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1416 Publications

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    03/09/20 | Basement Membrane Regulates Fibronectin Organization Using Sliding Focal Adhesions Driven by a Contractile Winch
    Jiaoyang Lu , Andrew D. Doyle , Yoshinari Shinsato , Shaohe Wang , Molly A. Bodendorfer , Minhua Zheng , Kenneth M. Yamada
    Developmental Cell. 03/2020;52:631-646.e4. doi:

    Summary We have discovered that basement membrane and its major components can induce rapid, strikingly robust fibronectin organization. In this new matrix assembly mechanism, α5β1 integrin-based focal adhesions slide actively on the underlying matrix toward the ventral cell center through the dynamic shortening of myosin IIA-associated actin stress fibers to drive rapid fibronectin fibrillogenesis distal to the adhesion. This mechanism contrasts with classical fibronectin assembly based on stable or fixed-position focal adhesions containing αVβ3 integrins plus α5β1 integrin translocation into proximal fibrillar adhesions. On basement membrane components, these sliding focal adhesions contain standard focal adhesion constituents but completely lack classical αVβ3 integrins. Instead, peripheral α3β1 or α2β1 adhesions mediate initial cell attachment but over time are switched to α5β1 integrin-based sliding focal adhesions to assemble fibronectin matrix. This basement-membrane-triggered mechanism produces rapid fibronectin fibrillogenesis, providing a mechanistic explanation for the well-known widespread accumulation of fibronectin at many organ basement membranes.

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    03/03/20 | Functional Diversity of Glycinergic Commissural Inhibitory Neurons in Larval Zebrafish
    Chie Satou , Takumi Sugioka , Yuto Uemura , Takashi Shimazaki , Pawel Zmarz , Yukiko Kimura , Shin-ichi Higashijima
    Cell Reports. 03/2020;30:3036-3050.e4. doi:

    Summary Commissural inhibitory neurons in the spinal cord of aquatic vertebrates coordinate left-right body alternation during swimming. Their developmental origin, however, has been elusive. We investigate this by comparing the anatomy and function of two commissural inhibitory neuron types, dI6dmrt3a and V0d, derived from the pd6 and p0 progenitor domains, respectively. We find that both of these commissural neuron types have monosynaptic, inhibitory connections to neuronal populations active during fictive swimming, supporting their role in providing inhibition to the contralateral side. V0d neurons tend to fire during faster and stronger movements, while dI6dmrt3a neurons tend to fire more consistently during normal fictive swimming. Ablation of dI6dmrt3a neurons leads to an impairment of left-right alternating activity through abnormal co-activation of ventral root neurons on both sides of the spinal cord. Our results suggest that dI6dmrt3a and V0d commissural inhibitory neurons synergistically provide inhibition to the opposite side across different swimming behaviors.

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    01/23/20 | Cell-Surface Proteomic Profiling in the Fly Brain Uncovers Wiring Regulators.
    Li J, Han S, Li H, Udeshi ND, Svinkina T, Mani DR, Xu C, Guajardo R, Xie Q, Li T, Luginbuhl DJ, Wu B, McLaughlin CN, Xie A, Kaewsapsak P, Quake SR, Carr SA, Ting AY, Luo L
    Cell. 01/2020;180(2):373-386.e15. doi: 10.1016/j.cell.2019.12.029

    Molecular interactions at the cellular interface mediate organized assembly of single cells into tissues and, thus, govern the development and physiology of multicellular organisms. Here, we developed a cell-type-specific, spatiotemporally resolved approach to profile cell-surface proteomes in intact tissues. Quantitative profiling of cell-surface proteomes of Drosophila olfactory projection neurons (PNs) in pupae and adults revealed global downregulation of wiring molecules and upregulation of synaptic molecules in the transition from developing to mature PNs. A proteome-instructed in vivo screen identified 20 cell-surface molecules regulating neural circuit assembly, many of which belong to evolutionarily conserved protein families not previously linked to neural development. Genetic analysis further revealed that the lipoprotein receptor LRP1 cell-autonomously controls PN dendrite targeting, contributing to the formation of a precise olfactory map. These findings highlight the power of temporally resolved in situ cell-surface proteomic profiling in discovering regulators of brain wiring.

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    01/06/20 | Bump-and-Hole Engineering Identifies Specific Substrates of Glycosyltransferases in Living Cells
    Schumann B, Malaker SA, Wisnovsky SP, Debets MF, Agbay AJ, Fernandez D, Wagner LJ, Lin L, Li Z, Choi J, Fox DM, Peh J, Gray MA, Pedram K, Kohler JJ, Mrksich M, Bertozzi CR
    Molecular Cell. Jan-06-2020;78(5):824 - 834.e15. doi: 10.1016/j.molcel.2020.03.030

    Studying posttranslational modifications classically relies on experimental strategies that oversimplify the complex biosynthetic machineries of living cells. Protein glycosylation contributes to essential biological processes, but correlating glycan structure, underlying protein, and disease-relevant biosynthetic regulation is currently elusive. Here, we engineer living cells to tag glycans with editable chemical functionalities while providing information on biosynthesis, physiological context, and glycan fine structure. We introduce a non-natural substrate biosynthetic pathway and use engineered glycosyltransferases to incorporate chemically tagged sugars into the cell surface glycome of the living cell. We apply the strategy to a particularly redundant yet disease-relevant human glycosyltransferase family, the polypeptide N-acetylgalactosaminyl transferases. This approach bestows a gain-of-chemical-functionality modification on cells, where the products of individual glycosyltransferases can be selectively characterized or manipulated to understand glycan contribution to major physiological processes.


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    01/06/20 | Probabilistic Models of Larval Zebrafish Behavior Reveal Structure on Many Scales
    Robert Evan Johnson , Scott Linderman , Thomas Panier , Caroline Lei Wee , Erin Song , Kristian Joseph Herrera , Andrew Miller , Florian Engert
    Current Biology. 01/2020;30:70 - 82.e4. doi:

    Nervous systems have evolved to combine environmental information with internal state to select and generate adaptive behavioral sequences. To better understand these computations and their implementation in neural circuits, natural behavior must be carefully measured and quantified. Here, we collect high spatial resolution video of single zebrafish larvae swimming in a naturalistic environment and develop models of their action selection across exploration and hunting. Zebrafish larvae swim in punctuated bouts separated by longer periods of rest called interbout intervals. We take advantage of this structure by categorizing bouts into discrete types and representing their behavior as labeled sequences of bout types emitted over time. We then construct probabilistic models—specifically, marked renewal processes—to evaluate how bout types and interbout intervals are selected by the fish as a function of its internal hunger state, behavioral history, and the locations and properties of nearby prey. Finally, we evaluate the models by their predictive likelihood and their ability to generate realistic trajectories of virtual fish swimming through simulated environments. Our simulations capture multiple timescales of structure in larval zebrafish behavior and expose many ways in which hunger state influences their action selection to promote food seeking during hunger and safety during satiety.

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    11/22/19 | Associative conditioning remaps odor representations and modifies inhibition in a higher olfactory brain area.
    Frank T, Mönig NR, Satou C, Higashijima S, Friedrich RW
    Nat Neurosci. 11/2019;22(11):1844-1856. doi: 10.1038/s41593-019-0495-z

    Intelligent behavior involves associations between high-dimensional sensory representations and behaviorally relevant qualities such as valence. Learning of associations involves plasticity of excitatory connectivity, but it remains poorly understood how information flow is reorganized in networks and how inhibition contributes to this process. We trained adult zebrafish in an appetitive odor discrimination task and analyzed odor representations in a specific compartment of the posterior zone of the dorsal telencephalon (Dp), the homolog of mammalian olfactory cortex. Associative conditioning enhanced responses with a preference for the positively conditioned odor. Moreover, conditioning systematically remapped odor representations along an axis in coding space that represented attractiveness (valence). Interindividual variations in this mapping predicted variations in behavioral odor preference. Photoinhibition of interneurons resulted in specific modifications of odor representations that mirrored effects of conditioning and reduced experience-dependent, interindividual variations in odor-valence mapping. These results reveal an individualized odor-to-valence map that is shaped by inhibition and reorganized during learning.

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    10/29/19 | A Semi-high-throughput Imaging Method and Data Visualization Toolkit to Analyze <em>C. elegans</em> Embryonic Development
    Khaliullin R, Hendel J, Gerson-Gurwitz A, Wang S, Ochoa S, Zhao Z, Desai A, Oegema K, Green R
    Journal of Visualized Experiments. 10/2019(152):. doi: 10.3791/60362

    C. elegans is the premier system for the systematic analysis of cell fate specification and morphogenetic events during embryonic development. One challenge is that embryogenesis dynamically unfolds over a period of about 13 h; this half day-long timescale has constrained the scope of experiments by limiting the number of embryos that can be imaged. Here, we describe a semi-high-throughput protocol that allows for the simultaneous 3D time-lapse imaging of development in 80–100 embryos at moderate time resolution, from up to 14 different conditions, in a single overnight run. The protocol is straightforward and can be implemented by any laboratory with access to a microscope with point visiting capacity. The utility of this protocol is demonstrated by using it to image two custom-built strains expressing fluorescent markers optimized to visualize key aspects of germ-layer specification and morphogenesis. To analyze the data, a custom program that crops individual embryos out of a broader field of view in all channels, z-steps, and timepoints and saves the sequences for each embryo into a separate tiff stack was built. The program, which includes a user-friendly graphical user interface (GUI), streamlines data processing by isolating, pre-processing, and uniformly orienting individual embryos in preparation for visualization or automated analysis. Also supplied is an ImageJ macro that compiles individual embryo data into a multi-panel file that displays maximum intensity fluorescence projection and brightfield images for each embryo at each time point. The protocols and tools described herein were validated by using them to characterize embryonic development following knock-down of 40 previously described developmental genes; this analysis visualized previously annotated developmental phenotypes and revealed new ones. In summary, this work details a semi-high-throughput imaging method coupled with a cropping program and ImageJ visualization tool that, when combined with strains expressing informative fluorescent markers, greatly accelerates experiments to analyze embryonic development.

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    10/13/19 | Sequential and efficient neural-population coding of complex task information
    Koay SA, Thiberge SY, Brody CD, Tank DW
    bioRxiv. 10/2019:. doi: 10.1101/801654

    Recent work has highlighted that many types of variables are represented in each neocortical area. How can these many neural representations be organized together without interference, and coherently maintained/updated through time? We recorded from large neural populations in posterior cortices as mice performed a complex, dynamic task involving multiple interrelated variables. The neural encoding implied that correlated task variables were represented by uncorrelated modes in an information-coding subspace. We show via theory that this can enable optimal decoding directions to be insensitive to neural noise levels. Across posterior cortex, principles of efficient coding thus applied to task-specific information, with neural-population modes as the encoding unit. Remarkably, this encoding function was multiplexed with rapidly changing, sequential neural dynamics, yet reliably followed slow changes in task-variable correlations through time. We can explain this as due to a mathematical property of high-dimensional spaces that the brain might exploit as a temporal scaffold.

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    08/06/19 | Transsynaptic Fish-lips signaling prevents misconnections between nonsynaptic partner olfactory neurons.
    Xie Q, Wu B, Li J, Xu C, Li H, Luginbuhl DJ, Wang X, Ward A, Luo L
    Proc Natl Acad Sci U S A. 08/2019;116(32):16068-16073. doi: 10.1073/pnas.1905832116

    Our understanding of the mechanisms of neural circuit assembly is far from complete. Identification of wiring molecules with novel mechanisms of action will provide insights into how complex and heterogeneous neural circuits assemble during development. In the olfactory system, 50 classes of olfactory receptor neurons (ORNs) make precise synaptic connections with 50 classes of partner projection neurons (PNs). Here, we performed an RNA interference screen for cell surface molecules and identified the leucine-rich repeat-containing transmembrane protein known as Fish-lips (Fili) as a novel wiring molecule in the assembly of the olfactory circuit. Fili contributes to the precise axon and dendrite targeting of a small subset of ORN and PN classes, respectively. Cell-type-specific expression and genetic analyses suggest that Fili sends a transsynaptic repulsive signal to neurites of nonpartner classes that prevents their targeting to inappropriate glomeruli in the antennal lobe.

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    07/30/19 | Simple imaging protocol for autofluorescence elimination and optical sectioning in fluorescence endomicroscopy
    Zhang R, Chouket R, Tebo AG, Plamont M, Kelemen Z, Gissot L, Faure J, Gautier A, Croquette V, Jullien L, Saux TL
    Optica. 07/2019;6:972. doi: 10.1364/optica.6.000972

    Fiber-optic epifluorescence imaging with one-photon excitation benefits from its ease of use, cheap light sources, and full-frame acquisition, which enables it for favorable temporal resolution of image acquisition. However, it suffers from a lack of robustness against autofluorescence and light scattering. Moreover, it cannot easily eliminate the out-of-focus background, which generally results in low-contrast images. In order to overcome these limitations, we have implemented fast out-of-phase imaging after optical modulation (Speed OPIOM) for dynamic contrast in fluorescence endomicroscopy. Using a simple and cheap optical-fiber bundle-based endomicroscope integrating modulatable light sources, we first showed that Speed OPIOM provides intrinsic optical sectioning, which restricts the observation of fluorescent labels at targeted positions within a sample. We also demonstrated that this imaging protocol efficiently eliminates the interference of autofluorescence arising from both the fiber bundle and the specimen in several biological samples. Finally, we could perform multiplexed observations of two spectrally similar fluorophores differing by their photoswitching dynamics. Such attractive features of Speed OPIOM in fluorescence endomicroscopy should find applications in bioprocessing, clinical diagnostics, plant observation, and surface imaging.

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