Biology subjects

Nagayama, S.

Publications and source records attributed to Nagayama, S..

8 recordsLinked to original sources

bioRxiv2025

A cytosolic function of DNMT1 controls neuronal morphogenesis via microtubule regulation

Proteins traditionally confined to a single cellular compartment are increasingly recognized to exert non-canonical functions in alternative domains. The DNA methyltransferase 1 (DNMT1), classically defined as the maintenance methyltransferase that preserves DNA methylation patterns during replication, exemplifies this versatility. Beyond its canonical role, DNMT1 is highly expressed in the developing and adult brain, where it contributes to transcriptional regulation in postmitotic neurons. Notably, cytoplasmic DNMT1 localization has been observed in neural cells, and emerging evidence links DNMT1 to mitochondrial function with implications for neurodegenerative disease, whereby the underlying functional mechanisms remain to be fully elucidated. Here, we identify a previously unrecognized cytosolic function of DNMT1 in developing cortical excitatory neurons. Through genetic perturbation, proteomics, and high-resolution imaging, we show that DNMT1 regulates dendritic and axonal branching independently of its catalytic activity and nuclear localization. Instead, DNMT1 operates as a cytosolic scaffold interacting with the polarity regulator DOCK7 to modulate Rac1-STMN1 signaling, microtubule dynamics, and organelle trafficking. These findings expand the conceptual framework of DNMT1 from a genome guardian to a dual-compartment regulator that coordinates cytoskeletal remodeling and mitochondrial positioning. Beyond advancing our understanding of neuronal morphogenesis, this work provides mechanistic insight into how DNMT1 mutations may lead to neurodegenerative diseases.

neuroscience↗

bioRxiv2022

The role of geology in creating stream climate-change refugia along climate gradients

Identifying climate-change refugia is a key adaptation strategy for reducing global warming impacts. Knowledge of the effects of underlying geology on thermal regime along climate gradients and the ecological responses to the geology-controlled thermal regime is essential to plan appropriate climate adaptation strategies. The dominance of volcanic rocks in the watershed is used as a landscape-scale surrogate for cold groundwater inputs to clarify the importance of underlying geology. Using statistical models, we explored the relationship between watershed geology and the mean summer water temperature of mountain streams along climate gradients in the Japanese archipelago. Summer water temperature was explained by the interaction between the watershed geology and climate in addition to independent effects. The cooling effect associated with volcanic rocks was more pronounced in streams with less summer precipitation or lower air temperatures. We also examined the function of volcanic streams as cold refugia under contemporary and future climatic conditions. Community composition analyses revealed that volcanic streams hosted distinct stream communities composed of more cold-water species compared with non-volcanic streams. Scenario analyses revealed a geology-related pattern of thermal habitat loss for cold-water species. Non-volcanic streams rapidly declined in thermally suitable habitats for lotic sculpins even under the lowest emission scenario (RCP 2.6). In contrast, most volcanic streams will be sustained below the thermal threshold, especially for low and mid-level emission scenarios (RCP 2.6, 4.5). However, the distinct stream community in volcanic streams and geology-dependent habitat loss for lotic sculpins was not uniform and was more pronounced in areas with less summer precipitation or lower air temperatures. Although further studies are needed to understand underlying mechanisms of the interplay of watershed geology and climate, findings highlight that watershed geology, climate variability, and their interaction should be considered simultaneously for effective management of climate-change refugia in mountain streams.

ecology↗

bioRxiv2021

Prolonged and extended impacts of SARS-CoV-2 on the olfactory neurocircuit

The impact of SARS-CoV-2 on the olfactory pathway was studied over several time points using Syrian golden hamsters. We found an incomplete recovery of the olfactory sensory neurons, prolonged activation of glial cells in the olfactory bulb, and a decrease in the density of dendritic spines within the hippocampus. These data may be useful for elucidating the mechanism underlying long-lasting olfactory dysfunction and cognitive impairment as a post-acute COVID-19 syndrome.

neuroscience↗

bioRxiv2021

Differential immunopeptidome analysis revealed cancer specific amino acid usage of HLA class-I antigens and novel neoantigens of colorectal cancer

Understanding the properties of human leukocyte antigen (HLA) peptides (HLAp) is essential for cancer precision medicine, while the direct identification of HLAp from a tiny piece of clinical tissues by mass spectrometry (MS) is still confronted with technical challenges. Here, to overcome that hindrances, high-field asymmetric waveform ion mobility spectrometry (FAIMS) is introduced to conduct differential ion mobility (DIM)-MS by seamless gas-phase fractionation optimal for scarce samples. The global-immunopeptidomics analysis enables in-depth identification of 44,785 HLAp, including 2 neoantigens with KRAS-G12V and CPPED1-R228Q from stage IV colorectal cancer (CRC) tissues obtained from 17 subjects. Comparison of tissue-based personal immunopeptidome disclosed cancer-specific processing of HLAp. Since the direct identification of neoantigens from CRC tissues suggests more potential neoantigens have yet to been identified, the targeted-immunopeptidomics by screening-oriented parallel reaction monitoring (PRM) has been established and identified two more neoantigens with oncogenic KRAS. The targeted-immunopeptidomics analysis clarifies the presentation of aimed neoantigens, including neoantigens that are unpredictable by computational algorithms. The comprehensive-immunopeptidomics approach combining the FAIMS-assisted DIM-MS and the screening-oriented PRM contributes the direct and effective identification of HLAp and emerging neoantigens from clinical tissue samples, as an advanced strategy to identify the authentic and recurrent neoantigens for cancer immunotherapy.

cancer biology↗

bioRxiv2020

Development of Microsatellite Markers for a Soricid Water Shrew Chimarrogale platycephalus, and the Success of Individual Identification Using It.

The soricid water shrew, Chimarrogale platycephalus, is a mammal species endemic to the Japanese Islands. They inhabit the islands of Honshu and Kyushu, and are considered to be extinct in Shikoku. Information on this water shrew from Honshu and Kyushu is also scarce, and C. platycephalus is registered on the Japanese Governments red list as an endangered species. Almost all study areas such as regarding their ethology, ecology, also their phylogenetics are lacking. The delay in these foundational studies is due to difficulties related to them being both nocturnal and aquatic. In order to study of C. platycephalus, it is essential to conduct field research in mountain streams at night under such circumstances. In response to such difficult circumstances, we established a genetic analysis method using the feces of C. platycephalus, and as a result the accumulation of data on their phylogenetic evolution and phylogeography has increased which has improved our understanding of this species. Furthermore in this study, development of microsatellite markers was carried out, and a total of 21 loci marker analyses were performed. In addition, in order to confirm the credibility of these 21 microsatellite markers, as being able to validly differentiate individuals, all markers were examined using the fecal and tissues specimens from verified separately reared individuals (12 individuals) with the known history of having been reared in an aquarium. As a result, it was revealed that if analyses of the 12 loci were possible, individual differentiation with 100% accuracy was possible. The development of microsatellite markers in this study, and the establishment of individual identification methods by means of this will be expected to greatly contribute to future ecological and ethological research, population genetics and biogeographical research of the water shrew, C. platycephalus.

evolutionary biology↗

bioRxiv2019

Large scale genome-wide association study in a Japanese population identified 45 novel susceptibility loci for 22 diseases

INTRODUCTORY PARAGRAPHThe overwhelming majority of participants in current genetic studies are of European ancestry1-3, limiting our genetic understanding of complex disease in non-European populations. To address this, we aimed to elucidate polygenic disease biology in the East Asian population by conducting a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 383 independent signals in 331 loci for 30 diseases, among which 45 loci were novel (P < 5 x 10-8). Compared with known variants, novel variants have lower frequency in European populations but comparable frequency in East Asian populations, suggesting the advantage of this study in discovering these novel variants. Three novel signals were in linkage disequilibrium (r2 > 0.6) with missense variants which are monomorphic in European populations (1000 Genomes Project) including rs11235604(p.R220W of ATG16L2, a autophagy-related gene) associated with coronary artery disease. We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, andidentified 378 significant enrichments across nine diseases (FDR < 0.05) (e.g. NF-{kappa}B for immune-related diseases). This large-scale GWAS in a Japanese population provides insights into the etiology of common complex diseases and highlights the importance of performing GWAS in non-European populations.

genetics↗

bioRxiv2019

Comparison of odor responses of homologous medial and lateral glomeruli mapped in the olfactory bulb of the mouse

Olfactory sensory neurons expressing same-type odorant receptors typically project to a pair of glomeruli in the medial and lateral sides of the olfactory bulbs (OBs) in rodents. However, their functional properties remain unclear, because the majority of medial glomeruli are hidden in the septal OB. Recently, trace amine-associated odorant receptors were identified that project to a pair of glomeruli uniquely located in the dorsal OB. We measured the odorant-induced calcium responses of these glomeruli simultaneously and found that they exhibited similar temporal response patterns. However, the medial glomeruli had significantly larger respiration-locked calcium fluctuations than the lateral glomeruli. This trend was observed with/without odorant stimulation in postsynaptic neurons but not in presynaptic sensory axon terminals. This indicates that the medial rather than the lateral OB map enhances the respiration-locked rhythm and transfers this information to higher brain centers.\n\nImpact StatementThis study used in vivo calcium imaging to document the odor-evoked responses in paired glomeruli, demonstrating that activation in medial glomeruli more strongly impacts respiratory-linked odor processing.

neuroscience↗

bioRxiv2018

Narrowly confined and glomerulus-specific onset latencies of odor-evoked calcium transients in the periglomerular cells of the mouse main olfactory bulb

Odor information is transmitted from olfactory sensory neurons to principal neurons at the glomeruli of the olfactory bulb. The intraglomerular neuronal circuit also includes hundreds of GABAergic interneurons referred to as periglomerular (PG) cells. Stimulus selectivity is well correlated among PG cells that are associated with the same glomerulus, consistent with their highly homogeneous sensory inputs. However, much less is known about the temporal aspects of their activity, including the temporal coordination of their odor-evoked responses. As many PG cells within a glomerular module respond to the same stimulus, the extent to which their activity is temporally aligned will affect the temporal profile of their population inhibitory inputs. Using random-access high-speed two-photon microscopy, we recorded the odor-evoked calcium transients of mouse PG cells and compared the onset latency and rise time among neurons putatively associated with the same and different glomeruli. Whereas the overall onset latencies of odor-evoked transients were distributed across a ~150 ms time window, those from cells putatively associated with the same glomerulus were confined to a much narrower window of several tens of milliseconds. This result suggests that onset latency primarily depends on the associated glomerulus. We also observed glomerular specificity in the rise time. The glomerulus-specific temporal pattern of odor-evoked activity implies that the temporal patterns of inhibitory inputs are unique to individual glomerulus-odor pairs, which may contribute to efficient shaping of the temporal pattern of activity in the principal neurons.

neuroscience↗