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192 Publications

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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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    Svoboda Lab
    03/17/22 | A midbrain-thalamus-cortex circuit reorganizes cortical dynamics to initiate movement.
    Inagaki HK, Chen S, Ridder MC, Sah P, Li N, Yang Z, Hasanbegovic H, Gao Z, Gerfen CR, Svoboda K
    Cell. 2022 Mar 17;185(8):1065. doi: 10.1016/j.cell.2022.02.006

    Motor behaviors are often planned long before execution but only released after specific sensory events. Planning and execution are each associated with distinct patterns of motor cortex activity. Key questions are how these dynamic activity patterns are generated and how they relate to behavior. Here, we investigate the multi-regional neural circuits that link an auditory "Go cue" and the transition from planning to execution of directional licking. Ascending glutamatergic neurons in the midbrain reticular and pedunculopontine nuclei show short latency and phasic changes in spike rate that are selective for the Go cue. This signal is transmitted via the thalamus to the motor cortex, where it triggers a rapid reorganization of motor cortex state from planning-related activity to a motor command, which in turn drives appropriate movement. Our studies show how midbrain can control cortical dynamics via the thalamus for rapid and precise motor behavior.

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    03/16/22 | Small molecule inhibitors of mammalian glycosylation.
    Almahayni K, Spiekermann M, Fiore A, Yu G, Pedram K, Möckl L
    Matrix Biology Plus. 2022 Mar 16;16:100108. doi: 10.1016/j.mbplus.2022.100108

    Glycans are one of the fundamental biopolymers encountered in living systems. Compared to polynucleotide and polypeptide biosynthesis, polysaccharide biosynthesis is a uniquely combinatorial process to which interdependent enzymes with seemingly broad specificities contribute. The resulting intracellular cell surface, and secreted glycans play key roles in health and disease, from embryogenesis to cancer progression. The study and modulation of glycans in cell and organismal biology is aided by small molecule inhibitors of the enzymes involved in glycan biosynthesis. In this review, we survey the arsenal of currently available inhibitors, focusing on agents which have been independently validated in diverse systems. We highlight the utility of these inhibitors and drawbacks to their use, emphasizing the need for innovation for basic research as well as for therapeutic applications.

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    03/15/22 | Myosin VI regulates the spatial organisation of mammalian transcription initiation.
    Hari-Gupta Y, Fili N, Dos Santos Á, Cook AW, Gough RE, Reed HC, Wang L, Aaron J, Venit T, Wait E, Grosse-Berkenbusch A, Gebhardt JC, Percipalle P, Chew T, Martin-Fernandez M, Toseland CP
    Nature Communications. 2022 Mar 15;13(1):1346. doi: 10.1038/s41467-022-28962-w

    During transcription, RNA Polymerase II (RNAPII) is spatially organised within the nucleus into clusters that correlate with transcription activity. While this is a hallmark of genome regulation in mammalian cells, the mechanisms concerning the assembly, organisation and stability remain unknown. Here, we have used combination of single molecule imaging and genomic approaches to explore the role of nuclear myosin VI (MVI) in the nanoscale organisation of RNAPII. We reveal that MVI in the nucleus acts as the molecular anchor that holds RNAPII in high density clusters. Perturbation of MVI leads to the disruption of RNAPII localisation, chromatin organisation and subsequently a decrease in gene expression. Overall, we uncover the fundamental role of MVI in the spatial regulation of gene expression.

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    03/15/22 | When light meets biology - how the specimen affects quantitative microscopy.
    Reiche MA, Aaron JS, Boehm U, DeSantis MC, Hobson CM, Khuon S, Lee RM, Chew T
    Journal of Cell Science. 2022 Mar 15;135(6):. doi: 10.1242/jcs.259656

    Fluorescence microscopy images should not be treated as perfect representations of biology. Many factors within the biospecimen itself can drastically affect quantitative microscopy data. Whereas some sample-specific considerations, such as photobleaching and autofluorescence, are more commonly discussed, a holistic discussion of sample-related issues (which includes less-routine topics such as quenching, scattering and biological anisotropy) is required to appropriately guide life scientists through the subtleties inherent to bioimaging. Here, we consider how the interplay between light and a sample can cause common experimental pitfalls and unanticipated errors when drawing biological conclusions. Although some of these discrepancies can be minimized or controlled for, others require more pragmatic considerations when interpreting image data. Ultimately, the power lies in the hands of the experimenter. The goal of this Review is therefore to survey how biological samples can skew quantification and interpretation of microscopy data. Furthermore, we offer a perspective on how to manage many of these potential pitfalls.

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    03/14/22 | A population of descending neurons that regulates the flight motor of Drosophila.
    Namiki S, Ros IG, Morrow C, Rowell WJ, Card GM, Korff W, Dickinson MH
    Current Biology. 2022 Mar 14;32(5):1189-1196. doi: 10.1016/j.cub.2022.01.008

    Similar to many insect species, Drosophila melanogaster is capable of maintaining a stable flight trajectory for periods lasting up to several hours. Because aerodynamic torque is roughly proportional to the fifth power of wing length, even small asymmetries in wing size require the maintenance of subtle bilateral differences in flapping motion to maintain a stable path. Flies can even fly straight after losing half of a wing, a feat they accomplish via very large, sustained kinematic changes to both the damaged and intact wings. Thus, the neural network responsible for stable flight must be capable of sustaining fine-scaled control over wing motion across a large dynamic range. In this study, we describe an unusual type of descending neuron (DNg02) that projects directly from visual output regions of the brain to the dorsal flight neuropil of the ventral nerve cord. Unlike many descending neurons, which exist as single bilateral pairs with unique morphology, there is a population of at least 15 DNg02 cell pairs with nearly identical shape. By optogenetically activating different numbers of DNg02 cells, we demonstrate that these neurons regulate wingbeat amplitude over a wide dynamic range via a population code. Using two-photon functional imaging, we show that DNg02 cells are responsive to visual motion during flight in a manner that would make them well suited to continuously regulate bilateral changes in wing kinematics. Collectively, we have identified a critical set of descending neurons that provides the sensitivity and dynamic range required for flight control.

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    Card Lab
    03/11/22 | Context-dependent control of behavior in Drosophila.
    Oram TB, Card GM
    Current Opinion in Neurobiology. 2022 Mar 11;73:102523. doi: 10.1016/j.conb.2022.02.003

    The representation of contextual information peripheral to a salient stimulus is central to an animal's ability to correctly interpret and flexibly respond to that stimulus. While the computations and circuits underlying the context-dependent modulation of stimulus-response pairings have typically been studied in vertebrates, the genetic tractability, numeric simplification, and well-characterized connectivity patterns of the Drosophila melanogaster brain have facilitated circuit-level insights into contextual processing. Recent studies in flies reveal the neuronal mechanisms that create flexible context-dependent behavioral responses to sensory events in conditions of predation threat, feeding regulation, and social interaction.

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    03/11/22 | Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes.
    Park J, Phillips JW, Guo J, Martin KA, Hantman AW, Dudman JT
    Science Advances. 2022 Mar 11;8(10):eabj5167. doi: 10.1126/sciadv.abj5167

    The interaction of descending neocortical outputs and subcortical premotor circuits is critical for shaping skilled movements. Two broad classes of motor cortical output projection neurons provide input to many subcortical motor areas: pyramidal tract (PT) neurons, which project throughout the neuraxis, and intratelencephalic (IT) neurons, which project within the cortex and subcortical striatum. It is unclear whether these classes are functionally in series or whether each class carries distinct components of descending motor control signals. Here, we combine large-scale neural recordings across all layers of motor cortex with cell type-specific perturbations to study cortically dependent mouse motor behaviors: kinematically variable manipulation of a joystick and a kinematically precise reach-to-grasp. We find that striatum-projecting IT neuron activity preferentially represents amplitude, whereas pons-projecting PT neurons preferentially represent the variable direction of forelimb movements. Thus, separable components of descending motor cortical commands are distributed across motor cortical projection cell classes.

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    03/09/22 | Regulation of liver subcellular architecture controls metabolic homeostasis.
    Parlakgül G, Arruda AP, Pang S, Cagampan E, Min N, Güney E, Lee GY, Inouye K, Hess HF, Xu CS, Hotamışlıgil GS
    Nature. 2022 Mar 09;603(7902):736-742. doi: 10.1038/s41586-022-04488-5

    Cells display complex intracellular organization by compartmentalization of metabolic processes into organelles, yet the resolution of these structures in the native tissue context and their functional consequences are not well understood. Here we resolved the three-dimensional structural organization of organelles in large (more than 2.8 × 10 µm) volumes of intact liver tissue (15 partial or full hepatocytes per condition) at high resolution (8 nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy imaging followed by deep-learning-based automated image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese mice and found substantial alterations, particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural reorganization characterized by marked disorganization of stacks of ER sheets and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes by monitoring the effects of experimental recovery of the subcellular organization on cellular and systemic metabolism. We conclude that the hepatic subcellular organization of the ER architecture are highly dynamic, integrated with the metabolic state and critical for adaptive homeostasis and tissue health.

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    03/07/22 | Neuromuscular embodiment of feedback control elements in Drosophila flight
    Samuel C. Whitehead , Sofia Leone , Theodore Lindsay , Matthew Meiselman , Noah Cowan , Michael Dickinson , Nilay Yapici , David Stern , Troy Shirangi , Itai Cohen
    bioRxiv. 2022 Mar 07:. doi: 10.1101/2022.02.22.481344

    While insects like Drosophila are flying, aerodynamic instabilities require that they make millisecond-timescale adjustments to their wing motion to stay aloft and on course. These stabilization reflexes can be modeled as a proportional-integral (PI) controller; however, it is unclear how such control might be instantiated in insects at the level of muscles and neurons. Here, we show that the b1 and b2 motor units—prominent components of the fly’s steering muscles system—modulate specific elements of the PI controller: the angular displacement (integral, I) and angular velocity (proportional, P), respectively. Moreover, these effects are observed only during the stabilization of pitch. Our results provide evidence for an organizational principle in which each muscle contributes to a specific functional role in flight control, a finding that highlights the power of using top-down behavioral modeling to guide bottom-up cellular manipulation studies.

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