Biology subjects

Maki, T.

Publications and source records attributed to Maki, T..

8 recordsLinked to original sources

bioRxiv2026

COUNTERING AGE-ASSOCIATED ALTERATIONS IN OLIGODENDROCYTE-DERIVED EXTRACELLULAR MATRIX REJUVENATES COGNITION

Efforts to rejuvenate age-related cognitive decline have predominantly targeted neurons, often overlooking non-neuronal cell types in the aging brain. Here, we show that countering alterations in oligodendrocyte-derived extracellular matrix (ECM) in the aging hippocampus restores cognition. We identify broad age-associated transcriptional and proteomic changes in oligodendrocytes, including dysregulation of the matrisome, with marked upregulation of ECM components and associated regulators with age. Among these, we detect an increase in Hyaluronan and proteoglycan link protein 2 (HAPLN2), an oligodendrocyte-derived core matrisome protein that locates specifically at the nodes of Ranvier, in the hippocampus of aged mice and older humans. Hapln2 overexpression in oligodendrocytes of young mice recapitulated age-related memory impairments. Conversely, abrogating the age-related increase in Hapln2 induced synaptic plasticity-related hippocampal transcriptional signatures and improved memory in aged mice. Together, these data define oligodendrocyte-derived ECM remodeling as a hallmark of brain aging that can be targeted to rescue cognitive decline.

neuroscience↗

bioRxiv2025

Mouse pulmonary pathological characteristics induced by Asian-mineral dust transported with Coniothyrium fuckelii at a high altitude of 2,000 meters

Asian sand dust (ASD) events are known to transport not only mineral particles but also bioaerosols such as fungi across East Asia, posing complex respiratory health risks. Previously, we isolated Coniothyrium fuckelii (Strain Con-15H316)--a dematiaceous phytopathogenic fungus--from the ASD samples collected at an altitude of 2000 m over the Noto Peninsula, Japan. While Con-15H316 elicited potent immunological responses in our earlier cytokine-focused studies, its histopathological impact on mammalian lungs remained uncharacterized. Here, we re-evaluated formalin-fixed murine lung tissues from mice intratracheally administered heat-treated ASD (H-ASD: only mineral particles), Con-15H316, and Con-15H316 in combination with H-ASD. H-ASD alone induced macrophage-dominant alveolar granulomas, and Con-15H316 alone triggered peribronchiolitis with eosinophilic infiltration. Strikingly, co-exposure resulted in a qualitatively distinct and synergistically worsened phenotype, featuring neutrophil-rich suppurative alveolar pneumonia, granulomas, and peribronchiolitis. Bronchoalveolar lavage fluid (BALF) analysis revealed marked co-elevation of lactate dehydrogenase (LDH) and CCL2 (C-C motif chemokine 2, also known as monocyte chemoattractant protein-1, MCP-1), suggesting concurrent tissue injury and monocyte-driven immune activation. To elucidate the cellular origin of the CCL2 protein, we reanalyzed two publicly available single-cell RNA-seq datasets, identifying monocytes and interstitial macrophages as the dominant Ccl2-expressing populations in microbially injured lungs. Although C. fuckelii has been recognized generally as a plant pathogen, this study exhibited the first histological evidence of the potential of this fungus to induce or exacerbate mammalian lung injury, especially in combination with mineral dust. Our findings uncover a novel, non-allergic alveolar injury phenotype associated with microbial-particulate co-exposure, expanding current toxicological paradigms beyond pathologies associated with excessive immune reactions to inhaled particulates and bioaerosols.

pathology↗

bioRxiv2024

Oligodendrocyte precursor cells exacerbate acute CNS inflammation via macrophage and T cell activation in a mouse model of multiple sclerosis

Oligodendrocyte precursor cells (OPCs) are a type of glial cell that differentiates into mature oligodendrocytes, a cell type that contributes to myelination, but their roles in the pathologies are not fully understood. Activities other than differentiation into oligodendrocytes have recently been reported for OPCs present in the inflammatory milieu, but intervention studies using animal models are lacking. This study aimed to explore the role of OPCs in mouse MS model experimental autoimmune encephalomyelitis (EAE). Using inducible diphtheria toxin receptor-expressing transgenic mice, platelet-derived growth factor receptor A (PDGFR)+ OPCs were depleted in EAE mice. Surprisingly, OPC depletion in the acute phase improved clinical scores and reduced demyelination. Major histocompatibility complex (MHC) class II was reduced in the spinal cord, whereas astrocyte marker and blood-spinal cord barrier tight junction and adhesion molecule expressions were unaffected after OPC depletion. The numbers of T cells and IL17-expressing Th17 cells were decreased in the spinal cords of the OPC-depleted group. MHC class II expression in spinal cord macrophages was consistently decreased by OPC depletion. These data suggest that in the acute phase of EAE, OPCs are involved in activation of infiltrated macrophages and induce subsequent T cell activation and neuroinflammation. Although the precise mechanisms remain unclear, this implies that OPCs exist not only as the source for oligodendrocytes but also play a pivotal role in central nervous system (CNS) autoimmune inflammation. Table of Contents Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/596190v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@98162dorg.highwire.dtl.DTLVardef@d7f92dorg.highwire.dtl.DTLVardef@1280619org.highwire.dtl.DTLVardef@a85907_HPS_FORMAT_FIGEXP M_FIG C_FIG MAIN POINTSO_LIOPC depletion in the acute phase of EAE improved clinical scores and reduced demyelination. C_LIO_LIOPC depletion in the spinal cord suppressed Antigen presentation via MHC class II. C_LIO_LIOPCs are involved in activation of infiltrated macrophages and induce subsequent T cell activation and neuroinflammation. C_LI

neuroscience↗

bioRxiv2022

Fission yeast Swi2 designates cell-type specific donor and stimulates Rad51-driven strand exchange

A haploid of the fission yeast Schizosaccharomyces pombe expresses either the P or M matingtype, determined by the active, euchromatic, mat1 cassette. Mating-type is switched by Rad51-driven gene conversion of mat1 using a heterochromatic donor cassette, mat2-P or mat3-M. The Swi2-Swi5 complex, a mating-type switching factor, is central to this process by designating a preferred donor in a cell-type-specific manner. Swi2-Swi5 selectively enables one of two cisacting recombination enhancers, SRE2 adjacent to mat2-P or SRE3 adjacent to mat3-M. Here, we identified two functionally important motifs in Swi2, a Swi6 (HP1 homolog)-binding site and two DNA-binding AT-hooks. Genetic analysis demonstrated that the AT-hooks were required for Swi2 localization at SRE3 to select the mat3-M donor in P cells, while the Swi6-binding site was required for Swi2 localization at SRE2 to select mat2-P in M cells. In addition, the Swi2-Swi5 complex promoted Rad51-driven strand exchange in vitro. Taken together, our results show how the Swi2-Swi5 complex would localize to recombination enhancers through a cell-type specific binding mechanism and stimulate Rad51-driven gene conversion at the localization site.

molecular biology↗

bioRxiv2021

Euchromatin factors HULC and Set1C affect heterochromatin organization for mating-type switching in fission yeast Schizosaccharomyces pombe

Mating-type (P or M) of fission yeast Schizosaccharomyces pombe is determined by the transcriptionally active mat1 cassette and is switched by gene conversion using a donor, either mat2 or mat3, located in an adjacent heterochromatin region (mating-type switching; MTS). In the process, heterochromatic donors of genetic information are selected based on the P or M cell type and on the action of two recombination enhancers, SRE2 promoting the use of mat2-P and SRE3 promoting the use of mat3-M, leading to replacement of the content of the expressed mat1 cassette. Recently, we found that the histone H3K4 methyltransferase complex Set1C participates in donor selection, raising the question of how a complex best known for its effects in euchromatin controls recombination in heterochromatin. Here, we report that the histone H2BK119 ubiquitin ligase complex HULC functions with Set1C in MTS, as mutants in the shf1, brl1, brl2 and rad6 genes showed defects similar to Set1C mutants and belonged to the same epistasis group as set1{Delta}. Moreover, using H3K4R and H2BK119R histone mutants and a Set1-Y897A catalytic mutant indicated that ubiquitylation of histone H2BK119 by HULC and methylation of histone H3K4 by Set1C are functionally coupled in MTS. Cell-type biases in MTS in these mutants suggested that HULC and Set1C inhibit the use of the SRE3 recombination enhancer in M cells, thus favoring SRE2 and mat2-P. Consistently, imbalanced switching in the mutants was traced to compromised association of the directionality factor Swi6 with the recombination enhancers in M cells. Based on their known effects at other chromosomal locations, we speculate that HULC and Set1C might control nucleosome mobility and strand invasion near the SRE elements. In addition, we uncovered distinct effects of HULC and Set1C on histone H3K9 methylation and gene silencing, consistent with additional functions in the heterochromatic domain.

genetics↗

bioRxiv2019

Real-time tracking reveals the catalytic process of Rad51-driven DNA strand exchange

During homologous recombination, Rad51 forms a nucleoprotein filament on single-stranded DNA to promote DNA strand exchange. This filament binds to double-stranded DNA (dsDNA), searches for homology, and promotes transfer of the complementary strand, producing a new heteroduplex. Strand exchange proceeds via two distinct three-strand intermediates, C1 and C2. C1 contains the intact donor dsDNA whereas C2 contains newly formed heteroduplex DNA. Here, we show that conserved DNA binding motifs, loop 1 (L1) and loop 2 (L2) in site I of Rad51, play distinct roles in this process. L1 is involved in formation of the C1 complex whereas L2 mediates the C1-C2 transition, producing the heteroduplex. Another DNA binding motif, site II, serves as the DNA entry position for initial Rad51 filament formation, as well as for second donor dsDNA incorporation. Our study provides a comprehensive molecular model for the catalytic process of strand exchange mediated by eukaryotic RecA family recombinases.

molecular biology↗

bioRxiv2019

Rad51 Interaction Analysis Reveals a Functional Interplay Among Recombination Auxiliary Factors

Although Rad51 is the key protein in homologous recombination (HR), a major DNA double-strand break repair pathway, several auxiliary factors interact with Rad51 to promote productive HR. Here, we present an interdisciplinary characterization of the interaction between Rad51 and Swi5-Sfr1, a widely conserved auxiliary factor. NMR and site-specific crosslinking experiments revealed two distinct sites within the intrinsically disordered N-terminus of Sfr1 that cooperatively bind to Rad51. Although disruption of this binding severely impaired Rad51 stimulation in vitro, interaction mutants did not show any defects in DNA repair. Unexpectedly, in the absence of the Rad51 paralogs Rad55-Rad57, which constitute another auxiliary factor complex, these interaction mutants were unable to promote DNA repair. Our findings provide molecular insights into Rad51 stimulation by Swi5-Sfr1 and suggest that, rather than functioning in an independent subpathway of HR as was previously proposed, Rad55-Rad57 facilitates the recruitment of Swi5-Sfr1 to Rad51.

molecular biology↗

bioRxiv2018

Microbial dispersal limitation to isolated soil habitats in the McMurdo Dry Valleys of Antarctica

Dispersal is a critical yet poorly understood factor underlying macroecological patterns in microbial communities. Airborne microbial transport is assumed to occupy a central role in determining dispersal outcomes and extra-range dispersal has important implications for predicting ecosystem resilience and response to environmental change. One of the most pertinent biomes in this regard is Antarctica given its geographic isolation and vulnerability to climate change and human disturbance. Here we report the first characterisation of microbial diversity in near-ground and high-altitude air above a typical Antarctic Dry Valley as well as that of underlying soil microbial communities. We found that persistent airborne inputs were unable to fully explain local soil community assembly. Comparison with airborne microbial diversity from non-polar sources suggests that strong selection occurs during atmospheric transport resulting in regionally isolated airborne inputs and highly specialized soil communities where fungi displayed greater isolation than bacteria from non-polar sources. Overall microbial communities from this isolated Antarctic ecosystem displayed limited connectivity to the global microbial pool. Our findings provide critical insights to forecast the potential outcomes for microbial communities of climate change-mediated shifts in air circulation to the Dry Valleys, the largest ice-free region of Antarctica.

microbiology↗