulator analysis further predicted multiple candidate regulators associated with these pathways, including TGF-{beta}/SMAD, C4a/C4b, and MAPK14. Among genes associated with these pathways, several ECM-related genes were preferentially upregulated in BALB/c mice, whereas activity-dependent immediate early genes were preferentially downregulated in C57BL/6J mice. These findings suggest that the strain-dependent mPFC transcriptional programs identified here may contribute to differential stress susceptibility and resilience.

neuroscience↗

bioRxiv2026

When sleep reports diverge from physiology: correlates of sleep discrepancy in a health population

Study Objectives. Sleep characteristics are often estimated using self-reports, which may differ from objective measurements, a phenomenon known as sleep discrepancy. However, the factors associated with the degree of sleep discrepancy remain poorly understood. Methods. In the current study, a large healthy participant sample of the Budapest Sleep, Experiences and Traits Study (total N=267, 1899 nights) completed a 7-day protocol including mobile EEG recordings and sleep diaries, and also provided questionnaire-based reports of habitual sleep. We compared analogous sleep metrics from these three modalities, and used cross-validated LASSO regression to investigate demographic, psychological and lifestyle-related factors associated with increased sleep discrepancy across all three modalities, at both between- and within-participant levels. Results. Daily diaries estimated EEG-based sleep timing accurately (mean r=0.83), but were less accurate for sleep onset latency and quality. In contrast, questionnaire reports of habitual sleep provided inaccurate measures of even sleep timing (mean r=0.49) and considerably misestimated sleep timing and duration. Insomnia and depressive symptoms, napping, co-sleeping and personality traits were associated with increased sleep discrepancy. Conclusion. In healthy adults, questionnaires about habitual sleep provide only moderately accurate and biased estimates of actual sleep. Daily diaries provide considerably more accurate estimates, but sleep onset latency and physiological sleep quality is estimated by all self-reports less accurately than sleep timing. Sleep discrepancy is also present in healthy participants, it is particularly and its degree is affected by non-pathological characteristics. Long-term monitoring by daily diaries or wearables should be preferred to self-report questionnaires to measure sleep.

neuroscience↗

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations generally outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗

bioRxiv2026

Understanding the physiological alterations of Vibrio cholerae upon exposure to L-ascorbic acid

The scourge of cholera remains a major global public health threat. It affects up to 4 million people worldwide and causes tens of thousands of deaths each year. The disease is experiencing a concerning resurgence in many parts of Africa, the Middle East, and Asia. To effectively tackle cholera and circumvent rising antimicrobial resistance, targeted biological and preventive approaches, complementing traditional rehydration, are urgently needed. In this regard, our group has demonstrated the efficacy of L-ascorbic acid in controlling the growth and pathogenesis of Vibrio cholerae in vitro. The present work further provides a mechanistic elucidation of the L-ascorbic acid-mediated physiological changes in V. cholerae and also bolsters such a non-antibiotic approach to control cholera.

microbiology↗

bioRxiv2026

Physiological and anatomical leaf acclimation of understory trees subjected to a through-fall precipitation exclusion in a temperate rain forest in southern South America.

Water input is a key component of the ecosystems. Water defines the functionality, composition, and structure of biomes; therefore, any change in its availability would have an impact on ecosystem features. Moreover, a change in the water balance of an ecosystem affects its persistence as well as biochemical cycles, such as the carbon and nitrogen. Forests are ecosystems structured using high amounts of water. Thus, trees, the oldest living plants, are the prime species in these ecosystems and are the main managers of this abiotic element. Trees uptake water from the soil, store it in their biomass, and exchange it with the environment through leaf stomata. They also intercepted rainfall and fog with their canopies. All of this water is also transmitted to the entire biological diversity that inhabits these ecosystems. Any change in water input affects the web described above. The ability of trees to modify their anatomy or processes, that is, to acclimate to novel climates, is of great advantage in maintaining the characteristics of ecosystems. In this study, we took advantage of a precipitation exclusion experiment to reveal the acclimation of shade-tolerant understory trees, which will be the main component of a cold temperate rainforest in the future. We evaluated different anatomical and physiological leaf traits involved in the use of water by these species. We hypothesized that, as observed in similar experiments, species would adopt more conservative water-use strategies by adjusting their functional traits accordingly. Contrary to our hypotheses, we found that understory tree species inhabiting this temperate ecosystem will not become more conservative when using water. In minimal, but significant differences, most of the studied species displayed traits, in the precipitation exclusion treatment, that were demonstrated to be water spender, rather than conservative. We attributed these contrasting changes to root metabolism alleviation due to the flooded soils of Chiloe inhabited by these forests.

ecology↗

bioRxiv2026

Impact of Water Deficit on Growth, Biochemical, and Physiological Traits in Eggplant MAGIC Lines

Climate change exacerbates agricultural water scarcity, necessitating the development of drought-tolerant crop varieties. This study evaluates 12 eggplant lines from a MAGIC (Multi-parent Advanced Generation Intercross) population, previously selected for contrasting responses to water deficit during the vegetative stage. To validate tolerance under adult production conditions, plants underwent five irrigation-withholding cycles over a 170-day greenhouse growing period. Yield components, the Stress Tolerance Index (STI), and physiological parameters (water status and stomatal conductance) were evaluated. Additionally, photosynthetic pigments, oxidative stress markers, antioxidant compounds, and osmolytes were quantified to characterize the biochemical basis of tolerance alongside final biomass production. The results showed that four of the five lines that were previously classified as tolerant in the vegetative stage remained among the most tolerant at the reproductive stage. Specifically, lines L13, L78 and L179 were the most productive under water-limited conditions. While L13 and L179 exhibited stable tolerance throughout all developmental stages, L78 displayed stage-specific tolerance, manifested only during the reproductive growth phase. These findings emphasise the importance of integrating early-stage screening with adult-stage validation in order to capture the full spectrum of genetic drought tolerance. The most productive lines were characterised by moderate aboveground biomass, high leaf hydration and maintained stomatal conductance. However, the strategies employed differed: while L179 exhibited high photosynthetic pigment content, L13 was characterised by high total sugar accumulation. Overall, these results provide a multi-trait roadmap and identify elite MAGIC parental lines for breeding climate-resilient eggplant cultivars.

plant biology↗

bioRxiv2026

Physiology mediates transcontinental radiations of freshwater fishes

Adaptive radiations are clades that have rapidly accumulated exceptional species richness and ecological diversity. The ability to access sources of ecological opportunity, such as new habitats, is thought to be essential for their success. Transcontinental lineages of exclusively freshwater fishes, such as the 1,700 species of cichlids distributed across Central and South America, Africa, India, and Madagascar, are some of the most celebrated adaptive radiations. Yet, what features facilitated their dispersal across marine barriers and diversification in geologically young freshwater ecosystems remain debated. Here, we show that a common mechanism, saltwater tolerance, provides an explanation for how species-rich transcontinental freshwater fish radiations, including cichlids, killifishes, pupfishes, and livebearers, accessed ecological opportunity and subsequently diversified. Marine salinity tolerance was retained after cichlids, killifishes and their relatives emerged from a rapid radiation during the Cretaceous-Paleogene boundary. The retention of this ancestral physiological trait throughout the last 45 million years of Earth history repeatedly enabled cichlids and other fishes to disperse across marine barriers and radiate in freshwater ecosystems on multiple continents, including geologically young features in Africa and North America that have repeatedly experienced saline conditions over tens of thousands of years of global climate change. These results show how the larger evolutionary context of adaptive radiations can sculpt their responses to ecological opportunity.

evolutionary biology↗

bioRxiv2026

Seven gut microbiome types across two Japanese cohorts defined by co-abundance-based microbial guilds and associated with host physiology

Intensive efforts have been made to capture structural features of the gut microbiome for assessing microbiota status in relation to host health. However, gut microbiome function emerges not only from individual microbial taxa but also from their organization into ecological guilds, complicating microbiome structure-function relationships. To address this challenge, we applied a co-abundance-based analytical framework to identify gut microbiome types (GMTs) across a discovery cohort (D-cohort) and an independent validation cohort (V-cohort) of Japanese adults. Using paired fecal samples collected one month apart from 116 participants in the D-cohort, we identified 27 co-abundance groups (CAGs) based on 16S rRNA amplicon sequence variants. These CAGs defined seven GMTs (MT-1 to MT-7) with characteristic short-chain fatty acid and bile acid profiles. The GMTs showed temporal stability, with more than 70% of participants remaining in the same GMT across sampling points. The 27-CAG framework classified 404 participants in the independent V-cohort into the seven GMTs, which represented reproducible microbial ecological states across cohorts. MT-4 exhibited dysbiosis-like features, including reduced microbial diversity, depletion of Faecalibacterium and butyrate, and enrichment of inflammation-associated taxa, and was associated with higher alcohol consumption and elevated {gamma}-glutamyl transferase levels. In contrast, Bifidobacterium-enriched MT-5 was associated with favorable renal function profiles. Collectively, co-abundance-defined microbial guilds capture coherent ecological and functional states of the gut microbiota, providing a transferable framework for linking gut microbiome organization to host physiology beyond conventional taxonomy-based classification.

microbiology↗

bioRxiv2026

Low-dose ketamine tilts the cortical excitation--inhibition balance irrespective of systemic physiological response

Non-invasive proxies of cortical excitation--inhibition (E:I) balance, are increasingly used to understand human neural dynamics; especially so the aperiodic (1/f) electroencephalographic (EEG) exponent. Ketamine, an NMDA-receptor antagonist, is thought to shift this balance toward excitation. Propofol, a GABAA-receptor agonist, should behave oppositely. Here we show that these pharmacological manipulations at low doses tilt the noninvasive read-out of E:I balance as predicted, and we demonstrate this effect to be robust against potential mediation by the ketamine-related systemic cardiovascular response. In a single-blind, placebo-controlled crossover study, 25 healthy adults received low, subanesthetic doses of ketamine, propofol, or placebo by target-controlled infusion during resting-state EEG. We further analyzed electrocardiogram (ECG) and dissociating ratings. Ketamine flattened the aperiodic exponent (i.e., a shift toward excitation) and raised heart rate and blood pressure; propofol exerted its effects in the opposite direction, while both agents reduced alpha oscillatory power. Critically, the cardiovascular response did not mediate the cortical E:I shift. Controlling for heart rate left the ketamine effect not only intact but numerically stronger, suggesting that E:I balance findings might even be underestimated when ignoring the systemic physiological response.

neuroscience↗

bioRxiv2026

Disease-associated variants alter a novel physiological role of hnRNP H2 in neuronal development

Heterogeneous nuclear ribonucleoprotein H2 (hnRNP H2) is a member of the hnRNP family of RNA-binding proteins that regulate neuronal function through multiple aspects of RNA metabolism. Mutations in the nuclear localisation signal (NLS) and quasi-RNA recognition motifs (qRRMs) of hnRNP H2 have recently been linked to a severe developmental syndrome, termed HNRNPH2-related neurodevelopmental disorder. Despite its emerging importance, the physiological roles of hnRNP H2 in neuronal development and synaptic maturation, and how disease-associated variants alter these processes to drive pathology, remain poorly understood. Here, we show that hnRNP H2 is expressed in hippocampal neurons and localises to the synaptic compartment. Knockdown of hnRNP H2 revealed essential roles of the protein in the regulation of neuronal morphology, dendritic spine maturation, synaptic transmission, and cortical neuronal migration in vivo. Disease-associated hnRNP H2 variants altered protein localisation and activity-dependent synaptic recruitment, resulting in defects in neuronal morphology, in vivo cortical neuronal migration and laminar orientation, dendritic spine maturation, and synaptic function. Together, these findings establish hnRNP H2 as a critical regulator of neurodevelopment and identify a molecular basis for HNRNPH2-related neurodevelopmental disorder.

neuroscience↗