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5 Janelia Publications

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    07/22/23 | Towards Generalizable Organelle Segmentation in Volume Electron Microscopy.
    Heinrich L, Patton W, Bennett D, Ackerman D, Park G, Bogovic JA, Eckstein N, Petruncio A, Clements J, Pang S, Shan Xu C, Funke J, Korff W, Hess H, Lippincott-Schwartz J, Saalfeld S, Weigel A, CellMap Project Team
    Microscopy and Microanalysis. 2023 Jul 22;29(Supplement_1):975. doi: 10.1093/micmic/ozad067.487
    06/06/23 | A Connectome of the Male Drosophila Ventral Nerve Cord
    Shin-ya Takemura , Kenneth J Hayworth , Gary B Huang , Michal Januszewski , Zhiyuan Lu , Elizabeth C Marin , Stephan Preibisch , C Shan Xu , John Bogovic , Andrew S Champion , Han S J Cheong , Marta Costa , Katharina Eichler , William Katz , Christopher Knecht , Feng Li , Billy J Morris , Christopher Ordish , Patricia K Rivlin , Philipp Schlegel , Kazunori Shinomiya , Tomke Sturner , Ting Zhao , Griffin Badalamente , Dennis Bailey , Paul Brooks , Brandon S Canino , Jody Clements , Michael Cook , Octave Duclos , Christopher R Dunne , Kelli Fairbanks , Siqi Fang , Samantha Finley-May , Audrey Francis , Reed George , Marina Gkantia , Kyle Harrington , Gary Patrick Hopkins , Joseph Hsu , Philip M Hubbard , Alexandre Javier , Dagmar Kainmueller , Wyatt Korff , Julie Kovalyak , Dominik Krzeminski , Shirley A Lauchie , Alanna Lohff , Charli Maldonado , Emily A Manley , Caroline Mooney , Erika Neace , Matthew Nichols , Omotara Ogundeyi , Nneoma Okeoma , Tyler Paterson , Elliott Phillips , Emily M Phillips , Caitlin Ribeiro , Sean M Ryan , Jon Thomson Rymer , Anne K Scott , Ashley L Scott , David Shepherd , Aya Shinomiya , Claire Smith , Alia Suleiman , Satoko Takemura , Iris Talebi , Imaan F M Tamimi , Eric T Trautman , Lowell Umayam , John J Walsh , Tansy Yang , Gerald M Rubin , Louis K Scheffer , Jan Funke , Stephan Saalfeld , Harald F Hess , Stephen M Plaza , Gwyneth M Card , Gregory S X E Jefferis , Stuart Berg
    bioRxiv. 2023 Jun 06:. doi: 10.1101/2023.06.05.543757

    Animal behavior is principally expressed through neural control of muscles. Therefore understanding how the brain controls behavior requires mapping neuronal circuits all the way to motor neurons. We have previously established technology to collect large-volume electron microscopy data sets of neural tissue and fully reconstruct the morphology of the neurons and their chemical synaptic connections throughout the volume. Using these tools we generated a dense wiring diagram, or connectome, for a large portion of the Drosophila central brain. However, in most animals, including the fly, the majority of motor neurons are located outside the brain in a neural center closer to the body, i.e. the mammalian spinal cord or insect ventral nerve cord (VNC). In this paper, we extend our effort to map full neural circuits for behavior by generating a connectome of the VNC of a male fly.

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    08/23/22 | Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
    Zhu P, Hung H, Batchenkova N, Nixon-Abell J, Henderson J, Zheng P, Renvoisé B, Pang S, Xu CS, Saalfeld S, Funke J, Xie Y, Svara F, Hess HF, Blackstone C
    Human Molecular Genetics. 2022 Aug 23;31(16):2779-2795. doi: 10.1093/hmg/ddac072

    Hereditary spastic paraplegias (HSPs) comprise a large group of inherited neurologic disorders affecting the longest corticospinal axons (SPG1-86 plus others), with shared manifestations of lower extremity spasticity and gait impairment. Common autosomal dominant HSPs are caused by mutations in genes encoding the microtubule-severing ATPase spastin (SPAST; SPG4), the membrane-bound GTPase atlastin-1 (ATL1; SPG3A) and the reticulon-like, microtubule-binding protein REEP1 (REEP1; SPG31). These proteins bind one another and function in shaping the tubular endoplasmic reticulum (ER) network. Typically, mouse models of HSPs have mild, later onset phenotypes, possibly reflecting far shorter lengths of their corticospinal axons relative to humans. Here, we have generated a robust, double mutant mouse model of HSP in which atlastin-1 is genetically modified with a K80A knock-in (KI) missense change that abolishes its GTPase activity, whereas its binding partner Reep1 is knocked out. Atl1KI/KI/Reep1-/- mice exhibit early onset and rapidly progressive declines in several motor function tests. Also, ER in mutant corticospinal axons dramatically expands transversely and periodically in a mutation dosage-dependent manner to create a ladder-like appearance, on the basis of reconstructions of focused ion beam-scanning electron microscopy datasets using machine learning-based auto-segmentation. In lockstep with changes in ER morphology, axonal mitochondria are fragmented and proportions of hypophosphorylated neurofilament H and M subunits are dramatically increased in Atl1KI/KI/Reep1-/- spinal cord. Co-occurrence of these findings links ER morphology changes to alterations in mitochondrial morphology and cytoskeletal organization. Atl1KI/KI/Reep1-/- mice represent an early onset rodent HSP model with robust behavioral and cellular readouts for testing novel therapies.

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    03/26/22 | Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
    Zhu P, Hung H, Batchenkova N, Nixon-Abell J, Henderson J, Zheng P, Renvoisé B, Pang S, Xu CS, Saalfeld S, Funke J, Xie Y, Svara F, Hess HF, Blackstone C
    Human Molecular Genetics. 2022 Mar 26:. doi: 10.1093/hmg/ddac072

    Hereditary spastic paraplegias (HSPs) comprise a large group of inherited neurologic disorders affecting the longest corticospinal axons (SPG1-86 plus others), with shared manifestations of lower extremity spasticity and gait impairment. Common autosomal dominant HSPs are caused by mutations in genes encoding the microtubule-severing ATPase spastin (SPAST; SPG4), the membrane-bound GTPase atlastin-1 (ATL1; SPG3A), and the reticulon-like, microtubule-binding protein REEP1 (REEP1; SPG31). These proteins bind one another and function in shaping the tubular endoplasmic reticulum (ER) network. Typically, mouse models of HSPs have mild, later-onset phenotypes, possibly reflecting far shorter lengths of their corticospinal axons relative to humans. Here, we have generated a robust, double mutant mouse model of HSP in which atlastin-1 is genetically modified with a K80A knock-in (KI) missense change that abolishes its GTPase activity, while its binding partner Reep1 is knocked out. Atl1KI/KI/Reep1-/- mice exhibit early-onset and rapidly progressive declines in several motor function tests. Also, ER in mutant corticospinal axons dramatically expands transversely and periodically in a mutation dosage-dependent manner to create a ladder-like appearance, based on reconstructions of focused ion beam-scanning electron microscopy datasets using machine learning-based auto-segmentation. In lockstep with changes in ER morphology, axonal mitochondria are fragmented and proportions of hypophosphorylated neurofilament H and M subunits are dramatically increased in Atl1KI/KI/Reep1-/- spinal cord. Co-occurrence of these findings links ER morphology changes to alterations in mitochondrial morphology and cytoskeletal organization. Atl1KI/KI/Reep1-/- mice represent an early-onset rodent HSP model with robust behavioral and cellular readouts for testing novel therapies.

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    11/01/21 | Whole-cell organelle segmentation in volume electron microscopy.
    Heinrich L, Bennett D, Ackerman D, Park W, Bogovic J, Eckstein N, Petruncio A, Clements J, Pang S, Xu CS, Funke J, Korff W, Hess HF, Lippincott-Schwartz J, Saalfeld S, Weigel AV, COSEM Project Team
    Nature. 2021 Nov 01;599(7883):141-46. doi: 10.1038/s41586-021-03977-3

    Cells contain hundreds of organelles and macromolecular assemblies. Obtaining a complete understanding of their intricate organization requires the nanometre-level, three-dimensional reconstruction of whole cells, which is only feasible with robust and scalable automatic methods. Here, to support the development of such methods, we annotated up to 35 different cellular organelle classes-ranging from endoplasmic reticulum to microtubules to ribosomes-in diverse sample volumes from multiple cell types imaged at a near-isotropic resolution of 4 nm per voxel with focused ion beam scanning electron microscopy (FIB-SEM). We trained deep learning architectures to segment these structures in 4 nm and 8 nm per voxel FIB-SEM volumes, validated their performance and showed that automatic reconstructions can be used to directly quantify previously inaccessible metrics including spatial interactions between cellular components. We also show that such reconstructions can be used to automatically register light and electron microscopy images for correlative studies. We have created an open data and open-source web repository, 'OpenOrganelle', to share the data, computer code and trained models, which will enable scientists everywhere to query and further improve automatic reconstruction of these datasets.

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