Biology subjects

Abe, M.

Publications and source records attributed to Abe, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Asymmetric turnover dynamics of Nav1.6 voltage-gated sodium channels at the axon initial segment

Nav1.6 voltage-gated sodium channels are critical for shaping action potentials, and their precise localization at the axon initial segment (AIS) is essential for neuronal excitability. However, the turnover mechanisms that maintain this spatial pattern remain unclear. Here, we present a genetically engineered mouse in which endogenous Nav1.6 carries a Cre-switchable fluorescent tag, enabling us to simultaneously trace the turnover of pre-existing and newly synthesized Nav1.6 without perturbing AIS structure. Using this system, we determine the physiological lifetimes of Nav1.6 at the AIS in vivo and in vitro, and further uncover the spatially asymmetric turnover dynamics, with the proximal and distal AIS organizing a source-to-sink gradient. Based on the quantified parameters, computational modeling clarifies that this asymmetry promotes efficient clearance of older molecules, thereby supporting AIS quality control. Collectively, these findings provide a technical and conceptual foundation for understanding how molecular turnover contributes to AIS homeostasis.

neuroscience↗

bioRxiv2026

Oxidized phosphatidylinositol impairs lysosomal membrane repair to promote ferroptosis

Ferroptosis is a regulated form of cell death driven by iron-dependent and unrestrained lipid peroxidation, which generates phospholipid hydroperoxides that cause membrane rupture. Oxidized phospholipid species, including oxidized arachidonic acid-containing phosphatidylethanolamines (PE), are abundant during ferroptosis. However, previous studies have examined only a limited number of lipid species, and it remains unclear which oxidized phospholipids consistently arise across distinct cell types and ferroptosis-inducing conditions. Here, we comprehensively profiled oxidized phospholipids generated during ferroptosis across multiple cell lines and animal models. We identified PE 18:0_20:4;O3 and phosphatidylinositol (PI) 18:0_20:4;O3 as oxidized phospholipid species that are consistently detectable across all tested ferroptosis-inducing conditions. Furthermore, oxidized phosphatidylinositol impairs the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway, a key mechanism for lysosomal membrane repair. These results indicate that the oxidized phospholipids identified here may serve as markers of ferroptosis while also acting as bioactive mediators that compromise lysosomal membrane homeostasis and repair.

cell biology↗

bioRxiv2026

VLCFA-mediated inter-cell layer communication controls cellular pluripotency in Arabidopsis callus

Plants have remarkable capacity to reconstruct entire organ systems from tissue explants. In Arabidopsis two-step tissue culture system, pluripotency regulators are specifically expressed in the middle-cell layer of the stratified callus tissue. However, regulatory mechanisms underlying the radial patterning of callus remained unclear. Here, we found that very-long-chain fatty acids (VLCFAs) synthesized in the epidermis-like outermost layer are essential for pluripotency acquisition and successful shoot regeneration. Our genetic and transcriptomic analyses revealed that the regulatory roles of VLCFAs on pluripotency acquisition involve inter-cell layer signaling in callus tissue, while they are at least partly independent of ATML1/PDF2 functions and cuticular wax synthesis in the outermost layer. VLCFAs spatially restrict procambium cell identity by non-cell-autonomously suppressing cytokinin signaling, thereby allowing for establishment of the middle-cell layer. We propose that the inhibitory relationships between layer-specific regulators underlie the intricate balance of cellular fate determination in pluripotent callus.

plant biology↗

bioRxiv2026

Membrane PI(4,5)P2 and ErbB2 abundance regulate ErbB receptor signaling through receptor oligomerization and activation

Because ErbB receptors play distinct roles in regulating diverse cellular functions, the mechanisms governing ErbB receptor activation are likely to be more diverse than previously recognized. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] positively regulates ErbB1 kinase activity, but the role of PI(4,5)P2 in regulating other ErbB family members in living cells remains poorly understood. We show that disruption of PI(4,5)P2 binding enhances ErbB4 oligomerization and kinase activity while reducing both processes in ErbB1. Analysis of chimeric receptors identified the juxtamembrane (JM) regions of ErbB1 and ErbB4 as key determinants of their distinct responses to PI(4,5)P2 during receptor oligomerization and kinase activation. Furthermore, the JM-kinase module of ErbB1 is more active in the presence of PI(4,5)P2, whereas that of ErbB4 is activated by the disruption of PI(4,5)P2 binding. In contrast, the JM-kinase module of ErbB2 exhibits weak dependence on PI(4,5)P2. ErbB2 preferentially promotes ErbB4 oligomerization over ErbB1 oligomerization, thereby enhancing ErbB4 activation. Collectively, these findings identify plasma membrane PI(4,5)P2 availability and ErbB2 abundance as two factors that jointly govern ErbB receptor oligomerization and activation.

cell biology↗

bioRxiv2026

High basal autophagic activity in the brain revealed by systemic quantitative analysis using GFP-LC3-RFP mice

Autophagy is a fundamental intracellular degradation pathway with vital physiological functions. Although it is well known that autophagy is activated during starvation, the extent of basal autophagy remains unclear owing to challenges in measuring autophagic flux in vivo. In this study, we developed autophagy reporter (GFP-LC3-RFP) mice and quantified basal autophagic flux across tissues by comparing normal and autophagy-deficient conditions. Comparative analyses revealed uniformly low basal autophagic flux during embryogenesis, but significant tissue-specific variation in adult mice. In contrast to previous assumptions that basal autophagy in the brain is low, the brain, along with the liver and kidney, exhibited higher basal autophagic flux than the heart, skeletal muscle, and intestine. These data serve as foundational information on basal autophagic flux in mammals and provide a plausible explanation for the severe neurological phenotypes linked to autophagy gene mutations in mice and humans.

cell biology↗

bioRxiv2026

Subsecond whole-brain neural dynamics identified by hidden Markov modeling reflect value-based decision making in humans

Value-based decision making emerges from coordinated neural dynamics across distributed brain networks. Recent studies using noninvasive whole-brain measurements in humans have highlighted the importance of neural activity in the 2-10 Hz frequency band for value-based decision making. Using magnetoencephalography and hidden Markov model (HMM) analysis, we examined whether and how whole-brain neural dynamics in this frequency band, evolving on a timescale of a few hundred milliseconds, reflect value-based decision processes. Thirty-five healthy adults (females and males) made binary choices between risky and sure options. Trial-wise subjective values were estimated using behavioral economic modeling based on prospect theory. We found that HMM-derived trial-by-trial whole-brain neural dynamics (defined by 2-10 Hz amplitude envelopes in distributed brain regions and their interregional coupling) were associated with the subjective values of choice options in a manner distinct from simple perceptual- or motor-evoked activity. Notably, these trial-by-trial whole-brain dynamics covaried with the difference in subjective values between the chosen and unchosen options when the neural data were time-locked to participants responses, but not when time-locked to option onset. These findings revealed a crucial link between subsecond whole-brain neural dynamics and trial-by-trial decision variables, providing insights into how value-based decision processes unfold over time in the human brain.

neuroscience↗

bioRxiv2026

HAC1 contributes to stress adaptation and virulence in the emerging fungal pathogen Candida auris

Candida auris (Candidozyma auris) is an emerging multidrug-resistant fungal pathogen that poses a significant global health threat. However, the molecular mechanisms underlying its virulence remain incompletely understood. In this study, we performed in vivo transcriptome analysis using an immunosuppressed mouse gastrointestinal infection model to identify genes associated with host-adaptation and virulence during infection. By comparing fungal transcriptomes obtained from colonization and dissemination sites with those from in vitro cultures, we identified genes that were consistently upregulated during infection. Among these genes, the unfolded protein response regulator HAC1 was selected as a candidate virulence-associated gene for further analysis. RT-PCR and sequencing analyses revealed that HAC1 mRNA in C. auris undergoes an unconventional splicing event of 287 bp that is enhanced under ER stress conditions. The excised region spans the annotated open reading frame boundary, suggesting that the translated region of HAC1 may require re-evaluation. Notably, a proportion of HAC1 transcripts appeared to be spliced even under non-stress conditions, indicating a detectable basal level of UPR activation. Differences in splicing dynamics were also observed among clade strains. Functional analyses demonstrated that deletion of HAC1 increased sensitivity to ER stress and heat stress. The HAC1 deletion mutant also exhibited reduced virulence in both Galleria mellonella and immunosuppressed mouse infection models, as evidenced by delayed host mortality and decreased fungal burdens, respectively. These findings indicate that HAC1 contributes to ER stress adaptation, thermotolerance, and survival in the host environment, and identify HAC1 as a virulence-associated gene in C. auris.

microbiology↗

bioRxiv2026

A Knock-In Igfn1iCre transgenic mouse line provides partial developmental access to type-7 bipolar cells

1.Functional neuronal circuits in the vertebrate retina emerge through coordinated developmental events, yet the timeline by which bipolar cells acquire visual feature selectivity remains unclear. A major barrier is the limited genetic access to bipolar subtypes during early postnatal stages. Recent comprehensive transcriptomic study points to Igfn1 as a molecular marker for type-7 bipolar cells (BC 7), a subtype that exhibits direction-selective glutamate releases in adult. Here, we generated an Igfn1iCre knock-in mouse line and characterized Igfn1-positive cell morphology from postnatal day 4(P4) to adult using Cre-dependent tdTomato reporter mice. We found Igfn1-positive cells in the inner retina by P12-P15, predominantly labelling bipolar cells and some amacrine populations. At P15, about 71% of labelled bipolar cells stratified their axons in the S4 sublamina of the inner plexiform layer, consistent with BC 7 morphology. In adult retina, the widespread Igfn1-labelling appears slightly dominated in amacrine cells. To validate these observations, we analysed Igfn1 expression in the Mouse Retina Cell Atlas and confirmed strong Igfn1 enrichment in BC 7 and expression in additional retinal cell types, mirroring experimental results. Overall, these results reveal Igfn1iCre as a potential developmental tool for BC 7 access in the retina.

neuroscience↗

bioRxiv2025

Single-molecule behavior and cell-growth regulation in human RTKs

Receptor tyrosine kinases (RTKs) are a major family of cell surface receptor proteins responsible for various cellular functions in animal cells, including fate decisions, metabolism, polarization and migration. Lateral mobility, dimerization, clustering, and oligomerization are crucial behaviors in the activation process of RTKs on the cell surface. However, relationships between these molecular behaviors and molecular function remain to be elucidated, except for a few RTK members. Here, using an automated live-cell single-molecule imaging and analysis system, we studied the behavior of 52 of the 58 human RTK species on living cells over time during stimulation with ligands. We extracted 72 single-molecule parameters for each RTK species to examine their relationship to function, structure, and evolution. We noticed that RTKs ability to inhibit or support cell growth, as observed in a large-scale loss-of-function experiment in the public domain, significantly relates to their behavior. Growth-inhibitory signaling was coupled with the immediate formation of immobile clusters, followed by the enlargement of immobile and slow-mobile domains. In contrast, growth-supportive signaling coupled with higher lateral diffusivity and delayed clustering of immobile molecules. The relationship between structure and function suggests that functional differences are related to partitioning into membrane rafts and changes in mobility associated with phosphatidylinositol turnover. In multiple linear regression models, molecular behavior explained half or more of the molecular function related to cell growth. This level of explainability is comparable to that of evolutionary grouping.

biophysics↗

bioRxiv2025

Neural Underpinnings of Olfactory Dysfunction across Parkinson's and Alzheimer's Spectra

Olfactory dysfunction is a frequent yet understudied feature of neurodegenerative spectrum disorders, including Alzheimers disease (AD) and Parkinsons disease (PD). To disentangle the neural substrates of hyposmia across disease spectra, we examined 222 participants from the Parkinsons and Alzheimers disease Dimensional Neuroimaging Initiative cohort. Participants were classified according to the presence of cognitive disturbance, movement disorder, or both. Olfactory testing disclosed that cognitive disturbance and movement disorder were independently associated with hyposmia, and having both cognitive disturbance and movement disorder was associated with severe hyposmia. Whole-brain voxel-based morphometry revealed that hyposmia was associated with atrophy in the medial temporal lobe (MTL) in individuals with cognitive disturbance, whereas an artificial intelligence-based segmentation model identified olfactory bulb atrophy in those with movement disorder. Regression analysis and structural equation modeling further confirmed that the MTL and olfactory bulb volume contributed to olfactory performance through distinct processes. Individuals with cognitive disturbance and movement disorder had atrophy in both the MTL and olfactory bulb ("double hit"). We identified dual processes underlying hyposmia in the AD and PD spectra: a process linking MTL degeneration to cognitive disturbance and a process linking olfactory bulb degeneration to movement disorder. Our transdiagnostic approach enhances strategy in identifying specific neural correlates underlying hyposmia, lending support to the development of biomarkers for early intervention in AD and PD.

neuroscience↗

bioRxiv2025

Urinary exfoliated cells exhibit mesodermal lineage differentiation potential in the absence of dedicated culture conditions

IntroductionUrine contains various cells derived from the kidney, including renal tubular epithelial cells, glomerular epithelial cells, and mesenchymal stem cells. Urinary exfoliated mesenchymal stem cells can be differentiated into adipocytes, osteoblasts, chondrocytes, muscle cells, or neuronal cells, if grown in specialized culture conditions. In this study, however, we identified the development of multiple mesodermal cell lineages from urinary exfoliated cells despite using a single culture system not designed for these cell differentiations. MethodsUrinary exfoliated cells used for culturing were obtained from pediatric patients with kidney disease. All cultures were maintained using an identical, non-specifically supplemented, rich, DMEM/F12-based growth medium, refreshed regularly throughout the experiments. Cells of different mesodermal lineages--adipocytes, osteoblasts, and chondrocytes--were identified by staining with Oil Red O, Alizarin Red, and Alcian Blue solutions. Moreover, the expression of mRNA markers specific for adipocytes, osteoblasts, and chondrocytes, as well as for stem cells and--more specifically--mesenchymal stem cells, was analyzed by RT-PCR. ResultsAlthough the abundances varied, in all 11 cultures of urinary exfoliated cells from six patients, dye staining revealed multiple cell clusters of mesodermal lineages. All cultures contained clusters of the adipocyte and chondrocyte lineages, and seven also contained clusters of the osteoblast lineage. Morphology differences were found even between clusters stained with the same dye. RT-PCR confirmed the presence of the three lineages, while also revealing expression of genes specific to pluripotent stem cells (Nanog, Oct3/4, SOX2, and LIF) and genes more specific for mesenchymal stem cells (CD73, CD90, and CD105). ConclusionsAmong urinary exfoliated cells cultured using our method, clusters of cells of mesodermal lineages were observed without needing to selectively adjust the culture medium. The cells seemed to differentiate and proliferate from mesenchymal stem cells in the urine. We envision that these initial findings may eventually contribute to a deeper understanding of urinary stem cell differentiation and to optimizing lineage-specific differentiation for research and therapeutic applications.

cell biology↗

bioRxiv2025

Design of an orally bioavailable small molecule that modulates the microtubule-associated protein tau's pre-mRNA splicing

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by the aberrant alternative pre-mRNA splicing of microtubule-associated protein tau (MAPT) exon 10, the inclusion of which encodes for a toxic tau protein harboring four microtube domains (4R tau). Here, we describe the design of an RNA-targeted small molecule that thermodynamically stabilizes the structure of a pre-mRNA splicing regulator element in the MAPT pre-mRNA exon 10-intron junction to reduce the inclusion of exon 10 and hence 4R tau abundance. Structure-based drug design was used to obtain compounds that form a network of specific interactions to the RNA including multiple interactions between a one nucleotide A-bulge and the Hoogsteen face of a closing GC base pair, the latter of which was enabled by the design of base triple interactions. A battery of assays revealed that the compound binds the target in vitro and in cells and affects pre-mRNA splicing in various cellular models including primary neurons from a human tau (htau) knock-in mouse model. The orally bioavailable compound was administered per os (p.o.), where treatment diminished exon 10 inclusion, and reduced the 4R tau protein isoform. Further, the molecule mitigated cellular pathologies and behavioral phenotypes observed in the htau transgenic mouse model. This study provides a potentially general pipeline to design compounds that target RNAs and affect disease pathways and deliver compounds that have oral bioavailability and blood-brain barrier penetrance.

biochemistry↗

bioRxiv2025

Flexible value coding in the mesolimbic dopamine system depending on internal water and sodium balance

Homeostatic imbalances elicit strong cravings, such as thirst and salt appetite, to restore equilibrium. Although midbrain dopaminergic neurons are known to encode the value of foods, their nutritional state-dependency remains unknown. Here, we show that the activity of the dopaminergic mesolimbic pathway flexibly expresses the positive and negative values of water and salt depending on the internal state in mice. Mice showed behavioral preference and aversion to water and salt depending on their internal water and sodium balance. Fiber photometry recordings revealed that dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens flexibly showed bidirectional excitatory and inhibitory responses to water and salt intake in a state-dependent manner. Furthermore, these dopaminergic and behavioral responses could be simulated by a homeostatic reinforcement learning model. Our results demonstrate the nutritional state-dependency of value coding in mesolimbic dopamine systems, providing new insights into neural circuits underlying homeostatic regulation of appetitive and avoidance behaviors.

neuroscience↗

bioRxiv2025

Visualization of stochastic expression of clustered protocadherin β isoforms in vivo

The stochastic expression of clustered protocadherin (cPcdh) establishes a single-cell identity fundamental to cellular self/non-self-discrimination. However, it has been challenging to reveal the spatiotemporal patterning of the stochastic cPcdh expression in vivo. We developed XFP (tdTomato or GFP) knock-in mice using a new strategy to enhance XFP expression, which allows us to visualize cPcdh{beta}3 or 19-positive cells throughout the brain. These mouse lines demonstrate the cell-type selectivity, spatial biases, inter-individual differences, left-right asymmetry, developmental regulation, alteration in pathological or aging brain, and monoallelic expression of stochastic cPcdh{beta} expression in vivo. Our findings further demonstrate that the cPcdh{beta}3 expression undergoes significant changes in the mature brain over time. These results demonstrate the potential of these reporter mice to advance our understanding of cPcdh cellular barcode in vivo.\n\nOne Sentence SummaryNovel established cPcdh{beta} reporter mouse lines reveal stochastic expression of cPcdh{beta} isoforms in vivo.

neuroscience↗

bioRxiv2025

KEAP1 retention in phase-separated p62 bodies drives liver damage in autophagy-deficient conditions

Phase-separated p62 bodies activate NRF2, a key transcription factor for antioxidant response, by sequestering KEAP1, which targets NRF2 for degradation. Although p62 bodies containing KEAP1 are degraded by autophagy, they accumulate in various liver disorders. Their precise disease role remains unclear. We show that excessive KEAP1 retention in p62 bodies and NRF2 activation are major causes of liver damage when autophagy is impaired. In mice with weakened or blocked p62-KEAP1 interactions, KEAP1 retention and NRF2 activation under autophagy-deficient conditions were suppressed. Transcriptome and proteome analyses revealed that NRF2 targets upregulated by autophagy suppression normalized in p62 mutants unable to bind KEAP1. Autophagy deficiency caused organelle accumulation, especially of the ER, regardless of p62 mutation. Liver damage and hepatomegaly from autophagy suppression markedly improved in p62 mutants, particularly those with blocked KEAP1 binding. These findings highlight excessive KEAP1 retention in p62 bodies and defective organelle turnover as key drivers of liver pathology, underscoring the significance of phase separation in vivo.

cell biology↗

bioRxiv2024

PATROL1-mediated H+-ATPase translocation boosts plant growth under drought by optimizing root and leaf functions

Optimizing leaf photosynthesis and root water and mineral uptake in crops during drought is crucial for enhancing agricultural productivity under climate change. Although plasma membrane H+-ATPase plays a key role in plant physiological processes, its overexpression alone does not consistently improve growth. While PROTON ATPASE TRANSLOCATION CONTROL 1 (PATROL1) regulates H+-ATPase translocation in response to various environmental stimuli in leaves, its function in roots remains largely unknown. Here we show that H+-ATPase was coimmunoprecipitated with PATROL1 in roots of Arabidopsis thaliana. Micrografting between wild type and PATROL1 knockout or overexpression lines showed that PATROL1 are indispensable in both shoots and roots, indicating that root uptake and leaf photosynthesis are simultaneous limiting factors for plant growth under drought conditions. PATROL1 overexpression in whole plants resulted in a 41% increase above wild type in shoot dry weight under drought conditions. These findings highlight the potential of H+-ATPase regulation in roots as a new strategy to improve plant productivity, particularly under drought conditions.

plant biology↗

bioRxiv2024

Single-cell analysis of human diversity in circulating immune cells

Lack of diversity and proportionate representation in genomics datasets and databases contributes to inequity in healthcare outcomes globally1,2. The relationships of human diversity with biological and biomedical phenotypes are pervasive3, yet remain understudied, particularly in a single-cell genomics context. Here we present the Asian Immune Diversity Atlas (AIDA), a multi-national single-cell RNA-sequencing (scRNA-seq) healthy reference atlas of human immune cells. AIDA comprises 1,265,624 circulating immune cells from 619 healthy donors and 6 controls, spanning 7 population groups across 5 countries. AIDA is one of the largest healthy blood datasets in terms of number of cells, and also the most diverse in terms of number of population groups. Though population groups are frequently compared at the continental level, we identified a pervasive impact of sub-continental diversity on cellular and molecular properties of immune cells. These included cell populations and genes implicated in disease risk and pathogenesis as well as those relevant for diagnostics. We detected single-cell signatures of human diversity not apparent at the level of cell types, as well as modulation of the effects of age and sex by self-reported ethnicity. We discovered functional genetic variants influencing cell type-specific gene expression, including context-dependent effects, which were under-represented in analyses of non-Asian population groups, and which helped contextualise disease-associated variants. We validated our findings using multiple independent datasets and cohorts. AIDA provides fundamental insights into the relationships of human diversity with immune cell phenotypes, enables analyses of multi-ancestry disease datasets, and facilitates the development of precision medicine efforts in Asia and beyond.

genomics↗

bioRxiv2024

Sex-dependant differences in the ability of nicotine to modulate discrimination learning and cognitive flexibility in mice.

1Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex-dependent differences in the effect of daily nicotine administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, nicotine significantly improved performance in VDR, but not VD, task, while, in female mice, nicotine significantly worsened performance in the VD, but not VDR, task. Next, to investigate the cellular mechanisms that underlie the sex differences in the effects of nicotine on cognition, transcriptomic analyses were performed on prefrontal cortex tissue samples from male and female mice that had undergone VD and VDR tasks. Pathway enrichment analysis and Protein-protein interaction (P-PI) analysis using gene sets with altered gene expression found three types of effects of nicotine: those common to both sexes, those in males only, and those in females only. Decreased expression of postsynaptic-related genes in males and increased expression of innate immunity-related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility.

animal behavior and cognition↗