네이처 컨텐츠

Editorials

Head start p.5

Europe’s mega-project to simulate the human brain has much to offer neuroscience research — whether or not it delivers on its central promise.

doi: 10.1038/503005a

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Historic work p.6

Governments need to strengthen support for scientists who preserve our cultural heritage.

doi: 10.1038/503006a

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Follow the crowd p.6

The behaviour of millions of minuscule beads reveals some secrets of collective motion.

doi: 10.1038/503006b

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News

X-rays top space agenda p.13

European agency selects mission themes, with X-ray telescope the biggest winner.

Elizabeth Gibney

doi: 10.1038/503013a

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News Features

New angles on the brain p.21

Technologies that probe neural circuitry could greatly advance the study of human cognition.

doi: 10.1038/503021a

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Smart connections p.22

Computer chips inspired by human neurons can do more with less power.

M. Mitchell Waldrop

doi: 10.1038/503022a

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Brain storm p.26

Barack Obama announced his BRAIN Initiative on 2 April. Ever since, neuroscientists have been scrambling to work out what it actually is.

Helen Shen

doi: 10.1038/503026a

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News & Views

Sculpting neuronal connectivity p.42

It emerges that a transcription program differentially regulates inhibitory inputs in distinct neuronal compartments — an unexpected coordinated switch for achieving experience-dependent 'plasticity' in neural circuits. See Letter p.121

Emily Sylwestrak & Peter Scheiffele

doi: 10.1038/503042a

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On a roll p.43

Populations of rolling particles have been shown to display unidirectional collective motion in a racetrack enclosure. Theoretical modelling suggests that hydrodynamic and electrostatic effects promote such behaviour. See Letter p.95

Michael Shelley

doi: 10.1038/503043a

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Novelty makes the heart grow fonder p.44

Research on guppies provides the most definitive evidence yet for the rare-male effect — a long-standing hypothesis to explain the perplexing maintenance of variation in traits that are subject to strong mate choice. See Letter p.108

Jeffrey S. McKinnon & Maria R. Servedio

doi: 10.1038/nature12701

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What to do and how p.45

Decisions can differ depending on the context that surrounds them. Analyses of the prefrontal cortex region of the monkey brain indicate that a dynamical process at the neuronal population level controls this behaviour. See Article p.78

Jeffrey C. Erlich & Carlos D. Brody

doi: 10.1038/503045a

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Uncertain then, irrelevant now p.47

Uncertainty in estimates of the effects of aerosols on climate stems from poor knowledge of the past, pristine atmosphere — so getting a better understanding of these effects might not be as useful as was thought. See Article p.67

Bjorn Stevens

doi: 10.1038/503047a

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Good and bad news on the adolescent brain p.48

In response to bad news about risk, young adolescents alter estimates of their own vulnerability to adverse events less accurately than older people. The finding has implications for managing risk-taking behaviour in young people.

Valerie F. Reyna

doi: 10.1038/nature12704

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Reviews

Cortical connectivity and sensory coding p.51

The sensory cortex contains a wide array of neuronal types, which are connected together into complex but partially stereotyped circuits. Sensory stimuli trigger cascades of electrical activity through these circuits, causing specific features of sensory scenes to be encoded in the firing patterns of cortical populations. Recent research is beginning to reveal how the connectivity of individual neurons relates to the sensory features they encode, how differences in the connectivity patterns of different cortical cell classes enable them to encode information using different strategies, and how feedback connections from higher-order cortex allow sensory information to be integrated with behavioural context.

Kenneth D. Harris & Thomas D. Mrsic-Flogel

doi: 10.1038/nature12654

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Cooperation between brain and islet in glucose homeostasis and diabetes p.59

Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as ‘glucose effectiveness’, account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not.

Michael W. Schwartz, Randy J. Seeley, Matthias H. Tschöp, Stephen C. Woods, Gregory J. Morton, Martin G. Myers & David D’Alessio

doi: 10.1038/nature12709

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Articles

Large contribution of natural aerosols to uncertainty in indirect forcing p.67

It has been assumed that a better understanding of the effects of anthropogenic aerosols will greatly reduce the large uncertainties associated with our predictions of the radiative forcing effects of aerosols on climate; however, this study shows that nearly half of the uncertainty in the radiative effect of aerosols on clouds derives from uncertainties in pre-industrial natural aerosols.

K. S. Carslaw, L. A. Lee, C. L. Reddington, K. J. Pringle, A. Rap, P. M. Forster, G. W. Mann, D. V. Spracklen, M. T. Woodhouse, L. A. Regayre + et al.

doi: 10.1038/nature12674

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SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties p.72

Mouse and human studies reveal that incorrect gene dosage of SHANK3 (a gene linked to some human neuropsychiatric disorders, including autism spectrum disorder) is associated with behavioural abnormalities including mania, possibly because of actin regulation problems in excitatory/inhibitory synapses.

Kihoon Han, J. Lloyd Holder Jr, Christian P. Schaaf, Hui Lu, Hongmei Chen, Hyojin Kang, Jianrong Tang, Zhenyu Wu, Shuang Hao, Sau Wai Cheung + et al.

doi: 10.1038/nature12630

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Context-dependent computation by recurrent dynamics in prefrontal cortex p.78

This study shows that in monkeys making context-dependent decisions, task-relevant and task-irrelevant signals are confusingly intermixed in single units of the prefrontal cortex, but are readily understood in the framework of a dynamical process unfolding at the level of the population; a recurrently connected neural network model reproduces key features of the data and suggests a novel mechanism for selection and integration of task-relevant evidence towards a decision.

Valerio Mante, David Sussillo, Krishna V. Shenoy & William T. Newsome

doi: 10.1038/nature12742

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Letters

Demonstration of electron acceleration in a laser-driven dielectric microstructure p.91

The enormous size and cost of current state-of-the-art accelerators based on conventional radio-frequency technology has spawned great interest in the development of new acceleration concepts that are more compact and economical. Micro-fabricated dielectric laser accelerators (DLAs) are an attractive approach, because such dielectric microstructures can support accelerating fields one to two orders of magnitude higher than can radio-frequency cavity-based accelerators. DLAs use commercial lasers as a power source, which are smaller and less expensive than the radio-frequency klystrons that power today’s accelerators. In addition, DLAs are fabricated via low-cost, lithographic techniques that can be used for mass production. However, despite several DLA structures having been proposed recently, no successful demonstration of acceleration in these structures has so far been shown. Here we report high-gradient (beyond 250 MeV m−1) acceleration of electrons in a DLA. Relativistic (60-MeV) electrons are energy-modulated over 563 ± 104 optical periods of a fused silica grating structure, powered by a 800-nm-wavelength mode-locked Ti:sapphire laser. The observed results are in agreement with analytical models and electrodynamic simulations. By comparison, conventional modern linear accelerators operate at gradients of 10–30 MeV m−1, and the first linear radio-frequency cavity accelerator was ten radio-frequency periods (one metre) long with a gradient of approximately 1.6 MeV m−1 (ref. 5). Our results set the stage for the development of future multi-staged DLA devices composed of integrated on-chip systems. This would enable compact table-top accelerators on the MeV–GeV (106–109 eV) scale for security scanners and medical therapy, university-scale X-ray light sources for biological and materials research, and portable medical imaging devices, and would substantially reduce the size and cost of a future collider on the multi-TeV (1012 eV) scale.

E. A. Peralta, K. Soong, R. J. England, E. R. Colby, Z. Wu, B. Montazeri, C. McGuinness, J. McNeur, K. J. Leedle, D. Walz + et al.

doi: 10.1038/nature12664

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Emergence of macroscopic directed motion in populations of motile colloids p.95

From the formation of animal flocks to the emergence of coordinated motion in bacterial swarms, populations of motile organisms at all scales display coherent collective motion. This consistent behaviour strongly contrasts with the difference in communication abilities between the individuals. On the basis of this universal feature, it has been proposed that alignment rules at the individual level could solely account for the emergence of unidirectional motion at the group level. This hypothesis has been supported by agent-based simulations. However, more complex collective behaviours have been systematically found in experiments, including the formation of vortices, fluctuating swarms, clustering and swirling. All these (living and man-made) model systems (bacteria, biofilaments and molecular motors, shaken grains and reactive colloids) predominantly rely on actual collisions to generate collective motion. As a result, the potential local alignment rules are entangled with more complex, and often unknown, interactions. The large-scale behaviour of the populations therefore strongly depends on these uncontrolled microscopic couplings, which are extremely challenging to measure and describe theoretically. Here we report that dilute populations of millions of colloidal rolling particles self-organize to achieve coherent motion in a unique direction, with very few density and velocity fluctuations. Quantitatively identifying the microscopic interactions between the rollers allows a theoretical description of this polar-liquid state. Comparison of the theory with experiment suggests that hydrodynamic interactions promote the emergence of collective motion either in the form of a single macroscopic ‘flock’, at low densities, or in that of a homogenous polar phase, at higher densities. Furthermore, hydrodynamics protects the polar-liquid state from the giant density fluctuations that were hitherto considered the hallmark of populations of self-propelled particles. Our experiments demonstrate that genuine physical interactions at the individual level are sufficient to set homogeneous active populations into stable directed motion.

Antoine Bricard, Jean-Baptiste Caussin, Nicolas Desreumaux, Olivier Dauchot & Denis Bartolo

doi: 10.1038/nature12673

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Colloidal assembly directed by virtual magnetic moulds p.99

Interest in assemblies of colloidal particles has long been motivated by their applications in photonics, electronics, sensors and microlenses. Existing assembly schemes can position colloids of one type relatively flexibly into a range of desired structures, but it remains challenging to produce multicomponent lattices, clusters with precisely controlled symmetries and three-dimensional assemblies. A few schemes can efficiently produce complex colloidal structures, but they require system-specific procedures. Here we show that magnetic field microgradients established in a paramagnetic fluid can serve as ‘virtual moulds’ to act as templates for the assembly of large numbers (∼108) of both non-magnetic and magnetic colloidal particles with micrometre precision and typical yields of 80 to 90 per cent. We illustrate the versatility of this approach by producing single-component and multicomponent colloidal arrays, complex three-dimensional structures and a variety of colloidal molecules from polymeric particles, silica particles and live bacteria and by showing that all of these structures can be made permanent. In addition, although our magnetic moulds currently resemble optical traps in that they are limited to the manipulation of micrometre-sized objects, they are massively parallel and can manipulate non-magnetic and magnetic objects simultaneously in two and three dimensions.

Ahmet F. Demirörs, Pramod P. Pillai, Bartlomiej Kowalczyk & Bartosz A. Grzybowski

doi: 10.1038/nature12591

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Structural change in molten basalt at deep mantle conditions p.104

Silicate liquids play a key part at all stages of deep Earth evolution, ranging from core and crust formation billions of years ago to present-day volcanic activity. Quantitative models of these processes require knowledge of the structural changes and compression mechanisms that take place in liquid silicates at the high pressures and temperatures in the Earth’s interior. However, obtaining such knowledge has long been impeded by the challenging nature of the experiments. In recent years, structural and density information for silica glass was obtained at record pressures of up to 100 GPa (ref. 1), a major step towards obtaining data on the molten state. Here we report the structure of molten basalt up to 60 GPa by means of in situ X-ray diffraction. The coordination of silicon increases from four under ambient conditions to six at 35 GPa, similar to what has been reported in silica glass. The compressibility of the melt after the completion of the coordination change is lower than at lower pressure, implying that only a high-order equation of state can accurately describe the density evolution of silicate melts over the pressure range of the whole mantle. The transition pressure coincides with a marked change in the pressure-evolution of nickel partitioning between molten iron and molten silicates, indicating that melt compressibility controls siderophile-element partitioning.

Chrystèle Sanloup, James W. E. Drewitt, Zuzana Konôpková, Philip Dalladay-Simpson, Donna M. Morton, Nachiketa Rai, Wim van Westrenen & Wolfgang Morgenroth

doi: 10.1038/nature12668

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Mating advantage for rare males in wild guppy populations p.108

To understand the processes that maintain genetic diversity is a long-standing challenge in evolutionary biology, with implications for predicting disease resistance, response to environmental change, and population persistence. Simple population genetic models are not sufficient to explain the high levels of genetic diversity sometimes observed in ecologically important traits. In guppies (Poecilia reticulata), male colour pattern is both diverse and heritable, and is arguably one of the most extreme examples of morphological polymorphism known. Negative frequency-dependent selection (NFDS), a form of selection in which genotypes are favoured when they are rare, can potentially maintain such extensive polymorphism, but few experimental studies have confirmed its operation in nature. Here we use highly replicated experimental manipulations of natural populations to show that males with rare colour patterns have higher reproductive fitness, demonstrating NFDS mediated by sexual selection. Rare males acquired more mates and sired more offspring compared to common males and, as previously reported, had higher rates of survival. Orange colour, implicated in other studies of sexual selection in guppies, did predict male reproductive success, but only in one of three populations. These data support the hypothesis that NFDS maintains diversity in the colour patterns of male guppies through two selective agents, mates and predators. Similar field-based manipulations of genotype frequencies could provide a powerful approach to reveal the underlying ecological and behavioural mechanisms that maintain genetic and phenotypic diversity.

Kimberly A. Hughes, Anne E. Houde, Anna C. Price & F. Helen Rodd

doi: 10.1038/nature12717

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Genetic identification of a neural circuit that suppresses appetite p.111

Appetite suppression occurs after a meal and in conditions when it is unfavourable to eat, such as during illness or exposure to toxins. A brain region proposed to play a role in appetite suppression is the parabrachial nucleus, a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The parabrachial nucleus is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin, as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively. Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice. However, the identities of neurons in the parabrachial nucleus that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomical, optogenetic and pharmacogenetic tools, we demonstrate that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated. Taken together, our data demonstrate that this neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression in conditions when it is unfavourable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.

Matthew E. Carter, Marta E. Soden, Larry S. Zweifel & Richard D. Palmiter

doi: 10.1038/nature12596

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Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo p.115

Neuronal dendrites are electrically excitable: they can generate regenerative events such as dendritic spikes in response to sufficiently strong synaptic input. Although such events have been observed in many neuronal types, it is not well understood how active dendrites contribute to the tuning of neuronal output in vivo. Here we show that dendritic spikes increase the selectivity of neuronal responses to the orientation of a visual stimulus (orientation tuning). We performed direct patch-clamp recordings from the dendrites of pyramidal neurons in the primary visual cortex of lightly anaesthetized and awake mice, during sensory processing. Visual stimulation triggered regenerative local dendritic spikes that were distinct from back-propagating action potentials. These events were orientation tuned and were suppressed by either hyperpolarization of membrane potential or intracellular blockade of NMDA (N-methyl-d-aspartate) receptors. Both of these manipulations also decreased the selectivity of subthreshold orientation tuning measured at the soma, thus linking dendritic regenerative events to somatic orientation tuning. Together, our results suggest that dendritic spikes that are triggered by visual input contribute to a fundamental cortical computation: enhancing orientation selectivity in the visual cortex. Thus, dendritic excitability is an essential component of behaviourally relevant computations in neurons.

Spencer L. Smith, Ikuko T. Smith, Tiago Branco & Michael Häusser

doi: 10.1038/nature12600

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The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition p.121

A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of excitatory synaptic potentials and prevent the generation of dendritic calcium spikes. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinatesthe redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.

Brenda L. Bloodgood, Nikhil Sharma, Heidi Adlman Browne, Alissa Z. Trepman & Michael E. Greenberg

doi: 10.1038/nature12743

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Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma p.126

In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell–matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell–matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.

Elizabeth E. Gerber, Elena M. Gallo, Stefani C. Fontana, Elaine C. Davis, Fredrick M. Wigley, David L. Huso & Harry C. Dietz

doi: 10.1038/nature12614

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A directional switch of integrin signalling and a new anti-thrombotic strategy p.131

Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin αIIbβ3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Gα13 and greatly expands thrombi. Here we show that Gα13 and talin bind to mutually exclusive but distinct sites within the integrin β3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Gα13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Gα13–integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.

Bo Shen, Xiaojuan Zhao, Kelly A. O’Brien, Aleksandra Stojanovic-Terpo, M. Keegan Delaney, Kyungho Kim, Jaehyung Cho, Stephen C.-T. Lam & Xiaoping Du

doi: 10.1038/nature12613

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LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy p.136

The dense glycan coat that surrounds every cell is essential for cellular development and physiological function, and it is becoming appreciated that its composition is highly dynamic. Post-translational addition of the polysaccharide repeating unit [-3-xylose-α1,3-glucuronic acid-β1-]n by like-acetylglucosaminyltransferase (LARGE) is required for the glycoprotein dystroglycan to function as a receptor for proteins in the extracellular matrix. Reductions in the amount of [-3-xylose-α1,3-glucuronic acid-β1-]n (hereafter referred to as LARGE-glycan) on dystroglycan result in heterogeneous forms of muscular dystrophy. However, neither patient nor mouse studies has revealed a clear correlation between glycosylation status and phenotype. This disparity can be attributed to our lack of knowledge of the cellular function of the LARGE-glycan repeat. Here we show that coordinated upregulation of Large and dystroglycan in differentiating mouse muscle facilitates rapid extension of LARGE-glycan repeat chains. Using synthesized LARGE-glycan repeats we show a direct correlation between LARGE-glycan extension and its binding capacity for extracellular matrix ligands. Blocking Large upregulation during muscle regeneration results in the synthesis of dystroglycan with minimal LARGE-glycan repeats in association with a less compact basement membrane, immature neuromuscular junctions and dysfunctional muscle predisposed to dystrophy. This was consistent with the finding that patients with increased clinical severity of disease have fewer LARGE-glycan repeats. Our results reveal that the LARGE-glycan of dystroglycan serves as a tunable extracellular matrix protein scaffold, the extension of which is required for normal skeletal muscle function.

Matthew M. Goddeeris, Biming Wu, David Venzke, Takako Yoshida-Moriguchi, Fumiaki Saito, Kiichiro Matsumura, Steven A. Moore & Kevin P. Campbell

doi: 10.1038/nature12605

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Structural basis for action by diverse antidepressants on biogenic amine transporters p.141

The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.

Hui Wang, April Goehring, Kevin H. Wang, Aravind Penmatsa, Ryan Ressler & Eric Gouaux

doi: 10.1038/nature12648

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