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2496 Publications

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    05/31/24 | Salivary gland developmental mechanics
    Morales EA, Wang S
    Current Topics in Developmental Biology:. doi: 10.1016/bs.ctdb.2024.05.002

    The salivary gland undergoes branching morphogenesis to elaborate into a tree-like structure with numerous saliva-secreting acinar units, all joined by a hierarchical ductal system. The expansive epithelial surface generated by branching morphogenesis serves as the structural basis for the efficient production and delivery of saliva. Here, we elucidate the process of salivary gland morphogenesis, emphasizing the role of mechanics. Structurally, the developing salivary gland is characterized by a stratified epithelium tightly encased by the basement membrane, which is in turn surrounded by a mesenchyme consisting of a dense network of interstitial matrix and mesenchymal cells. Diverse cell types and extracellular matrices bestow this developing organ with organized, yet spatially varied mechanical properties. For instance, the surface epithelial sheet of the bud is highly fluidic due to its high cell motility and weak cell-cell adhesion, rendering it highly pliable. In contrast, the inner core of the bud is more rigid, characterized by reduced cell motility and strong cell-cell adhesion, which likely provide structural support for the tissue. The interactions between the surface epithelial sheet and the inner core give rise to budding morphogenesis. Furthermore, the basement membrane and the mesenchyme offer mechanical constraints that could play a pivotal role in determining the higher-order architecture of a fully mature salivary gland.

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    06/10/24 | Transport and Organization of Individual Vimentin Filaments Within Dense Networks Revealed by Single Particle Tracking and 3D FIB-SEM
    Renganathan B, Moore AS, Yeo W, Petruncio A, Ackerman D, Wiegel A, CellMap Team , Pasolli HA, Xu CS, Hess HF, Serpinskaya AS, Zhang HF, Lippincott-Schwartz J, Gelfand VI
    bioRxiv. 2024 Jun 10:. doi: 10.1101/2024.06.10.598346

    Vimentin intermediate filaments (VIFs) form complex, tight-packed networks; due to this density, traditional ensemble labeling and imaging approaches cannot accurately discern single filament behavior. To address this, we introduce a sparse vimentin-SunTag labeling strategy to unambiguously visualize individual filament dynamics. This technique confirmed known long-range dynein and kinesin transport of peripheral VIFs and uncovered extensive bidirectional VIF motion within the perinuclear vimentin network, a region we had thought too densely bundled to permit such motility. To examine the nanoscale organization of perinuclear vimentin, we acquired high-resolution electron microscopy volumes of a vitreously frozen cell and reconstructed VIFs and microtubules within a 50 um3 window. Of 583 VIFs identified, most were integrated into long, semi-coherent bundles that fluctuated in width and filament packing density. Unexpectedly, VIFs displayed minimal local co-alignment with microtubules, save for sporadic cross-over sites that we predict facilitate cytoskeletal crosstalk. Overall, this work demonstrates single VIF dynamics and organization in the cellular milieu for the first time.

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    06/06/24 | Comparative connectomics of the descending and ascending neurons of the Drosophila nervous system: stereotypy and sexual dimorphism
    Stürner T, Brooks P, Serratosa Capdevila L, Morris BJ, Javier A, Fang S, Gkantia M, Cachero S, Beckett IR, Champion AS, Moitra I, Richards A, Klemm F, Kugel L, Namiki S, Cheong HS, Kovalyak J, Tenshaw E, Parekh R, Schlegel P, Phelps JS, Mark B, Dorkenwald S, Bates AS, Matsliah A, Yu S, McKellar CE, Sterling A, Seung S, Murthy M, Tuthill J, Lee WA, Card GM, Costa M, Jefferis GS, Eichler K
    bioRxiv. 2024 Jun 06:. doi: 10.1101/2024.06.04.596633

    In most complex nervous systems there is a clear anatomical separation between the nerve cord, which contains most of the final motor outputs necessary for behaviour, and the brain. In insects, the neck connective is both a physical and information bottleneck connecting the brain and the ventral nerve cord (VNC, spinal cord analogue) and comprises diverse populations of descending (DN), ascending (AN) and sensory ascending neurons, which are crucial for sensorimotor signalling and control.Integrating three separate EM datasets, we now provide a complete connectomic description of the ascending and descending neurons of the female nervous system of Drosophila and compare them with neurons of the male nerve cord. Proofread neuronal reconstructions have been matched across hemispheres, datasets and sexes. Crucially, we have also matched 51% of DN cell types to light level data defining specific driver lines as well as classifying all ascending populations.We use these results to reveal the general architecture, tracts, neuropil innervation and connectivity of neck connective neurons. We observe connected chains of descending and ascending neurons spanning the neck, which may subserve motor sequences. We provide a complete description of sexually dimorphic DN and AN populations, with detailed analysis of circuits implicated in sex-related behaviours, including female ovipositor extrusion (DNp13), male courtship (DNa12/aSP22) and song production (AN hemilineage 08B). Our work represents the first EM-level circuit analyses spanning the entire central nervous system of an adult animal.

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    05/31/24 | Periodic ER-plasma membrane junctions support long-range Ca2+ signal integration in dendrites
    Benedetti L, Fan R, Weigel AV, Moore AS, Houlihan PR, Kittisopikul M, Park G, Petruncio A, Hubbard PM, Pang S, Xu CS, Hess HF, Saalfeld S, Rangaraju V, Clapham DE, De Camilli P, Ryan TA, Lippincott-Schwartz J
    bioRxiv. 2024 May 31:. doi: 10.1101/2024.05.27.596121

    Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at \~1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca2+ channels and ER Ca2+-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca2+ homeostasis, and local activation of the Ca2+/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca2+ modulatory machinery facilitating voltage-independent signal transmission and ryanodine receptor-dependent Ca2+ release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca2+ release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.HighlightsPeriodic ER-PM junctions tile neuronal dendritic plasma membrane in rodent and fly.ER-PM junctions are populated by ER tethering and Ca2+ release and influx machinery.ER-PM junctions act as sites for local activation of CaMKII.Local spine activation drives Ca2+ release from RyRs at ER-PM junctions over 20 μm.

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    06/05/24 | Spatial Single-cell Analysis Decodes Cortical Layer and Area Specification
    Qian X, Coleman K, Jiang S, Kriz AJ, Marciano JH, Luo C, Cai C, Manam MD, Caglayan E, Otani A, Ghosh U, Shao DD, Andersen RE, Neil JE, Johnson R, LeFevre A, Hecht JL, Miller MB, Sun L, Stringer C, Li M, Walsh CA
    bioRxiv. 2024 Jun 05:. doi: 10.1101/2024.06.05.597673

    The human cerebral cortex, pivotal for advanced cognitive functions, is composed of six distinct layers and dozens of functionally specialized areas. The layers and areas are distinguished both molecularly, by diverse neuronal and glial cell subtypes, and structurally, through intricate spatial organization3,4. While single-cell transcriptomics studies have advanced molecular characterization of human cortical development, a critical gap exists due to the loss of spatial context during cell dissociation. Here, we utilized multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based cell segmentation, to examine the molecular, cellular, and cytoarchitectural development of human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing 16 million single cells, spans eight cortical areas across four time points in the second and third trimesters. We uncovered an early establishment of the six-layer structure, identifiable in the laminar distribution of excitatory neuronal subtypes by mid-gestation, long before the emergence of cytoarchitectural layers. Notably, while anterior-posterior gradients of neuronal subtypes were generally observed in most cortical areas, a striking exception was the sharp molecular border between primary (V1) and secondary visual cortices (V2) at gestational week 20. Here we discovered an abrupt binary shift in neuronal subtype specification at the earliest stages, challenging the notion that continuous morphogen gradients dictate mid-gestation cortical arealization. Moreover, integrating single-nuclei RNA-sequencing and in situ whole transcriptomics revealed an early upregulation of synaptogenesis in V1-specific Layer 4 neurons, suggesting a role of synaptogenesis in this discrete border formation. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This work not only provides a valuable resource for the field, but also establishes a spatially resolved single-cell analysis paradigm that paves the way for a comprehensive developmental atlas of the human brain.

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    06/02/24 | Mechanosensory representation of wing deformations
    Yarger AM, Maeda M, Siwanowicz I, Kajiyama H, Walker SM, Bomphrey RJ, Lin H
    bioRxiv. 2024 Jun 02:. doi: 10.1101/2024.06.02.596338

    Efficient representation of structural deformations is crucial for monitoring the instantaneous state of biological structures. Insects’ ability to encode wing deformations during flight demonstrates a general morphological computing principle applicable across sensory systems in nature as well as engineered systems. To characterize how relevant features are encoded, we measured and modelled displacement and strain across dragonfly wing surfaces in tethered and free flight. Functional interpretations were supported by neuroanatomical maps, and ablation and perturbation experiments. We find that signal redundancy is reduced by non-random sensor distributions and that morphology limits the stimulus space such that sensory systems can monitor natural states with few sensors. Deviations from the natural states are detected by a flexible population of additional sensors with many distinguishable activation patterns.

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    06/01/24 | It only takes seconds for a human monoclonal autoantibody to inhibit N-methyl-D-aspartate receptors
    Yang S, Heckmann J, Taha A, Gao S, Steinke S, Hust M, Prüß H, Furukawa H, Geis C, Heckmann M, Yu-Strzelczyk J
    bioRxiv. 2024 Jun 01:. doi: 10.1101/2024.05.28.595700

    Transfer of autoantibodies targeting ionotropic N-methyl-D-aspartate receptors in autoimmune encephalitis patients into mice leads to typical disease signs. Long-term effects of the pathogenic antibodies consist of immunoglobulin G-induced crosslinking and receptor internalization. We focused on the direct and immediate impact of a specific pathogenic patient-derived monoclonal autoantibody (immunoglobulin G #003-102) on receptor function.We performed cell-attached recordings in cells transfected with the GluN1 and GluN2A subunit of the N-methyl-D-aspartate receptor. Immunoglobulin G #003-102 binds to the amino-terminal domain of the glycine-binding GluN1 subunit. It reduced simultaneous receptor openings significantly compared to controls at both low and high glutamate and glycine concentrations. Closer examination of our data in 50-second to 2-second intervals revealed, that Immunoglobulin G #003-102 rapidly decreases the number of open receptors. However, antigen-binding fragments of immunoglobulin G #003-102 did not reduce the receptor openings.In conclusion, patient-derived immunoglobulin G #003-102 inhibits N-methyl-D-aspartate receptors rapidly and directly before receptor internalization occurs and the entire immunoglobulin G is necessary for this acute inhibitory effect. This suggests an application of the antigen-binding fragment-like constructs of #003-102 as a potential new treatment strategy for shielding the pathogenic epitopes on the N-methyl-D-aspartate receptors.

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    05/30/24 | Aging atlas reveals cell-type-specific effects of pro-longevity strategies.
    Gao SM, Qi Y, Zhang Q, Guan Y, Lee Y, Ding L, Wang L, Mohammed AS, Li H, Fu Y, Wang MC
    Nat Aging. 2024 May 30:. doi: 10.1038/s43587-024-00631-1

    Organismal aging involves functional declines in both somatic and reproductive tissues. Multiple strategies have been discovered to extend lifespan across species. However, how age-related molecular changes differ among various tissues and how those lifespan-extending strategies slow tissue aging in distinct manners remain unclear. Here we generated the transcriptomic Cell Atlas of Worm Aging (CAWA, ) of wild-type and long-lived strains. We discovered cell-specific, age-related molecular and functional signatures across all somatic and germ cell types. We developed transcriptomic aging clocks for different tissues and quantitatively determined how three different pro-longevity strategies slow tissue aging distinctively. Furthermore, through genome-wide profiling of alternative polyadenylation (APA) events in different tissues, we discovered cell-type-specific APA changes during aging and revealed how these changes are differentially affected by the pro-longevity strategies. Together, this study offers fundamental molecular insights into both somatic and reproductive aging and provides a valuable resource for in-depth understanding of the diversity of pro-longevity mechanisms.

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    05/23/24 | Norepinephrine changes behavioral state via astroglial purinergic signaling
    Chen AB, Duque M, Wang VM, Dhanasekar M, Mi X, Rymbek A, Tocquer L, Narayan S, Prober D, Yu G, Wyart C, Engert F, Ahrens MB
    bioRxiv. 2024 May 23:. doi: 10.1101/2024.05.23.595576

    Both neurons and glia communicate via diffusible neuromodulatory substances, but the substrates of computation in such neuromodulatory networks are unclear. During behavioral transitions in the larval zebrafish, the neuromodulator norepinephrine drives fast excitation and delayed inhibition of behavior and circuit activity. We find that the inhibitory arm of this feedforward motif is implemented by astroglial purinergic signaling. Neuromodulator imaging, behavioral pharmacology, and perturbations of neurons and astroglia reveal that norepinephrine triggers astroglial release of adenosine triphosphate, extracellular conversion into adenosine, and behavioral suppression through activation of hindbrain neuronal adenosine receptors. This work, along with a companion piece by Lefton and colleagues demonstrating an analogous pathway mediating the effect of norepinephrine on synaptic connectivity in mice, identifies a computational and behavioral role for an evolutionarily conserved astroglial purinergic signaling axis in norepinephrine-mediated behavioral and brain state transitions.

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    05/20/24 | SciJava Ops: An Improved Algorithms Framework for Fiji and Beyond
    Gabriel J. Selzer , Curtis T. Rueden , Mark C. Hiner , Edward L. Evans III au2 , David Kolb , Marcel Wiedenmann , Christian Birkhold , Tim-Oliver Buchholz , Stefan Helfrich , Brian Northan , Alison Walter , Johannes Schindelin , Tobias Pietzsch , Stephan Saalfeld , Michael R. Berthold , Kevin W. Eliceiri
    arXiv. 2024-05-20:. doi: 10.48550/arXiv.2405.12385

    Many scientific software platforms provide plugin mechanisms that simplify the integration, deployment, and execution of externally developed functionality. One of the most widely used platforms in the imaging space is Fiji, a popular open-source application for scientific image analysis. Fiji incorporates and builds on the ImageJ and ImageJ2 platforms, which provide a powerful plugin architecture used by thousands of plugins to solve a wide variety of problems. This capability is a major part of Fiji's success, and it has become a widely used biological image analysis tool and a target for new functionality. However, a plugin-based software architecture cannot unify disparate platforms operating on incompatible data structures; interoperability necessitates the creation of adaptation or "bridge" layers to translate data and invoke functionality. As a result, while platforms like Fiji enable a high degree of interconnectivity and extensibility, they were not fundamentally designed to integrate across the many data types, programming languages, and architectural differences of various software help address this challenge, we present SciJava Ops, a foundational software library for expressing algorithms as plugins in a unified and extensible way. Continuing the evolution of Fiji's SciJava plugin mechanism, SciJava Ops enables users to harness algorithms from various software platforms within a central execution environment. In addition, SciJava Ops automatically adapts data into the most appropriate structure for each algorithm, allowing users to freely and transparently combine algorithms from otherwise incompatible tools. While SciJava Ops is initially distributed as a Fiji update site, the framework does not require Fiji, ImageJ, or ImageJ2, and would be suitable for integration with additional image analysis platforms.

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