Monday, July 11, 2011

Hot off the presses! Jul 12 Curr Biol

The Jul 12 issue of the Curr Biol is now up on Pubget (About Curr Biol): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • African genomes
    - Curr Biol 21(13):R481-R484 (2011)
    Africa hosts the majority of human genetic diversity, the clues to human origins, and the heaviest disease burden. Yet genomics has so far focused on people of European descent. Now Africans and other populations left out are hoping to reap the benefits as well. Michael Gross reports.
  • Bruce Lyon
    - Curr Biol 21(13):R484-R485 (2011)
  • Houses made by protists
    - Curr Biol 21(13):R485-R487 (2011)
  • Toll-like receptors
    - Curr Biol 21(13):R488-R493 (2011)
    Beginning with the physical barrier presented by the epithelium, infectious agents such as viruses and bacteria encounter an array of cellular and molecular countermeasures that evolved within the host to resist them. Host immune responses are of two types, termed innate and adaptive. Immediate defensive responses, which include inflammation, phagocytosis of pathogens, and recruitment of a variety of immune cells, are employed against all classes of microbe, irrespective of prior exposure, and are collectively termed the innate immune response. Innate immunity is evolutionarily ancient, and selected mechanisms are known to be conserved from plants to humans. In contrast, the adaptive immune response is mobilized over a more protracted timescale, is influenced by prior exposure, and, by virtue of antigen-specific receptors generated through somatic DNA recombination within lymphoid clones, is highly specific at the molecular level, often to the point of specificity for ! a particular microbial species. Adaptive immunity evolved relatively recently and exists only in vertebrates. In mammals, the immune response encompasses the innate and adaptive responses, and, although cross-talk occurs between them, each can be carried out independently by distinct cellular and molecular mechanisms.
  • Learning to reach for 'invisible' visual input
    - Curr Biol 21(13):R493-R494 (2011)
    Patients who have suffered damage to primary visual cortex can report being blind but display some proficiency when manually interacting with 'unseen' objects — a phenomenon known as blindsight [1], [2], [3] and [4]. There is conflicting evidence about analogous situations in normally sighted people [5], [6] and [7]; however, to date no study has attempted to assess a directly analogous situation, to have normally sighted people interact with unseen stimuli. We used a form of binocular masking to suppress awareness of oriented stimuli [8]. Despite initial insensitivity when making verbal judgements, participants who reached as if to grasp perceptually suppressed stimuli displayed increasing proficiency with training and feedback. This was not simply due to practise, as another group did not develop such proficiency when completing a matched number of trials, with feedback, while making verbal responses; however, this same group subsequently developed sensitivity ! when they too completed training with reaching and feedback. Our data thus reveal a special status for attempts to grasp perceptually suppressed stimuli.
  • Asexuality: The Insects that Stick With It
    - Curr Biol 21(13):R495-R497 (2011)
    One hope of trying to understand why sex is so powerful and prevalent a mode of reproduction relies on the rare examples of animals that persist long-term without having sex. Now, several species of stick insects join that illustrious circle.
  • Basal Ganglia: Insights into Origins from Lamprey Brains
    - Curr Biol 21(13):R497-R500 (2011)
    The lamprey brain has now been shown to have basal ganglia circuitry, with an output that acts tonically on midbrain and brainstem motor centers and is modulated by ascending dopaminergic input. This condition was believed to represent the tetrapod condition, but now appears to be far more ancient.
  • Phagocytes: Fussy about Carbs
    - Curr Biol 21(13):R500-R502 (2011)
    A new mechanistic model based on the formation of a phagocytic synapse explains how immune cells detect and respond to direct contact with fungal pathogens.
  • Phyllotaxis: In Search of the Golden Angle
    - Curr Biol 21(13):R502-R504 (2011)
    How are the regular patterns of organs established along a plant stem and how are the transitions between different patterns regulated? Now genes of the PLETHORA family have been shown to modulate these transitions by fine-tuning the mechanisms of polar transport of auxin, a key effector of organogenesis.
  • Olfactory Coding: Giant Inhibitory Neuron Governs Sparse Odor Codes
    - Curr Biol 21(13):R504-R506 (2011)
    Electrophysiological investigations in locusts have revealed that the sparseness of odor representations, in the brain region expected to mediate olfactory learning, is shaped by a unique inhibitory neuron.
  • Vesicle Transport: Springing the TRAPP
    - Curr Biol 21(13):R506-R508 (2011)
    When a coated transport vesicle docks with its target membrane, the coat proteins and docking machinery must be released before the membranes can fuse. A recent paper shows how this disassembly is triggered at precisely the right time.
  • Animal Cooperation: Keeping a Clean(ing) Reputation
    - Curr Biol 21(13):R508-R510 (2011)
    Cleaner wrasses are a model for the study of animal cooperation. Prospective clients can observe whether the cleaner works faithfully, and cleaners being watched remove just parasites while those that are not, nip the client for a tastier snack.
  • Apiology: Royal Secrets in the Queen's Fat Body
    - Curr Biol 21(13):R510-R512 (2011)
    Royalactin, a component of royal jelly, induces queen differentiation in honeybees. Surprisingly, royalactin has a similar effect on growth in fruit flies, highlighting many unexpected features of growth regulation by the insect fat tissue.
  • New Moves in Motor Control
    - Curr Biol 21(13):R513-R524 (2011)
    Motor behaviour results from information processing across multiple neural networks acting at all levels from initial selection of the behaviour to its final generation. Understanding how motor behaviour is produced requires identifying the constituent neurons of these networks, their cellular properties, and their pattern of synaptic connectivity. Neural networks have been traditionally studied with neurophysiological and neuroanatomical approaches. These approaches have been highly successful in particularly suitable 'model' preparations, typically ones in which the numbers of neurons in the networks were relatively small, neural network composition was unvarying across individual animals, and the preparations continued to produce fictive motor patterns in vitro. However, analysing networks without these characteristics, and analysing the complete ensemble of networks that cooperatively generate behaviours, is difficult with these approaches. Recently developed m! olecular and neurogenetic tools provide additional avenues for analysing motor networks by allowing individual or groups of neurons within networks to be manipulated in novel ways and allowing experiments to be performed not only in vitro but also in vivo. We review here some of the new insights into motor network function that these advances have provided and indicate how these advances might bridge gaps in our understanding of motor control. To these ends, we first review motor neural network organisation highlighting cross-phylum principles. We then use prominent examples from the field to show how neurogenetic approaches can complement classical physiological studies, and identify additional areas where these approaches could be advantageously applied.
  • Evolutionary Conservation of the Basal Ganglia as a Common Vertebrate Mechanism for Action Selection
    - Curr Biol 21(13):1081-1091 (2011)
    Background Although the basal ganglia are thought to play a key role in action selection in mammals, it is unknown whether this mammalian circuitry is present in lower vertebrates as a conserved selection mechanism. We aim here, using lamprey, to elucidate the basal ganglia circuitry in the phylogenetically oldest group of vertebrates (cyclostomes) and determine how this selection architecture evolved to accommodate the increased behavioral repertoires of advanced vertebrates. Results We show, using immunohistochemistry, tract tracing, and whole-cell recordings, that all parts of the mammalian basal ganglia (striatum, globus pallidus interna [GPi] and externa [GPe], and subthalamic nucleus [STN]) are present in the lamprey forebrain. In addition, the circuit features, molecular markers, and physiological activity patterns are conserved. Thus, GABAergic striatal neurons expressing substance P project directly to the pallidal output layer, whereas enkephalin-expressing striatal neurons project indirectly via nuclei homologous to the GPe and STN. Moreover, pallidal output neurons tonically inhibit tectum, mesencephalic, and diencephalic motor regions. Conclusions These results show that the detailed basal ganglia circuitry is present in the phylogenetically oldest vertebrates and has been conserved, most likely as a mechanism for action selection used by all vertebrates, for over 560 million years. Our data also suggest that the mammalian basal ganglia evolved through a process of exaptation, where the ancestral core unit has been co-opted for multiple functions, allowing them to process cognitive, emotional, and motor information in parallel and control a broader range of behaviors.
  • Modularity of the Bacterial Cell Cycle Enables Independent Spatial and Temporal Control of DNA Replication
    - Curr Biol 21(13):1092-1101 (2011)
    Background Complex regulatory circuits in biology are often built of simpler subcircuits or modules. In most cases, the functional consequences and evolutionary origins of modularity remain poorly defined. Results Here, by combining single-cell microscopy with genetic approaches, we demonstrate that two separable modules independently govern the temporal and spatial control of DNA replication in the asymmetrically dividing bacterium Caulobacter crescentus. DNA replication control involves DnaA, which promotes initiation, and CtrA, which silences initiation. We show that oscillations in DnaA activity dictate the periodicity of replication while CtrA governs the asymmetric replicative fates of daughter cells. Importantly, we demonstrate that DnaA activity oscillates independently of CtrA. Conclusions The genetic separability of spatial and temporal control modules in Caulobacter reflects their evolutionary history. DnaA is the central component of an ancient and phylogenetically widespread circuit that governs replication periodicity in Caulobacter and most other bacteria. By contrast, CtrA, which is found only in the asymmetrically dividing α-proteobacteria, was integrated later in evolution to enforce replicative asymmetry on daughter cells.
  • Phosphorylation of Groucho Mediates RTK Feedback Inhibition and Prolonged Pathway Target Gene Expression
    - Curr Biol 21(13):1102-1110 (2011)
    Background Signaling by receptor tyrosine kinase (RTK) pathways plays fundamental roles in processes of cell-fate determination, often through the induction of specific transcriptional responses. Yet it is not fully understood how continuous target gene expression, required for irreversible cell-fate specification, is preserved after RTK signaling has ended. Here we address this question using the Drosophila embryo, a model system that has been instrumental in elucidating the developmental functions of RTK signal transduction. Results The Groucho corepressor is phosphorylated and downregulated in response to RTK signaling. Here we show that RTK pathways use Groucho phosphorylation as a general mechanism for inducing expression of pathway target genes encoding cell-fate determinants as well as feedback antagonists, indicating that relief of Groucho-dependent repression is an integral element of RTK signaling networks. We further demonstrate that after mitogen-activated protein kinase (MAPK) has been deactivated, sustained phosphorylation of Groucho is essential for persistent RTK-induced target gene expression and cell-fate determination in several developmental contexts. Conclusions Phosphorylation of Groucho by MAPK plays a dual role in the regulation of RTK responses: (1) it mediates rapid feedback inhibition, and (2) it provides a stable memory mechanism of past MAPK activity. We propose that, in this manner, phosphorylation of Groucho enables transiently active RTK pathways to fix the spatiotemporal expression profiles of downstream targets over time.
  • Retromer Controls Epithelial Cell Polarity by Trafficking the Apical Determinant Crumbs
    - Curr Biol 21(13):1111-1117 (2011)
    The evolutionarily conserved apical determinant Crumbs (Crb) is essential for maintaining apicobasal polarity and integrity of many epithelial tissues [1]. Crb levels are crucial for cell polarity and homeostasis, yet strikingly little is known about its trafficking or the mechanism of its apical localization. Using a newly established, liposome-based system described here, we determined Crb to be an interaction partner and cargo of the retromer complex. Retromer is essential for the retrograde transport of numerous transmembrane proteins from endosomes to the trans-Golgi network (TGN) and is conserved between plants, fungi, and animals [2]. We show that loss of retromer function results in a substantial reduction of Crb in Drosophila larvae, wing discs, and the follicle epithelium. Moreover, loss of retromer phenocopies loss of crb by preventing apical localization of key polarity molecules, such as atypical protein kinase C (aPKC) and Par6 in the follicular epitheliu! m, an effect that can be rescued by overexpression of Crb. Additionally, loss of retromer results in multilayering of the follicular epithelium, indicating that epithelial integrity is severely compromised. Our data reveal a mechanism for Crb trafficking by retromer that is vital for maintaining Crb levels and localization. We also show a novel function for retromer in maintaining epithelial cell polarity.
  • From Part- to Whole-Body Ownership in the Multisensory Brain
    - Curr Biol 21(13):1118-1122 (2011)
    The question of how we experience ownership of an entire body distinct from the external world is a fundamental problem in psychology and neuroscience [[1], [2], [3], [4], [5] and [6]]. Earlier studies suggest that integration of visual, tactile, and proprioceptive information in multisensory areas [[7], [8], [9], [10] and [11]] mediates self-attribution of single limbs. However, it is still unknown how ownership of individual body parts translates into the unitary experience of owning a whole body. Here, we used a "body-swap" illusion [12], in which people experienced an artificial body to be their own, in combination with functional magnetic resonance imaging to reveal a coupling between the experience of full-body ownership and neural responses in bilateral ventral premotor and left intraparietal cortices, and left putamen. Importantly, activity in the ventral premotor cortex reflected the construction of ownership of a whole body from the parts, because it was ! stronger when the stimulated body part was attached to a body, was present irrespective of whether the illusion was triggered by stimulation of the hand or the abdomen, and displayed multivoxel patterns carrying information about full-body ownership. These findings suggest that the unitary experience of owning an entire body is produced by neuronal populations that integrate multisensory information across body segments.
  • Arabidopsis PLETHORA Transcription Factors Control Phyllotaxis
    - Curr Biol 21(13):1123-1128 (2011)
    The pattern of plant organ initiation at the shoot apical meristem (SAM), termed phyllotaxis, displays regularities that have long intrigued botanists and mathematicians alike. In the SAM, the central zone (CZ) contains a population of stem cells that replenish the surrounding peripheral zone (PZ), where organs are generated in regular patterns. These patterns differ between species and may change in response to developmental or environmental cues [1]. Expression analysis of auxin efflux facilitators of the PIN-FORMED (PIN) family combined with modeling of auxin transport has indicated that organ initiation is associated with intracellular polarization of PIN proteins and auxin accumulation [[2], [3], [4], [5], [6], [7], [8], [9] and [10]]. However, regulators that modulate PIN activity to determine phyllotactic patterns have hitherto been unknown. Here we reveal that three redundantly acting PLETHORA (PLT)-like AP2 domain transcription factors control shoot organ posi! tioning in the model plant Arabidopsis thaliana. Loss of PLT3, PLT5, and PLT7 function leads to nonrandom, metastable changes in phyllotaxis. Phyllotactic changes in plt3plt5plt7 mutants are largely attributable to misregulation of PIN1 and can be recapitulated by reducing PIN1 dosage, revealing that PLT proteins are key regulators of PIN1 activity in control of phyllotaxis.
  • Molecular Evidence for Ancient Asexuality in Timema Stick Insects
    - Curr Biol 21(13):1129-1134 (2011)
    Asexuality is rare in animals in spite of its apparent advantage relative to sexual reproduction, indicating that it must be associated with profound costs [[1], [2], [3], [4], [5], [6], [7], [8] and [9]]. One expectation is that reproductive advantages gained by new asexual lineages will be quickly eroded over time [[3], [5], [6] and [7]]. Ancient asexual taxa that have evolved and adapted without sex would be "scandalous" exceptions to this rule, but it is often difficult to exclude the possibility that putative asexuals deploy some form of "cryptic" sex, or have abandoned sex more recently than estimated from divergence times to sexual relatives [10]. Here we provide evidence, from high intraspecific divergence of mitochondrial sequence and nuclear allele divergence patterns, that several independently derived Timema stick-insect lineages have persisted without recombination for more than a million generations. Nuclear alleles in the asexual lineages display! ed significantly higher intraindividual divergences than in related sexual species. In addition, within two asexuals, nuclear allele phylogenies suggested the presence of two clades, with sequences from the same individual appearing in both clades. These data strongly support ancient asexuality in Timema and validate the genus as an exceptional opportunity to attack the question of how asexual reproduction can be maintained over long periods of evolutionary time.
  • Perceiving Spatial Relations via Attentional Tracking and Shifting
    - Curr Biol 21(13):1135-1139 (2011)
    Perceiving which of a scene's objects are adjacent may require selecting them with a limited-capacity attentional process. Previous results support this notion [[1], [2] and [3]] but leave open whether the process operates simultaneously on several objects or proceeds one by one. With arrays of colored discs moving together, we first tested the effect of moving the discs faster than the speed limit for following them with attentional selection [4]. At these high speeds, participants could identify which colors were present and determine whether identical arrays were aligned or offset by one disc. They could not, however, apprehend which colors in the arrays were adjacent, indicating that attentional selection is required for this judgment. If selection operates serially to determine which colors are neighbors, then after the color of one disc is identified, attention must shift to the adjacent disc. As a result of the motion, attention might occasionally miss its targe! t and land on the trailing disc. We cued attention to first select one or the other of a pair of discs and found the pattern of errors predicted. Perceiving these spatial relationships evidently requires selecting and processing objects one by one and is only possible at low object speeds.
  • Cleaner Wrasses Labroides dimidiatus Are More Cooperative in the Presence of an Audience
    - Curr Biol 21(13):1140-1144 (2011)
    Humans may help others even in situations where the recipient will not reciprocate [[1], [2], [3], [4] and [5]]. In some cases, such behavior can be explained by the helpers increasing their image score, which will increase the probability that bystanders will help them in the future [[5], [6] and [7]]. For other animals, the notion that many interactions take place in an environment containing an audience of eavesdropping bystanders has also been proposed to have important consequences for social behavior, including levels of cooperation [8]. However, experimental evidence is currently restricted to the demonstration that cleaner fish Labroides dimidiatus can learn to solve a foraging task [9]. The cleaners learned to feed against their preference on artificial clients if that allowed them to access additional artificial clients, which would translate into cooperatively eating ectoparasites rather than cheating by eating client mucus under natural conditions [10]. Her! e we show that cleaners immediately increase current levels of cooperation in the presence of bystander client reef fish. Furthermore, we find that bystanders respond to any occurrence of cleaners cheating their current client with avoidance. In conclusion, the results demonstrate, for the first time, that image scoring by an audience indeed leads to increased levels of cooperation in a nonhuman animal.
  • Plk1 Controls the Nek2A-PP1γ Antagonism in Centrosome Disjunction
    - Curr Biol 21(13):1145-1151 (2011)
    In human cells, separation of the centrosomes and formation of a bipolar spindle are essential for correct chromosome segregation [1]. During interphase, centrosomes are joined together by the linker proteins C-Nap1 and rootletin [[2], [3] and [4]]. At the onset of mitosis, these linker proteins are phosphorylated and displaced from centrosomes by the Nek2A kinase, which is regulated by two Hippo pathway components, Mst2 kinase and the scaffold protein hSav1. The kinesin-5 motor protein Eg5 promotes centrosome separation in a parallel pathway to Nek2A [5]. Here, we report that Polo-like kinase 1 (Plk1) functions upstream of the Mst2-Nek2A kinase module in centrosome disjunction as well as being important for Eg5 localization at centrosomes. Plk1 regulates Mst2-Nek2A-induced centrosome disjunction by phosphorylating Mst2. The absence of Plk1 phosphorylation of Mst2 promotes assembly of Nek2A-PP1γ-Mst2 complexes, in which PP1γ counteracts Nek2A kinase activity. In cont! rast, Plk1 phosphorylation of Mst2 prevents PP1γ binding to Mst2-Nek2A, allowing Nek2A activity to promote centrosome disjunction. We propose that centrosome disjunction is regulated by Plk1, providing a well-balanced control between the counteracting Nek2A and PP1γ activities on the centrosome linker.
  • Regulation of DNA Replication through Sld3-Dpb11 Interaction Is Conserved from Yeast to Humans
    - Curr Biol 21(13):1152-1157 (2011)
    Cyclin-dependent kinases (CDKs) play crucial roles in promoting DNA replication and preventing rereplication in eukaryotic cells [[1], [2], [3] and [4]]. In budding yeast, CDKs promote DNA replication by phosphorylating two proteins, Sld2 and Sld3, which generates binding sites for pairs of BRCT repeats (breast cancer gene 1 [BRCA1] C terminal repeats) in the Dpb11 protein [[5] and [6]]. The Sld3-Dpb11-Sld2 complex generated by CDK phosphorylation is required for the assembly and activation of the Cdc45-Mcm2-7-GINS (CMG) replicative helicase. In response to DNA replication stress, the interaction between Sld3 and Dpb11 is blocked by the checkpoint kinase Rad53 [7], which prevents late origin firing [[7] and [8]]. Here we show that the two key CDK sites in Sld3 are conserved in the human Sld3-related protein Treslin/ticrr and are essential for DNA replication. Moreover, phosphorylation of these two sites mediates interaction with the orthologous pair of BRCT repeats in ! the human Dpb11 ortholog, TopBP1. Finally, we show that DNA replication stress prevents the interaction between Treslin/ticrr and TopBP1 via the Chk1 checkpoint kinase. Our results indicate that Treslin/ticrr is a genuine ortholog of Sld3 and that the Sld3-Dpb11 interaction has remained a critical nexus of S phase regulation through eukaryotic evolution.
  • Feedback Control in Sensing Chromosome Biorientation by the Aurora B Kinase
    - Curr Biol 21(13):1158-1165 (2011)
    Maintenance of genome stability during cell division depends on establishing correct attachments between chromosomes and spindle microtubules. Correct, bioriented attachments are stabilized, whereas incorrect attachments are selectively destabilized. This process relies largely on increased phosphorylation of kinetochore substrates of Aurora B kinase at misaligned versus aligned kinetochores. Current models explain this differential phosphorylation by spatial changes in the position of substrates relative to a constant pool of kinase at the inner centromere. However, these models are based on studies in aneuploid cells. We show that normal diploid cells have a more robust error-correction machinery. Aurora B is enriched at misaligned centromeres in these cells, and the dynamic range of Aurora B substrate phosphorylation at misaligned versus aligned kinetochores is increased. These findings indicate that in addition to Aurora B regulating kinetochore-microtubule binding! , the kinetochore also controls Aurora B recruitment to the inner centromere. We show that this recruitment depends on both activity of Plk1, a kinetochore-localized kinase, and activity of Aurora B itself. Our results suggest a feedback mechanism in which Aurora B both regulates and is regulated by chromosome attachment to the spindle, which amplifies the differential phosphorylation of kinetochore substrates and increases the efficiency of error correction.

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