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1358 Publications

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    11/18/16 | The sacral autonomic outflow is sympathetic
    I. Espinosa-Medina , O. Saha , F. Boismoreau , Z. Chettouh , F. Rossi , W. D. Richardson , J.-F. Brunet
    Science. 11/2016;354:893-897. doi: 10.1126/science.aah5454

    The autonomic nervous system regulates the function of internal organs such as the gut. The parasympathetic and sympathetic arms of this system tend to operate antagonistically. Espinosa-Medina et al. used anatomical and molecular analyses to reevaluate the assignment of neurons in the sacral autonomic nervous system (see the Perspective by Adameyko). Previously categorized as parasympathetic, these neurons are now identified as sympathetic. The results resolve a persistent confusion about how the two systems developed and open the avenue to more predictable outcomes in developing treatments targeted to the pelvic autonomic nervous system. Science, this issue p. 893; see also p. 833 Contrary to a century-old dogma, the pelvic nerves and ganglia do not belong to the parasympathetic nervous system but to the sympathetic one. A kinship between cranial and pelvic visceral nerves of vertebrates has been accepted for a century. Accordingly, sacral preganglionic neurons are considered parasympathetic, as are their targets in the pelvic ganglia that prominently control rectal, bladder, and genital functions. Here, we uncover 15 phenotypic and ontogenetic features that distinguish pre- and postganglionic neurons of the cranial parasympathetic outflow from those of the thoracolumbar sympathetic outflow in mice. By every single one, the sacral outflow is indistinguishable from the thoracolumbar outflow. Thus, the parasympathetic nervous system receives input from cranial nerves exclusively and the sympathetic nervous system from spinal nerves, thoracic to sacral inclusively. This simplified, bipartite architecture offers a new framework to understand pelvic neurophysiology as well as development and evolution of the autonomic nervous system.

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    09/01/22 | Leveraging the model-experiment loop: Examples from cellular slime mold chemotaxis.
    Zhu X, Hager ER, Huyan C, Sgro AE
    Exp Cell Res. 09/2022;418(1):113218. doi: 10.1016/j.yexcr.2022.113218

    Interplay between models and experimental data advances discovery and understanding in biology, particularly when models generate predictions that allow well-designed experiments to distinguish between alternative mechanisms. To illustrate how this feedback between models and experiments can lead to key insights into biological mechanisms, we explore three examples from cellular slime mold chemotaxis. These examples include studies that identified chemotaxis as the primary mechanism behind slime mold aggregation, discovered that cells likely measure chemoattractant gradients by sensing concentration differences across cell length, and tested the role of cell-associated chemoattractant degradation in shaping chemotactic fields. Although each study used a different model class appropriate to their hypotheses - qualitative, mathematical, or simulation-based - these examples all highlight the utility of modeling to formalize assumptions and generate testable predictions. A central element of this framework is the iterative use of models and experiments, specifically: matching experimental designs to the models, revising models based on mismatches with experimental data, and validating critical model assumptions and predictions with experiments. We advocate for continued use of this interplay between models and experiments to advance biological discovery.

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    07/20/22 | Transcription factor Acj6 controls dendrite targeting via a combinatorial cell-surface code.
    Xie Q, Li J, Li H, Udeshi ND, Svinkina T, Orlin D, Kohani S, Guajardo R, Mani DR, Xu C, Li T, Han S, Wei W, Shuster SA, Luginbuhl DJ, Quake SR, Murthy SE, Ting AY, Carr SA, Luo L
    Neuron. 07/2022;110(14):2299-2314.e8. doi: 10.1016/j.neuron.2022.04.026

    Transcription factors specify the fate and connectivity of developing neurons. We investigate how a lineage-specific transcription factor, Acj6, controls the precise dendrite targeting of Drosophila olfactory projection neurons (PNs) by regulating the expression of cell-surface proteins. Quantitative cell-surface proteomic profiling of wild-type and acj6 mutant PNs in intact developing brains, and a proteome-informed genetic screen identified PN surface proteins that execute Acj6-regulated wiring decisions. These include canonical cell adhesion molecules and proteins previously not associated with wiring, such as Piezo, whose mechanosensitive ion channel activity is dispensable for its function in PN dendrite targeting. Comprehensive genetic analyses revealed that Acj6 employs unique sets of cell-surface proteins in different PN types for dendrite targeting. Combined expression of Acj6 wiring executors rescued acj6 mutant phenotypes with higher efficacy and breadth than expression of individual executors. Thus, Acj6 controls wiring specificity of different neuron types by specifying distinct combinatorial expression of cell-surface executors.

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    06/09/22 | Budding epithelial morphogenesis driven by cell-matrix versus cell-cell adhesion
    Shaohe Wang , Kazue Matsumoto , Samantha R. Lish , Alexander X. Cartagena-Rivera , Kenneth M. Yamada
    Cell;184:3702-3716.e30. doi:

    Summary Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of stratified epithelia, such as in the embryonic salivary gland and pancreas. Here, we performed live-organ imaging of mouse embryonic salivary glands at single-cell resolution to reveal that budding morphogenesis is driven by expansion and folding of a distinct epithelial surface cell sheet characterized by strong cell-matrix adhesions and weak cell-cell adhesions. Profiling of single-cell transcriptomes of this epithelium revealed spatial patterns of transcription underlying these cell adhesion differences. We then synthetically reconstituted budding morphogenesis by experimentally suppressing E-cadherin expression and inducing basement membrane formation in 3D spheroid cultures of engineered cells, which required β1-integrin-mediated cell-matrix adhesion for successful budding. Thus, stratified epithelial budding, the key first step of branching morphogenesis, is driven by an overall combination of strong cell-matrix adhesion and weak cell-cell adhesion by peripheral epithelial cells.

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    05/07/22 | Microbial models of development: Inspiration for engineering self-assembled synthetic multicellularity.
    Ricci-Tam C, Kuipa S, Kostman MP, Aronson MS, Sgro AE
    Semin Cell Dev Biol. 05/2022:. doi: 10.1016/j.semcdb.2022.04.014

    While the field of synthetic developmental biology has traditionally focused on the study of the rich developmental processes seen in metazoan systems, an attractive alternate source of inspiration comes from microbial developmental models. Microbes face unique lifestyle challenges when forming emergent multicellular collectives. As a result, the solutions they employ can inspire the design of novel multicellular systems. In this review, we dissect the strategies employed in multicellular development by two model microbial systems: the cellular slime mold Dictyostelium discoideum and the biofilm-forming bacterium Bacillus subtilis. Both microbes face similar challenges but often have different solutions, both from metazoan systems and from each other, to create emergent multicellularity. These challenges include assembling and sustaining a critical mass of participating individuals to support development, regulating entry into development, and assigning cell fates. The mechanisms these microbial systems exploit to robustly coordinate development under a wide range of conditions offer inspiration for a new toolbox of solutions to the synthetic development community. Additionally, recreating these phenomena synthetically offers a pathway to understanding the key principles underlying how these behaviors are be coordinated naturally.

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    04/15/22 | KIRCD8 T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.
    Li J, Zaslavsky M, Su Y, Guo J, Sikora MJ, van Unen V, Christophersen A, Chiou S, Chen L, Li J, Ji X, Wilhelmy J, McSween AM, Palanski BA, Mallajosyula VV, Bracey NA, Dhondalay GK, Bhamidipati K, Pai J, Kipp LB, Dunn JE, Hauser SL, Oksenberg JR, Satpathy AT, Robinson WH, Dekker CL, Steinmetz LM, Khosla C, Utz PJ, Sollid LM, Chien Y, Heath JR, Fernandez-Becker NQ, Nadeau KC, Saligrama N, Davis MM
    Science. 04/2022;376(6590):eabi9591. doi: 10.1126/science.abi9591

    In this work, we find that CD8 T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49CD8 regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8 T cells efficiently eliminated pathogenic gliadin-specific CD4 T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIRCD8 T cells, but not CD4 regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49CD8 T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8 T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

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    03/04/22 | Fly Cell Atlas: A single-nucleus transcriptomic atlas of the adult fruit fly.
    Li H, Janssens J, De Waegeneer M, Kolluru SS, Davie K, Gardeux V, Saelens W, David FP, Brbić M, Spanier K, Leskovec J, McLaughlin CN, Xie Q, Jones RC, Brueckner K, Shim J, Tattikota SG, Schnorrer F, Rust K, Nystul TG, Carvalho-Santos Z, Ribeiro C, Pal S, Mahadevaraju S, Przytycka TM, Allen AM, Goodwin SF, Berry CW, Fuller MT, White-Cooper H, Matunis EL, DiNardo S, Galenza A, O'Brien LE, Dow JA, FCA Consortium§ , Jasper H, Oliver B, Perrimon N, Deplancke B, Quake SR, Luo L, Aerts S, Agarwal D, Ahmed-Braimah Y, Arbeitman M, Ariss MM, Augsburger J, Ayush K, Baker CC, Banisch T, Birker K, Bodmer R, Bolival B, Brantley SE, Brill JA, Brown NC, Buehner NA, Cai XT, Cardoso-Figueiredo R, Casares F, Chang A, Clandinin TR, Crasta S, Desplan C, Detweiler AM, Dhakan DB, Donà E, Engert S, Floc'hlay S, George N, González-Segarra AJ, Groves AK, Gumbin S, Guo Y, Harris DE, Heifetz Y, Holtz SL, Horns F, Hudry B, Hung R, Jan YN, Jaszczak JS, Jefferis GS, Karkanias J, Karr TL, Katheder NS, Kezos J, Kim AA, Kim SK, Kockel L, Konstantinides N, Kornberg TB, Krause HM, Labott AT, Laturney M, Lehmann R, Leinwand S, Li J, Li JS, Li K, Li K, Li L, Li T, Litovchenko M, Liu H, Liu Y, Lu T, Manning J, Mase A, Matera-Vatnick M, Matias NR, McDonough-Goldstein CE, McGeever A, McLachlan AD, Moreno-Roman P, Neff N, Neville M, Ngo S, Nielsen T, O'Brien CE, Osumi-Sutherland D, Ozel MN, Papatheodorou I, Petkovic M, Pilgrim C, Pisco AO, Reisenman C, Sanders EN, Dos Santos G, Scott K, Sherlekar A, Shiu P, Sims D, Sit RV, Slaidina M, Smith HE, Sterne G, Su Y, Sutton D, Tamayo M, Tan M, Tastekin I, Treiber C, Vacek D, Vogler G, Waddell S, Wang W, Wilson RI, Wolfner MF, Wong YE, Xie A, Xu J, Yamamoto S, Yan J, Yao Z, Yoda K, Zhu R, Zinzen RP
    Science. 03/2022;375(6584):eabk2432. doi: 10.1126/science.abk2432

    For more than 100 years, the fruit fly has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula , that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the community and serves as a reference to study genetic perturbations and disease models at single-cell resolution.

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    02/08/22 | Single-cell transcriptomes of developing and adult olfactory receptor neurons in Drosophila
    McLaughlin CN, Brbić M, Xie Q, Li T, Horns F, Kolluru SS, Kebschull JM, Vacek D, Xie A, Li J, Jones RC, Leskovec J, Quake SR, Luo L, Li H
    Elife. 02/2021;10:. doi: 10.7554/eLife.63856

    Recognition of environmental cues is essential for the survival of all organisms. Transcriptional changes occur to enable the generation and function of the neural circuits underlying sensory perception. To gain insight into these changes, we generated single-cell transcriptomes of olfactory- (ORNs), thermo-, and hygro-sensory neurons at an early developmental and adult stage using single-cell and single-nucleus RNA sequencing. We discovered that ORNs maintain expression of the same olfactory receptors across development. Using receptor expression and computational approaches, we matched transcriptomic clusters corresponding to anatomically and physiologically defined neuron types across multiple developmental stages. We found that cell-type-specific transcriptomes partly reflected axon trajectory choices in development and sensory modality in adults. We uncovered stage-specific genes that could regulate the wiring and sensory responses of distinct ORN types. Collectively, our data reveal transcriptomic features of sensory neuron biology and provide a resource for future studies of their development and physiology.

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    11/30/21 | Engineering of a fluorescent chemogenetic reporter with tunable color for advanced live-cell imaging.
    Benaissa H, Ounoughi K, Aujard I, Fischer E, Goïame R, Nguyen J, Tebo AG, Li C, Le Saux T, Bertolin G, Tramier M, Danglot L, Pietrancosta N, Morin X, Jullien L, Gautier A
    Nature Communications. 2021 Nov 30;12(1):6989. doi: 10.1038/s41467-021-27334-0

    Biocompatible fluorescent reporters with spectral properties spanning the entire visible spectrum are indispensable tools for imaging the biochemistry of living cells and organisms in real time. Here, we report the engineering of a fluorescent chemogenetic reporter with tunable optical and spectral properties. A collection of fluorogenic chromophores with various electronic properties enables to generate bimolecular fluorescent assemblies that cover the visible spectrum from blue to red using a single protein tag engineered and optimized by directed evolution and rational design. The ability to tune the fluorescence color and properties through simple molecular modulation provides a broad experimental versatility for imaging proteins in live cells, including neurons, and in multicellular organisms, and opens avenues for optimizing Förster resonance energy transfer (FRET) biosensors in live cells. The ability to tune the spectral properties and fluorescence performance enables furthermore to match the specifications and requirements of advanced super-resolution imaging techniques.

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    10/31/21 | Versatile On-Demand Fluorescent Labeling of Fusion Proteins Using Fluorescence-Activating and Absorption-Shifting Tag (FAST).
    Gautier A, Jullien L, Li C, Plamont M, Tebo AG, Thauvin M, Volovitch M, Vriz S
    Methods Mol Biol. 2021;2350:253-265. doi: 10.1007/978-1-0716-1593-5_16

    Observing the localization, the concentration, and the distribution of proteins in cells or organisms is essential to understand theirs functions. General and versatile methods allowing multiplexed imaging of proteins under a large variety of experimental conditions are thus essential for deciphering the inner workings of cells and organisms. Here, we present a general method based on the non-covalent labeling of a small protein tag, named FAST (fluorescence-activating and absorption-shifting tag), with various fluorogenic ligands that light up upon labeling, which makes the simple, robust, and versatile on-demand labeling of fusion proteins in a wide range of experimental systems possible.

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