TY - JOUR AB - Orientation in space is represented in specialized brain circuits. Persistent head direction signals are transmitted from anterior thalamus to the presubiculum, but the identity of the presubicular target neurons, their connectivity and function in local microcircuits are unknown. Here, we examine how thalamic afferents recruit presubicular principal neurons and Martinotti interneurons, and the ensuing synaptic interactions between these cells. Pyramidal neuron activation of Martinotti cells in superficial layers is strongly facilitating such that high-frequency head directional stimulation efficiently unmutes synaptic excitation. Martinotti-cell feedback plays a dual role: precisely timed spikes may not inhibit the firing of in-tune head direction cells, while exerting lateral inhibition. Autonomous attractor dynamics emerge from a modelled network implementing wiring motifs and timing sensitive synaptic interactions in the pyramidal - Martinotti-cell feedback loop. This inhibitory microcircuit is therefore tuned to refine and maintain head direction information in the presubiculum. AU - Simonnet, Jean AU - Nassar, Mérie AU - Stella, Federico AU - Cohen, Ivan AU - Mathon, Bertrand AU - Boccara, Charlotte AU - Miles, Richard AU - Fricker, Desdemona ID - 514 JF - Nature Communications SN - 20411723 TI - Activity dependent feedback inhibition may maintain head direction signals in mouse presubiculum VL - 8 ER - TY - JOUR AB - The conserved polymerase-Associated factor 1 complex (Paf1C) plays multiple roles in chromatin transcription and genomic regulation. Paf1C comprises the five subunits Paf1, Leo1, Ctr9, Cdc73 and Rtf1, and binds to the RNA polymerase II (Pol II) transcription elongation complex (EC). Here we report the reconstitution of Paf1C from Saccharomyces cerevisiae, and a structural analysis of Paf1C bound to a Pol II EC containing the elongation factor TFIIS. Cryo-electron microscopy and crosslinking data reveal that Paf1C is highly mobile and extends over the outer Pol II surface from the Rpb2 to the Rpb3 subunit. The Paf1-Leo1 heterodimer and Cdc73 form opposite ends of Paf1C, whereas Ctr9 bridges between them. Consistent with the structural observations, the initiation factor TFIIF impairs Paf1C binding to Pol II, whereas the elongation factor TFIIS enhances it. We further show that Paf1C is globally required for normal mRNA transcription in yeast. These results provide a three-dimensional framework for further analysis of Paf1C function in transcription through chromatin. AU - Xu, Youwei AU - Bernecky, Carrie A AU - Lee, Chung AU - Maier, Kerstin AU - Schwalb, Björn AU - Tegunov, Dimitri AU - Plitzko, Jürgen AU - Urlaub, Henning AU - Cramer, Patrick ID - 601 JF - Nature Communications SN - 20411723 TI - Architecture of the RNA polymerase II-Paf1C-TFIIS transcription elongation complex VL - 8 ER - TY - JOUR AB - Bacteria in groups vary individually, and interact with other bacteria and the environment to produce population-level patterns of gene expression. Investigating such behavior in detail requires measuring and controlling populations at the single-cell level alongside precisely specified interactions and environmental characteristics. Here we present an automated, programmable platform that combines image-based gene expression and growth measurements with on-line optogenetic expression control for hundreds of individual Escherichia coli cells over days, in a dynamically adjustable environment. This integrated platform broadly enables experiments that bridge individual and population behaviors. We demonstrate: (i) population structuring by independent closed-loop control of gene expression in many individual cells, (ii) cell-cell variation control during antibiotic perturbation, (iii) hybrid bio-digital circuits in single cells, and freely specifiable digital communication between individual bacteria. These examples showcase the potential for real-time integration of theoretical models with measurement and control of many individual cells to investigate and engineer microbial population behavior. AU - Chait, Remy P AU - Ruess, Jakob AU - Bergmiller, Tobias AU - Tkacik, Gasper AU - Guet, Calin C ID - 613 IS - 1 JF - Nature Communications SN - 20411723 TI - Shaping bacterial population behavior through computer interfaced control of individual cells VL - 8 ER - TY - JOUR AB - Migration frequently involves Rac-mediated protrusion of lamellipodia, formed by Arp2/3 complex-dependent branching thought to be crucial for force generation and stability of these networks. The formins FMNL2 and FMNL3 are Cdc42 effectors targeting to the lamellipodium tip and shown here to nucleate and elongate actin filaments with complementary activities in vitro. In migrating B16-F1 melanoma cells, both formins contribute to the velocity of lamellipodium protrusion. Loss of FMNL2/3 function in melanoma cells and fibroblasts reduces lamellipodial width, actin filament density and -bundling, without changing patterns of Arp2/3 complex incorporation. Strikingly, in melanoma cells, FMNL2/3 gene inactivation almost completely abolishes protrusion forces exerted by lamellipodia and modifies their ultrastructural organization. Consistently, CRISPR/Cas-mediated depletion of FMNL2/3 in fibroblasts reduces both migration and capability of cells to move against viscous media. Together, we conclude that force generation in lamellipodia strongly depends on FMNL formin activity, operating in addition to Arp2/3 complex-dependent filament branching. AU - Kage, Frieda AU - Winterhoff, Moritz AU - Dimchev, Vanessa AU - Müller, Jan AU - Thalheim, Tobias AU - Freise, Anika AU - Brühmann, Stefan AU - Kollasser, Jana AU - Block, Jennifer AU - Dimchev, Georgi A AU - Geyer, Matthias AU - Schnittler, Hams AU - Brakebusch, Cord AU - Stradal, Theresia AU - Carlier, Marie AU - Sixt, Michael K AU - Käs, Josef AU - Faix, Jan AU - Rottner, Klemens ID - 659 JF - Nature Communications SN - 20411723 TI - FMNL formins boost lamellipodial force generation VL - 8 ER - TY - JOUR AB - In the early visual system, cells of the same type perform the same computation in different places of the visual field. How these cells code together a complex visual scene is unclear. A common assumption is that cells of a single-type extract a single-stimulus feature to form a feature map, but this has rarely been observed directly. Using large-scale recordings in the rat retina, we show that a homogeneous population of fast OFF ganglion cells simultaneously encodes two radically different features of a visual scene. Cells close to a moving object code quasilinearly for its position, while distant cells remain largely invariant to the object's position and, instead, respond nonlinearly to changes in the object's speed. We develop a quantitative model that accounts for this effect and identify a disinhibitory circuit that mediates it. Ganglion cells of a single type thus do not code for one, but two features simultaneously. This richer, flexible neural map might also be present in other sensory systems. AU - Deny, Stephane AU - Ferrari, Ulisse AU - Mace, Emilie AU - Yger, Pierre AU - Caplette, Romain AU - Picaud, Serge AU - Tkacik, Gasper AU - Marre, Olivier ID - 1104 IS - 1 JF - Nature Communications SN - 20411723 TI - Multiplexed computations in retinal ganglion cells of a single type VL - 8 ER - TY - JOUR AB - Reconstructing the evolutionary history of metastases is critical for understanding their basic biological principles and has profound clinical implications. Genome-wide sequencing data has enabled modern phylogenomic methods to accurately dissect subclones and their phylogenies from noisy and impure bulk tumour samples at unprecedented depth. However, existing methods are not designed to infer metastatic seeding patterns. Here we develop a tool, called Treeomics, to reconstruct the phylogeny of metastases and map subclones to their anatomic locations. Treeomics infers comprehensive seeding patterns for pancreatic, ovarian, and prostate cancers. Moreover, Treeomics correctly disambiguates true seeding patterns from sequencing artifacts; 7% of variants were misclassified by conventional statistical methods. These artifacts can skew phylogenies by creating illusory tumour heterogeneity among distinct samples. In silico benchmarking on simulated tumour phylogenies across a wide range of sample purities (15–95%) and sequencing depths (25-800 × ) demonstrates the accuracy of Treeomics compared with existing methods. AU - Reiter, Johannes AU - Makohon Moore, Alvin AU - Gerold, Jeffrey AU - Božić, Ivana AU - Chatterjee, Krishnendu AU - Iacobuzio Donahue, Christine AU - Vogelstein, Bert AU - Nowak, Martin ID - 1080 JF - Nature Communications SN - 20411723 TI - Reconstructing metastatic seeding patterns of human cancers VL - 8 ER - TY - JOUR AB - Sex chromosomes evolve once recombination is halted between a homologous pair of chromosomes. The dominant model of sex chromosome evolution posits that recombination is suppressed between emerging X and Y chromosomes in order to resolve sexual conflict. Here we test this model using whole genome and transcriptome resequencing data in the guppy, a model for sexual selection with many Y-linked colour traits. We show that although the nascent Y chromosome encompasses nearly half of the linkage group, there has been no perceptible degradation of Y chromosome gene content or activity. Using replicate wild populations with differing levels of sexually antagonistic selection for colour, we also show that sexual selection leads to greater expansion of the non-recombining region and increased Y chromosome divergence. These results provide empirical support for longstanding models of sex chromosome catalysis, and suggest an important role for sexual selection and sexual conflict in genome evolution. AU - Wright, Alison AU - Darolti, Iulia AU - Bloch, Natasha AU - Oostra, Vicencio AU - Sandkam, Benjamin AU - Buechel, Séverine AU - Kolm, Niclas AU - Breden, Felix AU - Vicoso, Beatriz AU - Mank, Judith ID - 1085 JF - Nature Communications SN - 20411723 TI - Convergent recombination suppression suggests role of sexual selection in guppy sex chromosome formation VL - 8 ER - TY - JOUR AB - In real-world applications, observations are often constrained to a small fraction of a system. Such spatial subsampling can be caused by the inaccessibility or the sheer size of the system, and cannot be overcome by longer sampling. Spatial subsampling can strongly bias inferences about a system’s aggregated properties. To overcome the bias, we derive analytically a subsampling scaling framework that is applicable to different observables, including distributions of neuronal avalanches, of number of people infected during an epidemic outbreak, and of node degrees. We demonstrate how to infer the correct distributions of the underlying full system, how to apply it to distinguish critical from subcritical systems, and how to disentangle subsampling and finite size effects. Lastly, we apply subsampling scaling to neuronal avalanche models and to recordings from developing neural networks. We show that only mature, but not young networks follow power-law scaling, indicating self-organization to criticality during development. AU - Levina (Martius), Anna AU - Priesemann, Viola ID - 993 JF - Nature Communications SN - 20411723 TI - Subsampling scaling VL - 8 ER - TY - JOUR AB - Gene expression is controlled by networks of regulatory proteins that interact specifically with external signals and DNA regulatory sequences. These interactions force the network components to co-evolve so as to continually maintain function. Yet, existing models of evolution mostly focus on isolated genetic elements. In contrast, we study the essential process by which regulatory networks grow: the duplication and subsequent specialization of network components. We synthesize a biophysical model of molecular interactions with the evolutionary framework to find the conditions and pathways by which new regulatory functions emerge. We show that specialization of new network components is usually slow, but can be drastically accelerated in the presence of regulatory crosstalk and mutations that promote promiscuous interactions between network components. AU - Friedlander, Tamar AU - Prizak, Roshan AU - Barton, Nicholas H AU - Tkacik, Gasper ID - 955 IS - 1 JF - Nature Communications SN - 20411723 TI - Evolution of new regulatory functions on biophysically realistic fitness landscapes VL - 8 ER - TY - JOUR AB - Nonreciprocal circuit elements form an integral part of modern measurement and communication systems. Mathematically they require breaking of time-reversal symmetry, typically achieved using magnetic materials and more recently using the quantum Hall effect, parametric permittivity modulation or Josephson nonlinearities. Here we demonstrate an on-chip magnetic-free circulator based on reservoir-engineered electromechanic interactions. Directional circulation is achieved with controlled phase-sensitive interference of six distinct electro-mechanical signal conversion paths. The presented circulator is compact, its silicon-on-insulator platform is compatible with both superconducting qubits and silicon photonics, and its noise performance is close to the quantum limit. With a high dynamic range, a tunable bandwidth of up to 30 MHz and an in situ reconfigurability as beam splitter or wavelength converter, it could pave the way for superconducting qubit processors with multiplexed on-chip signal processing and readout. AU - Barzanjeh, Shabir AU - Wulf, Matthias AU - Peruzzo, Matilda AU - Kalaee, Mahmoud AU - Dieterle, Paul AU - Painter, Oskar AU - Fink, Johannes M ID - 798 IS - 1 JF - Nature Communications SN - 20411723 TI - Mechanical on chip microwave circulator VL - 8 ER - TY - JOUR AB - An outstanding question in animal development, tissue homeostasis and disease is how cell populations adapt to sensory inputs. During Drosophila larval development, hematopoietic sites are in direct contact with sensory neuron clusters of the peripheral nervous system (PNS), and blood cells (hemocytes) require the PNS for their survival and recruitment to these microenvironments, known as Hematopoietic Pockets. Here we report that Activin-β, a TGF-β family ligand, is expressed by sensory neurons of the PNS and regulates the proliferation and adhesion of hemocytes. These hemocyte responses depend on PNS activity, as shown by agonist treatment and transient silencing of sensory neurons. Activin-β has a key role in this regulation, which is apparent from reporter expression and mutant analyses. This mechanism of local sensory neurons controlling blood cell adaptation invites evolutionary parallels with vertebrate hematopoietic progenitors and the independent myeloid system of tissue macrophages, whose regulation by local microenvironments remain undefined. AU - Makhijani, Kalpana AU - Alexander, Brandy AU - Rao, Deepti AU - Petraki, Sophia AU - Herboso, Leire AU - Kukar, Katelyn AU - Batool, Itrat AU - Wachner, Stephanie AU - Gold, Katrina AU - Wong, Corinna AU - O'Connor, Michael AU - Brückner, Katja ID - 835 JF - Nature Communications SN - 20411723 TI - Regulation of Drosophila hematopoietic sites by Activin-β from active sensory neurons VL - 8 ER - TY - JOUR AB - Gamma oscillations (30–150 Hz) in neuronal networks are associated with the processing and recall of information. We measured local field potentials in the dentate gyrus of freely moving mice and found that gamma activity occurs in bursts, which are highly heterogeneous in their spatial extensions, ranging from focal to global coherent events. Synaptic communication among perisomatic-inhibitory interneurons (PIIs) is thought to play an important role in the generation of hippocampal gamma patterns. However, how neuronal circuits can generate synchronous oscillations at different spatial scales is unknown. We analyzed paired recordings in dentate gyrus slices and show that synaptic signaling at interneuron-interneuron synapses is distance dependent. Synaptic strength declines whereas the duration of inhibitory signals increases with axonal distance among interconnected PIIs. Using neuronal network modeling, we show that distance-dependent inhibition generates multiple highly synchronous focal gamma bursts allowing the network to process complex inputs in parallel in flexibly organized neuronal centers. AU - Strüber, Michael AU - Sauer, Jonas AU - Jonas, Peter M AU - Bartos, Marlene ID - 800 IS - 1 JF - Nature Communications SN - 20411723 TI - Distance-dependent inhibition facilitates focality of gamma oscillations in the dentate gyrus VL - 8 ER - TY - JOUR AB - Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-Aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-Activated long-Term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics. AU - Aloisi, Elisabetta AU - Le Corf, Katy AU - Dupuis, Julien AU - Zhang, Pei AU - Ginger, Melanie AU - Labrousse, Virginie AU - Spatuzza, Michela AU - Georg Haberl, Matthias AU - Costa, Lara AU - Shigemoto, Ryuichi AU - Tappe Theodor, Anke AU - Drago, Fillippo AU - Vincenzo Piazza, Pier AU - Mulle, Christophe AU - Groc, Laurent AU - Ciranna, Lucia AU - Catania, Maria AU - Frick, Andreas ID - 746 IS - 1 JF - Nature Communications SN - 20411723 TI - Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice VL - 8 ER - TY - JOUR AB - Moths and butterflies (Lepidoptera) usually have a pair of differentiated WZ sex chromosomes. However, in most lineages outside of the division Ditrysia, as well as in the sister order Trichoptera, females lack a W chromosome. The W is therefore thought to have been acquired secondarily. Here we compare the genomes of three Lepidoptera species (one Dytrisia and two non-Dytrisia) to test three models accounting for the origin of the W: (1) a Z-autosome fusion; (2) a sex chromosome turnover; and (3) a non-canonical mechanism (e.g., through the recruitment of a B chromosome). We show that the gene content of the Z is highly conserved across Lepidoptera (rejecting a sex chromosome turnover) and that very few genes moved onto the Z in the common ancestor of the Ditrysia (arguing against a Z-autosome fusion). Our comparative genomics analysis therefore supports the secondary acquisition of the Lepidoptera W by a non-canonical mechanism, and it confirms the extreme stability of well-differentiated sex chromosomes. AU - Fraisse, Christelle AU - Picard, Marion A AU - Vicoso, Beatriz ID - 614 IS - 1 JF - Nature Communications SN - 20411723 TI - The deep conservation of the Lepidoptera Z chromosome suggests a non canonical origin of the W VL - 8 ER -