Biology subjects

Hattori, Y.

Publications and source records attributed to Hattori, Y..

15 recordsLinked to original sources

bioRxiv2026

Embryonic macrophages chronologically change their brain-entry routes and competence for neural progenitor-induced microglial differentiation

Microglia arise from macrophage precursors that enter the developing brain and acquire microglial identity, but how these processes are coordinated remains unclear. We show that despite prominent entry of macrophages from the ventricles into the mouse telencephalon at embryonic day (E) 12.5, they enter from the meninges at E11.5, preferentially in the rostral pallium. Consistent with this regional pattern, whole-mount en face imaging revealed that focal holes in the pial basement membrane were most frequently observed in the rostral pallium. We found that neural progenitors, but not endothelial cells, promote acquisition of microglial properties through a process that requires close cellular proximity and partly depends on TGF-{beta} receptor signaling. This responsiveness is substantially stronger in E13.5 than in E17.5 meningeal macrophages, indicating stage-dependent competence to acquire microglial properties. These findings suggest that microglial establishment is developmentally regulated by macrophage access to the telencephalon and responsiveness to local neural cues.

developmental biology↗

bioRxiv2026

Calibrated ADAMTS13 inhibition prevents cardiovascular shear coagulopathy

Mechanical circulatory support essential for managing severe heart failure frequently triggers bleeding complications, driven by shear stress-induced over-proteolysis of von Willebrand factor (VWF) by ADAMTS13. Inhibiting ADAMTS13 presents a rationale to treat this condition, known as acquired von Willebrand syndrome (AVWS). However, conventional therapeutic strategies remain limited due to the risk of triggering thrombotic thrombocytopenic purpura. Here we show that HA10, a humanized anti-ADAMTS13 antibody, preserves a residual level of ADAMTS13 activity above the thrombosis-associated threshold. Multimodal structural and biophysical analyses--including NMR, SAXS, and SANS--revealed that HA10 bound to the disintegrin-like domain of ADAMTS13, dynamically competing with VWF while leaving 10- 20% residual enzymatic activity. The therapeutic efficacy and safety of HA10 were verified in non-human primate models of AVWS. Our findings establish a novel paradigm of enzymatic calibration rather than complete blockade, offering a mechanistically targeted and safe therapeutic approach for cardiovascular bleeding.

biochemistry↗

bioRxiv2026

Population genomics reveal genetic variants associated with lunar-regulated spawning time in grass puffer

High and low tides occur twice a day (every [~]12.4 hours), with the largest tidal ranges during spring tides around new and full moons (every [~]14.765 days). Although lunar cycles shape diverse animal phenotypes, particularly the reproduction of coastal animals, the genetic basis of lunar-related rhythms remains unclear. Since phenotypic variation is a valuable resource for elucidating such mechanisms, we examined geographic variation in the lunar-regulated mass spawning of the grass puffer (Takifugu alboplumbeus) along the Japanese coast. Western populations spawned during the first half of the spring tides, whereas eastern populations spawned during the second half. Furthermore, the spawning was restricted to a narrow daily time window that occurred earlier in the western populations than in the eastern ones. Assuming that spawning is regulated by circadian gating, this geographic shift in the daily spawning window could account for the population difference in semilunar spawning timing. Consistent with this hypothesis, the free-running circadian period ({tau}), which can affect the phase of the gating window, was shorter in the western populations. Mathematical modeling recapitulated the observed geographic difference in the spawning time window based on variation in {tau}. To identify candidate genes responsible for these differences, we conducted population genomics analysis and identified proline-rich transmembrane protein 1-like (prrt1l) as a candidate. Expression of prrt1l was observed in the circadian pacemaker suprachiasmatic nucleus, and triple CRISPR F0 knockout of prrt1l shortened the free-running period in larvae. These findings suggest a potential mechanism underlying the geographic variation in lunar-synchronized spawning behavior. HighlightsO_LIThe geographic variation exists in the lunar-regulated spawning of the grass puffer, with differences in spawning dates and times between western and eastern Japan. C_LIO_LIThe free-running period of western populations is shorter than that of eastern populations, which is consistent with their earlier spawning timing. C_LIO_LIPopulation genomics analysis identified prrt1l as a candidate gene harboring population-specific missense mutations, the knockout of which shortens the free-running period. C_LI

evolutionary biology↗

bioRxiv2025

Feline leukaemia virus subgrouping using the viral interference assay

Feline leukaemia virus subgroup A (FeLV-A) is transmitted among cats, and FeLV subgroups are frequently generated de novo. We investigated the frequency of detection of subgroups using interference assays in 50 cases. FeLV-A infection alone was detected in 38% of cases, whereas co-infection with both FeLV-A and FeLV-B was observed in 62% of cases. No cases of FeLV-B infection alone were observed. Cases of co-infection with FeLV-A and FeLV-B showed a higher prevalence than cases of FeLV-A infection alone. The X region containing FeLV was discovered in two new cases. This study may elucidate the mechanism underlying FeLV-B-induced diseases.

microbiology↗

bioRxiv2025

A Disease-Associated Mutation Impedes PPIA Through Allosteric Dynamics Modulation

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration. Peptidylprolyl cis-trans isomerase A (PPIA) is a molecular chaperone involved in protein folding, and its dysfunction has been linked to ALS pathogenesis as proline is recognized as a key residue for maintaining proper folding of ALS-related proteins. A recent study identified a K76E mutation in PPIA in sporadic ALS patients, but its effects on protein function and structure remain unclear. In this study, we used biochemical and biophysical techniques to investigate the structural and functional consequences of the K76E mutation. Our results show that K76E significantly reduces enzyme activity without affecting structure, monodispersity, or substrate recognition. Significant effects of K76E mutation were identified by relaxation dispersion NMR experiments, showing that K76E disrupts key protein dynamics and alters an allosteric network essential for isomerase activity. Corroborated by theoretical kinetic analysis, this dynamics data, revealing the exchange process for K76E approximately one-tenth that of the wild type, explain the reduced cis-trans isomerase activity of the K76E mutant. These findings suggest that the pathogenic effect of K76E arises primarily from impaired protein dynamics rather than direct structural disruption. Our study provides new insights into the molecular mechanisms underlying ALS-associated mutations and their impact on protein function. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/653011v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@82f81corg.highwire.dtl.DTLVardef@6f0a04org.highwire.dtl.DTLVardef@1fabe12org.highwire.dtl.DTLVardef@d49d11_HPS_FORMAT_FIGEXP M_FIG For Table of Contents C_FIG

biochemistry↗

bioRxiv2024

Ca2+-driven PDIA6 phase separation to ensure proinsulin quality control

The endoplasmic reticulum (ER) plays key roles in protein quality control1,2 and dynamic Ca2+ storage3,4 in eukaryotic cells. However, the protein homeostasis (proteostasis) system that regulates these ER functions is still incompletely characterised. Previous study revealed the importance of oligomerization in the function PDIA1, an ER-resident disulfide isomerase and molecular chaperone, regulates oligomeric states in accordance with client folding5. This result suggests that at least some of the 20 members of other PDI family may undergo regulated self-assembly in order to optimally function. Here, we show that Ca2+ triggers the phase separation of PDIA6 into liquid-like condensates. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the Ca2+-driven condensation of PDIA6 recruits PDIA3 and proinsulin, thus increasing their local concentrations. This process results in the 30-fold enhancement of proinsulin folding and in the inhibition of proinsulin aggregation. Our findings shed light on a condensation-driven Ca2+-mediated proteostasis cascade in the ER by revealing how the efficiency of the protein folding process can be enhanced within quality control granules.

biochemistry↗

bioRxiv2024

Healthy dietary choices involve prefrontal mechanisms associated with long-term reward maximization but not cognitive control

Taste and health are critical factors to be considered when choosing foods. Prioritizing healthiness over tastiness requires self-control. It has also been suggested that self-control is guided by cognitive control. We then hypothesized that neural mechanisms underlying healthy food choice are associated with both self-control and cognitive control. Human participants performed a food choice task and a working memory (WM) task during functional MRI scanning. Their degree of self-control was assessed behaviorally by the value discount of delayed monetary rewards in intertemporal choice. Prioritizing healthiness in food choice was associated with greater activity in the superior, dorsolateral, and medial prefrontal cortices. Importantly, the prefrontal activity was greater in individuals with smaller delay discounting (i.e., high self-control) who preferred a delayed larger reward to an immediate smaller reward in intertemporal choice. On the other hand, WM activity did not show a correlation with delay discounting or food choice activity, which was further supported by supplementary results that analyzed data from the Human Connectome Project. Our results suggest that the prefrontal cortex plays a critical role in healthy food choice, which requires self-control, but not cognitive control, for maximization of reward attainments in a remote future.

neuroscience↗

bioRxiv2023

Zinc finger domains bind low-complexity domain polymers

Self-association of low-complexity protein sequences (LC domains) is important for polymer formation. Several molecular chaperones are involved in the regulation of LC domain polymer formation. However, the mechanisms underlying cell recognition of LC domain polymers remain unclear. Here we show that zinc finger domains (ZnFs) bind LC domains of RNA-binding proteins in a cross-{beta} polymer-dependent manner. ZnFs bound to LC domain hydrogels and suppressed LC domain polymer formation. Moreover, ZnFs preferentially recognize LC domains in the polymeric state. These findings suggest that ZnFs act as physiological regulators of LC domain polymer formation.

biochemistry↗

bioRxiv2023

Identification of Core Yeast Species and Microbe-Microbe Interactions Impacting Larval Growth of Drosophila in the Wild

Microbiota consisting of various fungi and bacteria have a significant impact on the physiological functions of the host. However, it is unclear which species are essential to this impact and how they affect the host. This study analyzed and isolated microbes from natural food sources of Drosophila larvae, and investigated their functions. Hanseniaspora uvarum is the predominant yeast responsible for larval growth in the earlier stage of fermentation. As fermentation progresses, Acetobacter orientalis emerges as the key bacterium responsible for larval growth, although yeasts and lactic acid bacteria must coexist along with the bacterium to stabilize this host-bacterial association. By providing nutrients to the larvae in an accessible form, the microbiota contributes to the upregulation of various genes that function in larval cell growth and metabolism. Thus, this study elucidates the key microbial species that support animal growth under microbial transition.

developmental biology↗

bioRxiv2023

Propagation of neuronal micronuclei regulates microglial states

Microglia, resident immune cells in the central nervous system, undergo morphological and functional changes in response to signals from the local environment and mature into various homeostatic states. However, niche signals underlying microglial development and maturation remain largely unknown. In this study, we show that neuronal micronuclei propagate microglia, followed by changing microglial states during the postnatal period. We discovered that neurons passing through a dense region of the developing neocortex give rise to micronuclei and release them into the extracellular space. Moreover, neuronal micronuclei were incorporated into microglia and affected morphological changes. Loss of the cGAS gene alleviates effects on micronucleus-dependent morphological changes. Notably, neuronal micronuclei-harboring microglia exhibit unique transcriptome signatures. These results demonstrate that neuronal micronuclei serve as niche signals that produce novel microglial states. Our findings provide a potential mechanism for regulating the microglial state in the early-postnatal neocortex.

neuroscience↗

bioRxiv2022

Border-associated macrophages transventricularly infiltrate the early embryonic cerebral wall to differentiate into microglia

The relationships between microglia and macrophages, especially their lineage segregation outside the yolk sac, have been recently explored, providing a model in which a conversion from macrophages seeds microglia during brain development. However, spatiotemporal evidence to support such microglial seeding and to explain how it occurs has not been obtained. By cell tracking via slice culture, intravital imaging, and Flash tag-mediated labeling, we found that a group of intraventricular macrophages belonging to border-associated macrophages (BAMs), which were abundantly observed along the inner surface of the mouse cerebral wall at embryonic day 12, frequently entered the brain wall. Immunohistochemistry of the tracked cells showed that postinfiltrative BAMs acquired microglial properties while losing a macrophage phenotype. We also found that the intraventricular BAMs were supplied transepithelially from the roof plate. Thus, this study demonstrates that the "roof plate[->]ventricle[->]cerebral wall" route is an essential path for microglial colonization into the embryonic mouse brain.

neuroscience↗

bioRxiv2022

Aberrant regulation of serine metabolite drives extracellular vesicle release and cancer progression

Cancer cells secrete extracellular vesicles (EVs) to regulate cells in the tumor microenvironment to benefit their own growth and survive in the patients body. Although emerging evidence has demonstrated the molecular mechanisms of EV release, regulating cancer-specific EV secretion remains challenging. In this study, we applied a microRNA library to reveal the universal mechanisms of EV secretion from cancer cells. Here, we identified miR-891b and its direct target gene, phosphoserine aminotransferase 1 (PSAT1), which promotes EV secretion through the serine-ceramide synthesis pathway. Inhibition of PSAT1 affected EV secretion in multiple types of cancer, suggesting that the miR-891b/PSAT1 axis shares a common mechanism of EV secretion from cancer cells. Interestingly, aberrant PSAT1 expression also regulated cancer metastasis via EV secretion. Our data link between the PSAT1-controlled EV secretion mechanism and cancer metastasis and show the potential of this mechanism as a therapeutic target in multiple types of cancer.

cancer biology↗

bioRxiv2022

Inter-organ Wingless/Ror/Akt signaling regulates nutrient-dependent hyperarborization of somatosensory neurons

Nutrition in early life has profound effects on an organism, altering processes such as organogenesis. However, little is known about how specific nutrients affect neuronal development. Dendrites of class IV neurons in Drosophila larvae become more complex when the larvae are reared on a low-yeast diet compared to a high-yeast diet. Our systematic search for key nutrients revealed that the neurons increase their dendrite densities in response to a combined deficiency in vitamins, metal ions, and cholesterol. These nutrients affect dendrite branching through the Wingless/Ror/Akt pathway between the neuron and closely located muscles, and this short range-pathway is regulated by a systemic Upd2-Stat92E pathway between the fat body and muscles. Additionally, the low-yeast diet blunts neuronal light responsiveness and light avoidance behavior, which may help larvae optimize their survival strategies under low-nutritional conditions. Together, our studies illustrate how the availability of specific nutrients affects neuronal development through inter-organ signaling.

developmental biology↗

bioRxiv2021

Executive control by fronto-parietal activity explains counterintuitive decision behavior in complex value-based decision-making

In real life, humans make decisions by taking into account multiple independent factors, such as delay and probability. Cognitive psychology suggests that cognitive control mechanisms play a key role when facing such complex task conditions. However, in value-based decision-making, it still remains unclear to what extent cognitive control mechanisms become essential when the task condition is complex. In this study, we investigated decision-making behaviors and underlying neural mechanisms using a multifactor gambling task where participants simultaneously considered probability and delay. Decision-making behavior in the multifactor task was modulated by both probability and delay. The behavioral effect of probability was stronger than delay, consistent with previous studies. Furthermore, in a subset of conditions that recruited fronto-parietal activations, reaction times were paradoxically elongated despite lower probabilistic uncertainty. Notably, such a reaction time elongation did not occur in control tasks involving single factors. Meta-analysis of brain activations suggested an association between the paradoxical increase of reaction time and strategy switching. Together, these results suggest a novel aspect of complex value-based decision-makings that is strongly influenced by fronto-parietal cognitive control. Highlights* A value-based decision task with concurrent delay and probabilistic uncertainty * Stronger behavioral effect of probability than delay * Paradoxically long reaction time despite low probabilistic uncertainty * The task activated fronto-parietal cognitive control network * Reaction time elongation coincided with activation similar to strategy switching

neuroscience↗

bioRxiv2020

Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome

Kabuki syndrome (KS) is a rare cause of intellectual disability primarily caused by loss of function mutations in lysine-specific methyltransferase 2D (KMT2D), which normally adds methyl marks to lysine 4 on histone 3. Previous studies have shown that a mouse model of KS (Kmt2d+/{beta}Geo) demonstrates disruption of adult neurogenesis and hippocampal memory. Proof-of-principle studies have shown postnatal rescue of neurological dysfunction following treatments that promote chromatin opening, however, these strategies are non-specific and do not directly address the primary defect of histone methylation. Since lysine-specific demethylase 1A (LSD1/KDM1A) normally removes the H3K4 methyl marks added by KMT2D, we hypothesize that inhibition of KDM1A demethylase activity may ameliorate molecular and phenotypic defects stemming from KMT2D loss. To test this hypothesis, we evaluated a recently developed KDM1A inhibitor (TAK-418) in Kmt2d+/{beta}Geo mice. We find that orally administered TAK-418 increases the numbers of newly born Doublecortin (DCX)+ cells and processes in hippocampus in a dose dependent manner. We also observe TAK-418-dependent rescue of histone modification defects in hippocampus both by Western blot and ChIP-Seq. Treatment rescues gene expression abnormalities including those of immediate early genes such as FBJ osteosarcoma oncogene (Fos) and FBJ osteosarcoma oncogene homolog B (Fosb). After 2 weeks of TAK-418, Kmt2d+/{beta}Geo mice demonstrate normalization of hippocampal memory defects. In summary, our data suggest that KDM1A inhibition is a plausible treatment strategy for KS and support the hypothesis that the epigenetic dysregulation secondary to KMT2D dysfunction plays a major role in the postnatal neurological disease phenotype in KS.

genetics↗