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5 Janelia Publications

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    Zlatic Lab
    04/28/11 | A combinatorial semaphorin code instructs the initial steps of sensory circuit assembly in the Drosophila CNS.
    Wu Z, Sweeney LB, Ayoob JC, Chak K, Andreone BJ, Ohyama T, Kerr R, Luo L, Zlatic M, Kolodkin AL
    Neuron. 2011 Apr 28;70(2):281-98. doi: 10.1016/j.neuron.2011.02.050

    Longitudinal axon fascicles within the Drosophila embryonic CNS provide connections between body segments and are required for coordinated neural signaling along the anterior-posterior axis. We show here that establishment of select CNS longitudinal tracts and formation of precise mechanosensory afferent innervation to the same CNS region are coordinately regulated by the secreted semaphorins Sema-2a and Sema-2b. Both Sema-2a and Sema-2b utilize the same neuronal receptor, plexin B (PlexB), but serve distinct guidance functions. Localized Sema-2b attraction promotes the initial assembly of a subset of CNS longitudinal projections and subsequent targeting of chordotonal sensory afferent axons to these same longitudinal connectives, whereas broader Sema-2a repulsion serves to prevent aberrant innervation. In the absence of Sema-2b or PlexB, chordotonal afferent connectivity within the CNS is severely disrupted, resulting in specific larval behavioral deficits. These results reveal that distinct semaphorin-mediated guidance functions converge at PlexB and are critical for functional neural circuit assembly.

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    04/22/11 | Real-time observation of transcription initiation and elongation on an endogenous yeast gene.
    Larson DR, Zenklusen D, Wu B, Chao JA, Singer RH
    Science. 2011 Apr 22;332(6028):475-8. doi: 10.1126/science.1202142

    Cellular messenger RNA levels are achieved by the combinatorial complexity of factors controlling transcription, yet the small number of molecules involved in these pathways fluctuates stochastically. It has not yet been experimentally possible to observe the activity of single polymerases on an endogenous gene to elucidate how these events occur in vivo. Here, we describe a method of fluctuation analysis of fluorescently labeled RNA to measure dynamics of nascent RNA–including initiation, elongation, and termination–at an active yeast locus. We find no transcriptional memory between initiation events, and elongation speed can vary by threefold throughout the cell cycle. By measuring the abundance and intranuclear mobility of an upstream transcription factor, we observe that the gene firing rate is directly determined by trans-activating factor search times.

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    04/14/11 | Intracellular determinants of hippocampal CA1 place and silent cell activity in a novel environment.
    Epsztein J, Brecht M, Lee AK
    Neuron. 2011 Apr 14;70(1):109-20. doi: 10.1016/j.neuron.2011.03.006

    For each environment a rodent has explored, its hippocampus contains a map consisting of a unique subset of neurons, called place cells, that have spatially tuned spiking there, with the remaining neurons being essentially silent. Using whole-cell recording in freely moving rats exploring a novel maze, we observed differences in intrinsic cellular properties and input-based subthreshold membrane potential levels underlying this division into place and silent cells. Compared to silent cells, place cells had lower spike thresholds and peaked versus flat subthreshold membrane potentials as a function of animal location. Both differences were evident from the beginning of exploration. Additionally, future place cells exhibited higher burst propensity before exploration. Thus, internal settings appear to predetermine which cells will represent the next novel environment encountered. Furthermore, place cells fired spatially tuned bursts with large, putatively calcium-mediated depolarizations that could trigger plasticity and stabilize the new map for long-term storage. Our results provide new insight into hippocampal memory formation.

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    Menon Lab
    04/01/11 | Hallmarks of molecular action of microtubule stabilizing agents: effects of epothilone B, ixabepilone, peloruside A, and laulimalide on microtubule conformation.
    Khrapunovich-Baine M, Menon V, Yang CH, Northcote PT, Miller JH, Angeletti RH, Fiser A, Horwitz SB, Xiao H
    The Journal of biological chemistry. 2011 Apr 1;286(13):11765-78. doi: 10.1074/jbc.M110.162214

    Microtubule stabilizing agents (MSAs) comprise a class of drugs that bind to microtubule (MT) polymers and stabilize them against disassembly. Several of these agents are currently in clinical use as anticancer drugs, whereas others are in various stages of development. Nonetheless, there is insufficient knowledge about the molecular modes of their action. Recent studies from our laboratory utilizing hydrogen-deuterium exchange in combination with mass spectrometry (MS) provide new information on the conformational effects of Taxol and discodermolide on microtubules isolated from chicken erythrocytes (CET). We report here a comprehensive analysis of the effects of epothilone B, ixabepilone (IXEMPRA(TM)), laulimalide, and peloruside A on CET conformation. The results of our comparative hydrogen-deuterium exchange MS studies indicate that all MSAs have significant conformational effects on the C-terminal H12 helix of α-tubulin, which is a likely molecular mechanism for the previously observed modulations of MT interactions with microtubule-associated and motor proteins. More importantly, the major mode of MT stabilization by MSAs is the tightening of the longitudinal interactions between two adjacent αβ-tubulin heterodimers at the interdimer interface. In contrast to previous observations reported with bovine brain tubulin, the lateral interactions between the adjacent protofilaments in CET are particularly strongly stabilized by peloruside A and laulimalide, drugs that bind outside the taxane site. This not only highlights the significance of tubulin isotype composition in modulating drug effects on MT conformation and stability but also provides a potential explanation for the synergy observed when combinations of taxane and alternative site binding drugs are used.

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    04/01/11 | Wireless neural/EMG telemetry systems for small freely moving animals.
    Harrison RR, Fotowat H, Chan R, Kier RJ, Olberg R, Leonardo A, Gabbiani F
    IEEE Transactions on Biomedical Circuits and Systems. 2011 Apr;5(2):103-11. doi: 10.1109/TBCAS.2011.2131140

    We have developed miniature telemetry systems that capture neural, EMG, and acceleration signals from a freely moving insect or other small animal and transmit the data wirelessly to a remote digital receiver. The systems are based on custom low-power integrated circuits (ICs) that amplify, filter, and digitize four biopotential signals using low-noise circuits. One of the chips also digitizes three acceleration signals from an off-chip microelectromechanical-system accelerometer. All information is transmitted over a wireless ~ 900-MHz telemetry link. The first unit, using a custom chip fabricated in a 0.6- μm BiCMOS process, weighs 0.79 g and runs for two hours on two small batteries. We have used this system to monitor neural and EMG signals in jumping and flying locusts as well as transdermal potentials in weakly swimming electric fish. The second unit, using a custom chip fabricated in a 0.35-μ m complementary metal-oxide semiconductor CMOS process, weighs 0.17 g and runs for five hours on a single 1.5-V battery. This system has been used to monitor neural potentials in untethered perching dragonflies.

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