Bio

Academic Appointments


Honors & Awards


  • Pioneer Awardee, NIH (2007)
  • Scholar, McKnight Foundation (2006)
  • Fellow, Klingenstein Foundation (2005)
  • Burroughs-Wellcome Career Development Award, Burroughs-Wellcome Foundation (2000)
  • Searle Scholar, Searle Foundation (2003)
  • Alfred P. Sloan Fellow, Sloan Foundation (2003)

Professional Education


  • B.Sc., University of Alberta, Genetics (1990)
  • M.Sc., University of Calgary, Medical Genetics (1992)
  • Ph.D., Caltech, Biology (1998)

Research & Scholarship

Current Research and Scholarly Interests


My research program is focused on three central questions in neurobiology. How do neuronal circuits assemble during development? How are the functions of these circuits maintained during adult life? How do such circuits mediate the complex computations essential to animal behavior? Our work exploits the interplay between the cells and genes that underpin these processes to define new molecular mechanisms that control neuronal connection specificity, synapse maintenance, and to characterize the computational roles of specific circuits. The long term goal of our program is to understand how the genome programs neural circuits across adult life to implement the computations that underpin innate behavior, using the visual system of the fruit fly as a model.

Teaching

2013-14 Courses


Postdoctoral Advisees


Graduate and Fellowship Programs


Publications

Journal Articles


  • Flies and humans share a motion estimation strategy that exploits natural scene statistics. Nature neuroscience Clark, D. A., Fitzgerald, J. E., Ales, J. M., Gohl, D. M., Silies, M. A., Norcia, A. M., Clandinin, T. R. 2014; 17 (2): 296-303

    Abstract

    Sighted animals extract motion information from visual scenes by processing spatiotemporal patterns of light falling on the retina. The dominant models for motion estimation exploit intensity correlations only between pairs of points in space and time. Moving natural scenes, however, contain more complex correlations. We found that fly and human visual systems encode the combined direction and contrast polarity of moving edges using triple correlations that enhance motion estimation in natural environments. Both species extracted triple correlations with neural substrates tuned for light or dark edges, and sensitivity to specific triple correlations was retained even as light and dark edge motion signals were combined. Thus, both species separately process light and dark image contrasts to capture motion signatures that can improve estimation accuracy. This convergence argues that statistical structures in natural scenes have greatly affected visual processing, driving a common computational strategy over 500 million years of evolution.

    View details for DOI 10.1038/nn.3600

    View details for PubMedID 24390225

  • A Network of Cadherin-Mediated Interactions Polarizes Growth Cones to Determine Targeting Specificity CELL Schwabe, T., Neuert, H., Clandinin, T. R. 2013; 154 (2): 351-364

    Abstract

    Neuronal growth cones select synaptic partners through interactions with multiple cell surfaces in their environment. Many of these interactions are adhesive, yet it is unclear how growth cones integrate adhesive cues to direct their movements. Here, we examine the mechanisms that enable photoreceptors in the Drosophila visual system to choose synaptic partners. We demonstrate that the classical cadherin, N-cadherin, and an atypical cadherin, Flamingo, act redundantly to instruct the targeting choices made by every photoreceptor axon. These molecules gradually bias the spatial distribution of growth cone filopodia, polarizing each growth cone toward its future synaptic target before direct contact with the target occurs. We demonstrate that these molecules are localized to distinct subcellular domains and create a network of adhesive interactions distributed across many growth cones. Because this network comprises multiple redundant interactions, a complex wiring diagram can be constructed with extraordinary fidelity, suggesting a general principle.

    View details for DOI 10.1016/j.cell.2013.06.011

    View details for Web of Science ID 000321950700012

    View details for PubMedID 23870124

  • Modular Use of Peripheral Input Channels Tunes Motion-Detecting Circuitry NEURON Silies, M., Gohl, D. M., Fisher, Y. E., Freifeld, L., Clark, D. A., Clandinin, T. R. 2013; 79 (1): 111-127

    Abstract

    In the visual system, peripheral processing circuits are often tuned to specific stimulus features. How this selectivity arises and how these circuits are organized to inform specific visual behaviors is incompletely understood. Using forward genetics and quantitative behavioral studies, we uncover an input channel to motion detecting circuitry in Drosophila. The second-order neuron L3 acts combinatorially with two previously known inputs, L1 and L2, to inform circuits specialized to detect moving light and dark edges. In vivo calcium imaging of L3, combined with neuronal silencing experiments, suggests a neural mechanism to achieve selectivity for moving dark edges. We further demonstrate that different innate behaviors, turning and forward movement, can be independently modulated by visual motion. These two behaviors make use of different combinations of input channels. Such modular use of input channels to achieve feature extraction and behavioral specialization likely represents a general principle in sensory systems.

    View details for DOI 10.1016/j.neuron.2013.04.029

    View details for Web of Science ID 000321802000013

    View details for PubMedID 23849199

  • Specific Kinematics and Motor-Related Neurons for Aversive Chemotaxis in Drosophila CURRENT BIOLOGY Gao, X. J., Potter, C. J., Gohl, D. M., Silies, M., Katsov, A. Y., Clandinin, T. R., Luo, L. 2013; 23 (13): 1163-1172

    Abstract

    Chemotaxis, the ability to direct movements according to chemical cues in the environment, is important for the survival of most organisms. The vinegar fly, Drosophila melanogaster, displays robust olfactory aversion and attraction, but how these behaviors are executed via changes in locomotion remains poorly understood. In particular, it is not clear whether aversion and attraction bidirectionally modulate a shared circuit or recruit distinct circuits for execution.Using a quantitative behavioral assay, we determined that both aversive and attractive odorants modulate the initiation and direction of turns but display distinct kinematics. Using genetic tools to perturb these behaviors, we identified specific populations of neurons required for aversion, but not for attraction. Inactivation of these populations of cells affected the completion of aversive turns, but not their initiation. Optogenetic activation of the same populations of cells triggered a locomotion pattern resembling aversive turns. Perturbations in both the ellipsoid body and the ventral nerve cord, two regions involved in motor control, resulted in defects in aversion.Aversive chemotaxis in vinegar flies triggers ethologically appropriate kinematics distinct from those of attractive chemotaxis and requires specific motor-related neurons.

    View details for DOI 10.1016/j.cub.2013.05.008

    View details for Web of Science ID 000321605600017

    View details for PubMedID 23770185

  • GABAergic Lateral Interactions Tune the Early Stages of Visual Processing in Drosophila NEURON Freifeld, L., Clark, D. A., Schnitzer, M. J., Horowitz, M. A., Clandinin, T. R. 2013; 78 (6): 1075-1089

    Abstract

    Early stages of visual processing must capture complex, dynamic inputs. While peripheral neurons often implement efficient encoding by exploiting natural stimulus statistics, downstream neurons are specialized to extract behaviorally relevant features. How do these specializations arise? We use two-photon imaging in Drosophila to characterize a first-order interneuron, L2, that provides input to a pathway specialized for detecting moving dark edges. GABAergic interactions, mediated in part presynaptically, create an antagonistic and anisotropic center-surround receptive field. This receptive field is spatiotemporally coupled, applying differential temporal processing to large and small dark objects, achieving significant specialization. GABAergic circuits also mediate OFF responses and balance these with responses to ON stimuli. Remarkably, the functional properties of L2 are strikingly similar to those of bipolar cells, yet emerge through different molecular and circuit mechanisms. Thus, evolution appears to have converged on a common strategy for processing visual information at the first synapse.

    View details for DOI 10.1016/j.neuron.2013.04.024

    View details for Web of Science ID 000321026900013

    View details for PubMedID 23791198

  • Mapping and cracking sensorimotor circuits in genetic model organisms. Neuron Clark, D. A., Freifeld, L., Clandinin, T. R. 2013; 78 (4): 583-595

    Abstract

    One central goal of systems neuroscience is to understand how neural circuits implement the computations that link sensory inputs to behavior. Work combining electrophysiological and imaging-based approaches to measure neural activity with pharmacological and electrophysiological manipulations has provided fundamental insights. More recently, genetic approaches have been used to monitor and manipulate neural activity, opening up new experimental opportunities and challenges. Here, we discuss issues associated with applying genetic approaches to circuit dissection in sensorimotor transformations, outlining important considerations for experimental design and considering how modeling can complement experimental approaches.

    View details for DOI 10.1016/j.neuron.2013.05.006

    View details for PubMedID 23719159

  • Apical-Basal Polarity Proteins Are Required Cell-Type Specifically to Direct Photoreceptor Morphogenesis CURRENT BIOLOGY Hwa, J. J., Clandinin, T. R. 2012; 22 (24): 2319-2324

    Abstract

    Insect photoreceptor function is dependent on precise placement of the rhabdomeres, elaborated apical domains specialized for capturing light, within each facet of a compound eye. In Diptera, an asymmetric arrangement of rhabdomeres, combined with a particular pattern of axonal connections, enhances light sensitivity through the principle of neural superposition. To achieve the necessary retinal geometry, different photoreceptors (R cells) have distinct shapes. The Crumbs and Bazooka complexes play critical roles in directing rhabdomere development, but whether they might direct cell-type-specific apical architectures is unknown. We demonstrate that while mutations in Bazooka complex members cause pleiotropic morphogenesis defects in all R cell subtypes, Crumbs (Crb) and Stardust (Sdt) function cell autonomously to direct early stages in rhabdomere assembly in specific subsets of R cells. This requirement is reflected in the cell-type-specific expression of Crb protein and demonstrates that Sdt and Crb can act independently to similar effect. These two genes are also required for zonula adherens (ZA) assembly but display an unusual pattern of cellular redundancy for this function, as each gene is required in only one of two adjoining cells. Our results provide a direct link between fate specification and morphogenetic patterning and suggest a model for ZA assembly.

    View details for DOI 10.1016/j.cub.2012.10.027

    View details for Web of Science ID 000312760400021

    View details for PubMedID 23159598

  • Loom-Sensitive Neurons Link Computation to Action in the Drosophila Visual System CURRENT BIOLOGY de Vries, S. E., Clandinin, T. R. 2012; 22 (5): 353-362

    Abstract

    Many animals extract specific cues from rich visual scenes to guide appropriate behaviors. Such cues include visual motion signals produced both by self-movement and by moving objects in the environment. The complexity of these signals requires neural circuits to link particular patterns of motion to specific behavioral responses.Through electrophysiological recordings, we characterize genetically identified neurons in the optic lobe of Drosophila that are specifically tuned to detect motion signals produced by looming objects on a collision course with the fly. Using a genetic manipulation to specifically silence these neurons, we demonstrate that signals from these cells are important for flies to efficiently initiate the loom escape response. Moreover, through targeted expression of channelrhodopsin in these cells, in flies that are blind, we reveal that optogenetic stimulation of these neurons is typically sufficient to elicit escape, even in the absence of any visual stimulus.In this compact nervous system, a small group of neurons that extract a specific visual cue from local motion inputs serve to trigger the ethologically appropriate behavioral response.

    View details for DOI 10.1016/j.cub.2012.01.007

    View details for Web of Science ID 000301330200015

    View details for PubMedID 22305754

  • Genetic Dissection Reveals Two Separate Retinal Substrates for Polarization Vision in Drosophila CURRENT BIOLOGY Wernet, M. F., Velez, M. M., Clark, D. A., Baumann-Klausener, F., Brown, J. R., Klovstad, M., Labhart, T., Clandinin, T. R. 2012; 22 (1): 12-20

    Abstract

    Linearly polarized light originates from atmospheric scattering or surface reflections and is perceived by insects, spiders, cephalopods, crustaceans, and some vertebrates. Thus, the neural basis underlying how this fundamental quality of light is detected is of broad interest. Morphologically unique, polarization-sensitive ommatidia exist in the dorsal periphery of many insect retinas, forming the dorsal rim area (DRA). However, much less is known about the retinal substrates of behavioral responses to polarized reflections.Drosophila exhibits polarotactic behavior, spontaneously aligning with the e-vector of linearly polarized light, when stimuli are presented either dorsally or ventrally. By combining behavioral experiments with genetic dissection and ultrastructural analyses, we show that distinct photoreceptors mediate the two behaviors: inner photoreceptors R7+R8 of DRA ommatidia are necessary and sufficient for dorsal polarotaxis, whereas ventral responses are mediated by combinations of outer and inner photoreceptors, both of which manifest previously unknown features that render them polarization sensitive.Drosophila uses separate retinal pathways for the detection of linearly polarized light emanating from the sky or from shiny surfaces. This work establishes a behavioral paradigm that will enable genetic dissection of the circuits underlying polarization vision.

    View details for DOI 10.1016/j.cub.2011.11.028

    View details for Web of Science ID 000299144200016

    View details for PubMedID 22177904

  • The cytoskeletal regulator Genghis khan is required for columnar target specificity in the Drosophila visual system DEVELOPMENT Gontang, A. C., Hwa, J. J., Mast, J. D., Schwabe, T., Clandinin, T. R. 2011; 138 (22): 4899-4909

    Abstract

    A defining characteristic of neuronal cell type is the growth of axons and dendrites into specific layers and columns of the brain. Although differences in cell surface receptors and adhesion molecules are known to cause differences in synaptic specificity, differences in downstream signaling mechanisms that determine cell type-appropriate targeting patterns are unknown. Using a forward genetic screen in Drosophila, we identify the GTPase effector Genghis khan (Gek) as playing a crucial role in the ability of a subset of photoreceptor (R cell) axons to innervate appropriate target columns. In particular, single-cell mosaic analyses demonstrate that R cell growth cones lacking Gek function grow to the appropriate ganglion, but frequently fail to innervate the correct target column. Further studies reveal that R cell axons lacking the activity of the small GTPase Cdc42 display similar defects, providing evidence that these proteins regulate a common set of processes. Gek is expressed in all R cells, and a detailed structure-function analysis reveals a set of regulatory domains with activities that restrict Gek function to the growth cone. Although Gek does not normally regulate layer-specific targeting, ectopic expression of Gek is sufficient to alter the targeting choices made by another R cell type, the targeting of which is normally Gek independent. Thus, specific regulation of cytoskeletal responses to targeting cues is necessary for cell type-appropriate synaptic specificity.

    View details for DOI 10.1242/dev.069930

    View details for Web of Science ID 000296576700009

    View details for PubMedID 22007130

  • Symmetries in stimulus statistics shape the form of visual motion estimators PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fitzgerald, J. E., Katsov, A. Y., Clandinin, T. R., Schnitzer, M. J. 2011; 108 (31): 12909-12914

    Abstract

    The estimation of visual motion has long been studied as a paradigmatic neural computation, and multiple models have been advanced to explain behavioral and neural responses to motion signals. A broad class of models, originating with the Reichardt correlator model, proposes that animals estimate motion by computing a temporal cross-correlation of light intensities from two neighboring points in visual space. These models provide a good description of experimental data in specific contexts but cannot explain motion percepts in stimuli lacking pairwise correlations. Here, we develop a theoretical formalism that can accommodate diverse stimuli and behavioral goals. To achieve this, we treat motion estimation as a problem of Bayesian inference. Pairwise models emerge as one component of the generalized strategy for motion estimation. However, correlation functions beyond second order enable more accurate motion estimation. Prior expectations that are asymmetric with respect to bright and dark contrast use correlations of both even and odd orders, and we show that psychophysical experiments using visual stimuli with symmetric probability distributions for contrast cannot reveal whether the subject uses odd-order correlators for motion estimation. This result highlights a gap in previous experiments, which have largely relied on symmetric contrast distributions. Our theoretical treatment provides a natural interpretation of many visual motion percepts, indicates that motion estimation should be revisited using a broader class of stimuli, demonstrates how correlation-based motion estimation is related to stimulus statistics, and provides multiple experimentally testable predictions.

    View details for DOI 10.1073/pnas.1015680108

    View details for Web of Science ID 000293385700073

    View details for PubMedID 21768376

  • Defining the Computational Structure of the Motion Detector in Drosophila NEURON Clark, D. A., Bursztyn, L., Horowitz, M. A., Schnitzer, M. J., Clandinin, T. R. 2011; 70 (6): 1165-1177

    Abstract

    Many animals rely on visual motion detection for survival. Motion information is extracted from spatiotemporal intensity patterns on the retina, a paradigmatic neural computation. A phenomenological model, the Hassenstein-Reichardt correlator (HRC), relates visual inputs to neural activity and behavioral responses to motion, but the circuits that implement this computation remain unknown. By using cell-type specific genetic silencing, minimal motion stimuli, and in vivo calcium imaging, we examine two critical HRC inputs. These two pathways respond preferentially to light and dark moving edges. We demonstrate that these pathways perform overlapping but complementary subsets of the computations underlying the HRC. A numerical model implementing differential weighting of these operations displays the observed edge preferences. Intriguingly, these pathways are distinguished by their sensitivities to a stimulus correlation that corresponds to an illusory percept, "reverse phi," that affects many species. Thus, this computational architecture may be widely used to achieve edge selectivity in motion detection.

    View details for DOI 10.1016/j.neuron.2011.05.023

    View details for Web of Science ID 000292410700014

    View details for PubMedID 21689602

  • A versatile in vivo system for directed dissection of gene expression patterns NATURE METHODS Gohl, D. M., Silies, M. A., Gao, X. J., Bhalerao, S., Luongo, F. J., Lin, C., Potter, C. J., Clandinin, T. R. 2011; 8 (3): 231-U71

    Abstract

    Tissue-specific gene expression using the upstream activating sequence (UAS)–GAL4 binary system has facilitated genetic dissection of many biological processes in Drosophila melanogaster. Refining GAL4 expression patterns or independently manipulating multiple cell populations using additional binary systems are common experimental goals. To simplify these processes, we developed a convertible genetic platform, the integrase swappable in vivo targeting element (InSITE) system. This approach allows GAL4 to be replaced with any other sequence, placing different genetic effectors under the control of the same regulatory elements. Using InSITE, GAL4 can be replaced with LexA or QF, allowing an expression pattern to be repurposed. GAL4 can also be replaced with GAL80 or split-GAL4 hemi-drivers, allowing intersectional approaches to refine expression patterns. The exchanges occur through efficient in vivo manipulations, making it possible to generate many swaps in parallel. This system is modular, allowing future genetic tools to be easily incorporated into the existing framework.

    View details for DOI 10.1038/NMETH.1561

    View details for Web of Science ID 000287734800014

    View details for PubMedID 21473015

  • Complex interactions amongst N-cadherin, DLAR, and Liprin-alpha regulate Drosophila photoreceptor axon targeting DEVELOPMENTAL BIOLOGY Prakash, S., McLendon, H. M., Dubreuil, C. I., Ghose, A., Hwa, J., Dennehy, K. A., Tomalty, K. M., Clark, K. L., Van Vactor, D., Clandinin, T. R. 2009; 336 (1): 10-19

    Abstract

    The formation of stable adhesive contacts between pre- and post-synaptic neurons represents the initial step in synapse assembly. The cell adhesion molecule N-cadherin, the receptor tyrosine phosphatase DLAR, and the scaffolding molecule Liprin-alpha play critical, evolutionarily conserved roles in this process. However, how these proteins signal to the growth cone and are themselves regulated remains poorly understood. Using Drosophila photoreceptors (R cells) as a model, we evaluate genetic and physical interactions among these three proteins. We demonstrate that DLAR function in this context is independent of phosphatase activity but requires interactions mediated by its intracellular domain. Genetic studies reveal both positive and, surprisingly, inhibitory interactions amongst all three genes. These observations are corroborated by biochemical studies demonstrating that DLAR physically associates via its phosphatase domain with N-cadherin in Drosophila embryos. Together, these data demonstrate that N-cadherin, DLAR, and Liprin-alpha function in a complex to regulate adhesive interactions between pre- and post-synaptic cells and provide a novel mechanism for controlling the activity of Liprin-alpha in the developing growth cone.

    View details for DOI 10.1016/j.ydbio.2009.09.016

    View details for Web of Science ID 000271849000002

    View details for PubMedID 19766621

  • Making a visual map: mechanisms and molecules CURRENT OPINION IN NEUROBIOLOGY Clandinin, T. R., Feldheim, D. A. 2009; 19 (2): 174-180

    Abstract

    Visual system development utilizes global and local cues to assemble a topographic map of the visual world, arranging synaptic connections into columns and layers. Recent genetic studies have provided new insights into the mechanisms that underlie these processes. In flies, a precise temporal sequence of neural differentiation provides a global organizing cue; in vertebrates, gradients of ephrin-mediated signals, acting with neurotrophin co-receptors and neural activity, play crucial roles. In flies and mice, neural processes tile into precise arrays through homotypic, repulsive interactions, autocrine signals, and cell-intrinsic mechanisms. Laminar targeting specificity is achieved through temporally regulated cell-cell adhesion, as well as combinatorial expression of specific adhesion molecules. Future studies will define the interactions between these global and local cues.

    View details for DOI 10.1016/j.conb.2009.04.011

    View details for Web of Science ID 000269108900011

    View details for PubMedID 19481440

  • More than just glue The diverse roles of cell adhesion molecules in the Drosophila nervous system CELL ADHESION & MIGRATION Schwabe, T., Gontang, A. C., Clandinin, T. R. 2009; 3 (1): 36-42

    Abstract

    Cell adhesion is the fundamental driving force that establishes complex cellular architectures, with the nervous system offering a striking, sophisticated case study. Developing neurons adhere to neighboring neurons, their synaptic partners, and to glial cells. These adhesive interactions are required in a diverse array of contexts, including cell migration, axon guidance and targeting, as well as synapse formation and physiology. Forward and reverse genetic screens in the fruit fly Drosophila have uncovered several adhesion molecules that are required for neural development, and detailed cell biological analyses are beginning to unravel how these factors shape nervous system connectivity. Here we review our current understanding of the most prominent of these adhesion factors and their modes of action.

    View details for DOI 10.4161/cam.3.1.6918

    View details for Web of Science ID 000208234200010

    View details for PubMedID 19372748

  • Reactive oxygen species act remotely to cause synapse loss in a Drosophila model of developmental mitochondrial encephalopathy DEVELOPMENT Mast, J. D., Tomalty, K. M., Vogel, H., Clandinin, T. R. 2008; 135 (15): 2669-2679

    Abstract

    Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases, yet its precise role in disease pathology remains unclear. To examine this link directly, we subtly perturbed electron transport chain function in the Drosophila retina, creating a model of Leigh Syndrome, an early-onset neurodegenerative disorder. Using mutations that affect mitochondrial complex II, we demonstrate that mild disruptions of mitochondrial function have no effect on the initial stages of photoreceptor development, but cause degeneration of their synapses and cell bodies in late pupal and adult animals. In this model, synapse loss is caused by reactive oxygen species (ROS) production, not energy depletion, as ATP levels are normal in mutant photoreceptors, and both pharmacological and targeted genetic manipulations that reduce ROS levels prevent synapse degeneration. Intriguingly, these manipulations of ROS uncouple synaptic effects from degenerative changes in the cell body, suggesting that mitochondrial dysfunction activates two genetically separable processes, one that induces morphological changes in the cell body, and another that causes synapse loss. Finally, by blocking mitochondrial trafficking into the axon using a mutation affecting a mitochondrial transport complex, we find that ROS action restricted to the cell body is sufficient to cause synaptic degeneration, demonstrating that ROS need not act locally at the synapse. Thus, alterations in electron transport chain function explain many of the neurodegenerative changes seen in both early- and late-onset disorders.

    View details for DOI 10.1242/dev.020644

    View details for Web of Science ID 000257557200018

    View details for PubMedID 18599508

  • Motion processing streams in Drosophila are behaviorally specialized NEURON Katsov, A. Y., Clandinin, T. R. 2008; 59 (2): 322-335

    Abstract

    Motion vision is an ancient faculty, critical to many animals in a range of ethological contexts, the underlying algorithms of which provide central insights into neural computation. However, how motion cues guide behavior is poorly understood, as the neural circuits that implement these computations are largely unknown in any organism. We develop a systematic, forward genetic approach using high-throughput, quantitative behavioral analyses to identify the neural substrates of motion vision in Drosophila in an unbiased fashion. We then delimit the behavioral contributions of both known and novel circuit elements. Contrary to expectation from previous studies, we find that orienting responses to motion are shaped by at least two neural pathways. These pathways are sensitive to different visual features, diverge immediately postsynaptic to photoreceptors, and are coupled to distinct behavioral outputs. Thus, behavioral responses to complex stimuli can rely on surprising neural specialization from even the earliest sensory processing stages.

    View details for DOI 10.1016/j.neuron.2008.05.022

    View details for Web of Science ID 000258252700016

    View details for PubMedID 18667159

  • Neural circuitry: Seeing the parts that make the picture CURRENT BIOLOGY Velez, M. M., Clandinin, T. R. 2008; 18 (9): R378-R380

    Abstract

    What are the neural correlates of vision? A recent study on Drosophila has described the incredible neuronal diversity in the fly visual system, and traced the circuits that underlie color vision.

    View details for Web of Science ID 000255668400014

    View details for PubMedID 18460316

  • The cadherin flamingo mediates level-dependent interactions that guide photoreceptor target choice in Drosophila NEURON Chen, P., Clandinin, T. R. 2008; 58 (1): 26-33

    Abstract

    Quantitative differences in cadherin activity have been proposed to play important roles in patterning connections between pre- and postsynaptic neurons. However, no examples of such a function have yet been described, and the mechanisms that would allow such differences to direct growth cones to specific synaptic targets are unknown. In the Drosophila visual system, photoreceptors are genetically programmed to make a complex, stereotypic set of synaptic connections. Here we show that the atypical cadherin Flamingo functions as a short-range, homophilic signal, passing between specific R cell growth cones to influence their choice of postsynaptic partners. We find that individual growth cones are sensitive to differences in Flamingo activity through opposing interactions between neighboring cells and require these interactions to be balanced in order to extend along the appropriate trajectory.

    View details for DOI 10.1016/j.neuron.2008.01.007

    View details for Web of Science ID 000254946200007

    View details for PubMedID 18400160

  • The agrin/perlecan-related protein eyes shut is essential for epithelial lumen formation in the Drosophila retina DEVELOPMENTAL CELL Husain, N., Pellikka, M., Hong, H., Klimentova, T., Choe, K., Clandinin, T. R., Tepass, U. 2006; 11 (4): 483-493

    Abstract

    The formation of epithelial lumina is a fundamental process in animal development. Each ommatidium of the Drosophila retina forms an epithelial lumen, the interrhabdomeral space, which has a critical function in vision as it optically isolates individual photoreceptor cells. Ommatidia containing an interrhabdomeral space have evolved from ancestral insect eyes that lack this lumen, as seen, for example, in bees. In a genetic screen, we identified eyes shut (eys) as a gene that is essential for the formation of matrix-filled interrhabdomeral space. Eys is closely related to the proteoglycans agrin and perlecan and secreted by photoreceptor cells into the interrhabdomeral space. The honeybee ortholog of eys is not expressed in photoreceptors, raising the possibility that recruitment of eys expression has made an important contribution to insect eye evolution. Our findings show that the secretion of a proteoglycan into the apical matrix is critical for the formation of epithelial lumina in the fly retina.

    View details for DOI 10.1016/j.devcel.2006.08.012

    View details for Web of Science ID 000241123300010

    View details for PubMedID 17011488

  • Activity-independent prespecification of synaptic partners in the visual map of Drosophila CURRENT BIOLOGY Hiesinger, P. R., Zhai, R. G., Zhou, Y., Koh, T., Mehta, S. Q., Schulze, K. L., Cao, Y., Verstreken, P., Clandinin, T. R., Fischbach, K., Meinertzhagen, I. A., Bellen, H. J. 2006; 16 (18): 1835-1843

    Abstract

    Specifying synaptic partners and regulating synaptic numbers are at least partly activity-dependent processes during visual map formation in all systems investigated to date . In Drosophila, six photoreceptors that view the same point in visual space have to be sorted into synaptic modules called cartridges in order to form a visuotopically correct map . Synapse numbers per photoreceptor terminal and cartridge are both precisely regulated . However, it is unknown whether an activity-dependent mechanism or a genetically encoded developmental program regulates synapse numbers. We performed a large-scale quantitative ultrastructural analysis of photoreceptor synapses in mutants affecting the generation of electrical potentials (norpA, trp;trpl), neurotransmitter release (hdc, syt), vesicle endocytosis (synj), the trafficking of specific guidance molecules during photoreceptor targeting (sec15), a specific guidance receptor required for visual map formation (Dlar), and 57 other novel synaptic mutants affecting 43 genes. Remarkably, in all these mutants, individual photoreceptors form the correct number of synapses per presynaptic terminal independently of cartridge composition. Hence, our data show that each photoreceptor forms a precise and constant number of afferent synapses independently of neuronal activity and partner accuracy. Our data suggest cell-autonomous control of synapse numbers as part of a developmental program of activity-independent steps that lead to a "hard-wired" visual map in the fly brain.

    View details for DOI 10.1016/j.cub.2006.07.047

    View details for Web of Science ID 000240719800029

    View details for PubMedID 16979562

  • Liprin-alpha is required for photoreceptor target selection in Drosophila PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Choe, K., Prakash, S., Bright, A., Clandinin, T. R. 2006; 103 (31): 11601-11606

    Abstract

    Classical cadherin-mediated interactions between axons and dendrites are critical to target selection and synapse assembly. However, the molecular mechanisms by which these interactions are controlled are incompletely understood. In the Drosophila visual system, N-cadherin is required in both photoreceptor (R cell) axons and their targets to mediate stabilizing interactions required for R cell target selection. Here we identify the scaffolding protein Liprin-alpha as a critical component in this process. We isolated mutations in Liprin-alpha in a genetic screen for mutations affecting the pattern of synaptic connections made by R1-R6 photoreceptors. Using eye-specific mosaics, we demonstrate a previously undescribed, axonal function for Liprin-alpha in target selection: Liprin-alpha is required to be cell-autonomous in all subtypes of R1-R6 cells for their axons to reach their targets. Because Liprin-alpha, the receptor tyrosine phosphatase LAR, and N-cadherin share qualitatively similar mutant phenotypes in R1-R6 cells and are coexpressed in R cells and their synaptic targets, we infer that these three genes act at the same step in the targeting process. However, unlike N-cadherin, neither Liprin-alpha nor LAR is required postsynaptically for R cells to project to their correct targets. Thus, these two proteins, unlike N-cadherin, are functionally asymmetric between axons and dendrites. We propose that the adhesive mechanisms that link pre- and postsynaptic cells before synapse formation may be differentially regulated in these two compartments.

    View details for DOI 10.1073/pnas.0601185103

    View details for Web of Science ID 000239616400033

    View details for PubMedID 16864799

  • Insect vision: Remembering the shape of things CURRENT BIOLOGY Katsov, A., Clandinin, T. R. 2006; 16 (10): R369-R371

    Abstract

    How does the nervous system store a newly experienced visual pattern, and how is that pattern subsequently made available for recognition? Recent work in Drosophila suggests that specific pattern features are stored separately in the nervous system.

    View details for DOI 10.1016/j.cub.2006.04.006

    View details for Web of Science ID 000237874500016

    View details for PubMedID 16713946

  • The mechanisms and molecules that connect photoreceptor axons to their targets in Drosophila SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY Mast, J. D., Prakash, S., Chen, P. L., Clandinin, T. R. 2006; 17 (1): 42-49

    Abstract

    The development of the Drosophila visual system provides a framework for investigating how circuits assemble. A sequence of reciprocal interactions amongst photoreceptors, target neurons and glia creates a precise pattern of connections while reducing the complexity of the targeting process. Both afferent-afferent and afferent-target interactions are required for photoreceptor (R cell) axons to select appropriate synaptic partners. With the identification of some critical cell adhesion and signaling molecules, the logic by which axons make choices amongst alternate synaptic partners is becoming clear. These studies also provide an opportunity to examine the molecular basis of neural circuit evolution.

    View details for DOI 10.1016/j.semcdb.2005.11.004

    View details for Web of Science ID 000236492800006

    View details for PubMedID 16337412

  • An isoform-specific allele of Drosophila N-cadherin disrupts a late step of R7 targeting PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Nern, A., Nguyen, L. V., Herman, T., Prakash, S., Clandinin, T. R., Zipursky, S. L. 2005; 102 (36): 12944-12949

    Abstract

    Drosophila N-cadherin is required for the formation of precise patterns of connections in the fly brain. Alternative splicing is predicted to give rise to 12 N-cadherin isoforms. We identified an N-cadherin allele, N-cad(18Astop), that eliminates the six isoforms containing alternative exon 18A and demonstrate that it strongly disrupts the connections of R7 photoreceptor neurons. During the first half of pupal development, N-cadherin is required for R7 growth cones to terminate within a temporary target layer in the medulla. N-cadherin isoforms containing exon 18B are sufficient for this initial targeting. By contrast, 18A isoforms are preferentially expressed in R7 during the second half of pupal development and are necessary for R7 to terminate in the appropriate synaptic layer in the medulla neuropil. Transgene rescue experiments suggest that differences in isoform expression, rather than biochemical differences between isoforms, underlie the 18A isoform requirement in R7 neurons.

    View details for DOI 10.1073/pnas.0502888102

    View details for Web of Science ID 000231716700054

    View details for PubMedID 16123134

  • Surprising twists to exocyst function NEURON Clandinin, T. R. 2005; 46 (2): 164-166

    Abstract

    What do neurons use the exocyst complex for? In this issue of Neuron, using mutations in one exocyst component, Mehta et al. reach the surprising conclusion that exocyst function is divisible: different components play distinct roles. These studies also suggest that the exocyst may regulate membrane insertion of cell adhesion molecules required for synaptic partner choice.

    View details for DOI 10.1016/j.neuron.2005.04.003

    View details for Web of Science ID 000228674800002

    View details for PubMedID 15848794

  • Drosophila N-cadherin mediates an attractive interaction between photoreceptor axons and their targets NATURE NEUROSCIENCE Prakash, S., Caldwell, J. C., Eberl, D. F., Clandinin, T. R. 2005; 8 (4): 443-450

    Abstract

    Classical cadherins have been proposed to mediate interactions between pre- and postsynaptic cells that are necessary for synapse formation. We provide the first direct, genetic evidence in favor of this model by examining the role of N-cadherin in controlling the pattern of synaptic connections made by photoreceptor axons in Drosophila. N-cadherin is required in both individual photoreceptors and their target neurons for photoreceptor axon extension. Cell-by-cell reconstruction of wild-type photoreceptor axons extending within mosaic patches of mutant target cells shows that N-cadherin mediates attractive interactions between photoreceptors and their targets. This interaction is not limited to those cells that will become the synaptic partners of photoreceptors. Multiple N-cadherin isoforms are produced, but single isoforms can substitute for endogenous N-cadherin activity. We propose that N-cadherin mediates a homophilic, attractive interaction between photoreceptor growth cones and their targets that precedes synaptic partner choice.

    View details for DOI 10.1038/nn1415

    View details for Web of Science ID 000228040400014

    View details for PubMedID 15735641

  • Thinking about visual behavior; Learning about photoreceptor function CURRENT TOPICS IN DEVELOPMENTAL BIOLOGY, VOL 69 Choe, K. M., Clandinin, T. R. 2005; 69: 187-?

    Abstract

    Visual behavioral assays in Drosophila melanogaster were initially developed to explore the genetic control of behavior, but have a rich history of providing conceptual openings into diverse questions in cell and developmental biology. Here, we briefly summarize the early efforts to employ three of these behaviors: phototaxis, the UV-visible light choice, and the optomotor response. We then discuss how each of these assays has expanded our understanding of neuronal connection specificity and synaptic function. All of these studies have contributed to the development of sophisticated tools for manipulating gene expression, assessing cell fate specification, and visualizing neuronal development. With these tools in hand, the field is now poised to return to the original goal of understanding visual behavior using genetic approaches.

    View details for DOI 10.1016/S0070-2153(05)69007-2

    View details for Web of Science ID 000233986700007

    View details for PubMedID 16243600

  • The protocadherin Flamingo is required for axon target selection in the Drosophila visual system NATURE NEUROSCIENCE Lee, R. C., Clandinin, T. R., Lee, C. H., Chen, P. L., Meinertzhagen, I. A., Zipursky, S. L. 2003; 6 (6): 557-563

    Abstract

    Photoreceptor neurons (R cells) in the Drosophila visual system elaborate a precise map of visual space in the brain. The eye contains some 750 identical modules called ommatidia, each containing eight photoreceptor cells (R1-R8). Cells R1-R6 synapse in the lamina; R7 and R8 extend through the lamina and terminate in the underlying medulla. In a screen for visual behavior mutants, we identified alleles of flamingo (fmi) that disrupt the precise maps elaborated by these neurons. These mutant R1-R6 neurons select spatially inappropriate targets in the lamina. During target selection, Flamingo protein is dynamically expressed in R1-R6 growth cones. Loss of fmi function in R cells also disrupts the local pattern of synaptic terminals in the medulla, and Flamingo is transiently expressed in R8 axons as they enter the target region. We propose that Flamingo-mediated interactions between R-cell growth cones within the target field regulate target selection.

    View details for DOI 10.1038/nn1063

    View details for Web of Science ID 000183140400011

    View details for PubMedID 12754514

  • Making connections in the fly visual system NEURON Clandinin, T. R., Zipursky, S. L. 2002; 35 (5): 827-841

    Abstract

    Understanding the molecular mechanisms that regulate formation of precise patterns of neuronal connections within the central nervous system remains a challenging problem in neurobiology. Genetic studies in worms and flies and molecular studies in vertebrate systems have led to an increasingly sophisticated understanding of how growth cones navigate toward their targets and form topographic maps. Considerably less is known about how growth cones recognize their cellular targets and form synapses with them. Here, we review connection formation in the fly visual system, the methodological approaches used to study it, and recent progress in uncovering the molecular basis of connection specificity.

    View details for Web of Science ID 000177779800007

    View details for PubMedID 12372279

  • Drosophila LAR regulates R1-R6 and R7 target specificity in the visual system NEURON Clandinin, T. R., Lee, C. H., Herman, T., Lee, R. C., Yang, A. Y., Ovasapyan, S., Zipursky, S. L. 2001; 32 (2): 237-248

    Abstract

    Different classes of photoreceptor neurons (R cells) in the Drosophila compound eye connect to specific targets in the optic lobe. Using a behavioral screen, we identified LAR, a receptor tyrosine phosphatase, as being required for R cell target specificity. In LAR mutant mosaic eyes, R1-R6 cells target to the lamina correctly, but fail to choose the correct pattern of target neurons. Although mutant R7 axons initially project to the correct layer of the medulla, they retract into inappropriate layers. Using single cell mosaics, we demonstrate that LAR controls targeting of R1-R6 and R7 in a cell-autonomous fashion. The phenotypes of LAR mutant R cells are strikingly similar to those seen in N-cadherin mutants.

    View details for Web of Science ID 000171893700009

    View details for PubMedID 11683994

  • N-cadherin regulates target specificity in the Drosophila visual system NEURON Lee, C. H., Herman, T., Clandinin, T. R., LEE, R., Zipursky, S. L. 2001; 30 (2): 437-450

    Abstract

    Using visual behavioral screens in Drosophila, we identified multiple alleles of N-cadherin. Removal of N-cadherin selectively from photoreceptor neurons (R cells) causes deficits in specific visual behaviors that correlate with disruptions in R cell connectivity. These defects include disruptions in the pattern of neuronal connections made by all three classes of R cells (R1-R6, R7, and R8). N-cadherin is expressed in both R cell axons and their targets. By inducing mitotic recombination in a subclass of eye progenitors, we generated mutant R7 axons surrounded by largely wild-type R cell axons and a wild-type target. R7 axons lacking N-cadherin mistarget to the R8 recipient layer. We consider the implications of these findings in the context of the proposed role for cadherins in target specificity.

    View details for Web of Science ID 000168962000016

    View details for PubMedID 11395005

  • Afferent growth cone interactions control synaptic specificity in the Drosophila visual system NEURON Clandinin, T. R., Zipursky, S. L. 2000; 28 (2): 427-436

    Abstract

    In the Drosophila compound eye, photoreceptors (R cells) that respond to light from the same point in space are distributed across the retina and connect to the same target neurons. This complex connectivity pattern reconstructs visual space in the first optic ganglion, the lamina. We have used mutations that delete specific R cell subtypes or alter their retinal organization to define the cellular mechanisms that generate this pattern. R cell axons are programmed to search for targets within a local region in the lamina but their selection of appropriate postsynaptic targets requires specific interactions among R cell growth cones. The orientation of the projections is controlled both by the spatial arrangement of R cells in the retina and by cues in the target.

    View details for Web of Science ID 000165493700018

    View details for PubMedID 11144353

  • Hedgehog and spitz: Making a match between photoreceptor axons and their targets CELL Salecker, I., Clandinin, T. R., Zipursky, S. L. 1998; 95 (5): 587-590

    View details for Web of Science ID 000077253700004

    View details for PubMedID 9845360

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