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Kang Shen - One of the best experts on this subject based on the ideXlab platform.
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Cellular and molecular mechanisms of Synaptic Specificity.
Annual review of cell and developmental biology, 2014Co-Authors: Shaul Yogev, Kang ShenAbstract:Precise connectivity in neuronal circuits is a prerequisite for proper brain function. The dauntingly complex environment encountered by axons and dendrites, even after navigation to their target area, prompts the question of how Specificity of Synaptic connections arises during development. We review developmental strategies and molecular mechanisms that are used by neurons to ensure their precise matching of pre- and postSynaptic elements. The emerging theme is that each circuit uses a combination of simple mechanisms to achieve its refined, often complex connectivity pattern. At increasing levels of resolution, from lamina choice to subcellular targeting, similar signaling concepts are reemployed to narrow the choice of potential matches. Temporal control over synapse development and synapse elimination further ensures the Specificity of connections in the nervous system.
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Genetic dissection of Synaptic Specificity.
Current opinion in neurobiology, 2010Co-Authors: Celine I. Maeder, Kang ShenAbstract:Nervous systems are built of a myriad of neurons connected by an even larger number of synapses. While it has been long known that neurons specifically select their Synaptic partners among many possible choices during development, we only begin to understand how they make those decisions. Recent findings have started to elucidate the molecular mechanisms underlying Synaptic target selection including positive as well as negative cues from Synaptic partners, intermediate targets and surrounding tissues. Furthermore, emerging evidence suggests that Synaptic connections are not only formed among specific sets of neurons, but also targeted to specific subcellular domains. Finally, spatial and temporal transcriptional regulation of these molecular cues represents an additional, versatile mechanism to provide wiring Specificity.
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Molecular mechanisms of Synaptic Specificity.
Molecular and cellular neurosciences, 2009Co-Authors: Milica A. Margeta, Kang ShenAbstract:Synapses are specialized junctions that mediate information flow between neurons and their targets. A striking feature of the nervous system is the Specificity of its Synaptic connections: an individual neuron will form synapses only with a small subset of available preSynaptic and postSynaptic partners. Synaptic Specificity has been classically thought to arise from homophilic or heterophilic interactions between adhesive molecules acting across the Synaptic cleft. Over the past decade, many new mechanisms giving rise to Synaptic Specificity have been identified. Synapses can be specified by secreted molecules that promote or inhibit synaptogenesis, and their source can be a neighboring guidepost cell, not just preSynaptic and postSynaptic neurons. Furthermore, lineage, fate, and timing of development can also play critical roles in shaping neural circuits. Future work utilizing large-scale screens will aim to elucidate the full scope of cellular mechanisms and molecular players that can give rise to Synaptic Specificity.
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Functional dissection of SYG-1 and SYG-2, cell adhesion molecules required for selective synaptogenesis in C. elegans.
Molecular and cellular neurosciences, 2008Co-Authors: Daniel L. Chao, Kang ShenAbstract:Cell adhesion molecules of the Immunoglobulin superfamily (IgCAMs) play diverse functions during neural development. Previously, we have identified SYG-1/Neph1 and SYG-2/Nephrin, IgCAMs necessary for Synaptic Specificity in Caenorhabditis elegans. Here, we conduct an in vivo structure-function analysis of SYG-1 and SYG-2 to identify domains of SYG-1 and SYG-2 necessary for heterophilic binding as well as Synaptic Specificity. We find the first Ig domain of SYG-1 and the first 5 Ig domains of SYG-2 are necessary and sufficient for their binding in vivo, as well as for synapse formation. We also find the SYG-2 cytoplasmic domain is required for SYG-2 subcellular trafficking, while the intracellular region of SYG-1 is required for Synaptic function at earlier developmental stages, but is dispensable for later stages. This study defines the domain requirements for SYG-1/SYG-2 heterophilic binding and suggests that unknown SYG-1 extracellular interactors may play a role in SYG-1-mediated Synaptic Specificity.
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Building a synapse: lessons on Synaptic Specificity and preSynaptic assembly from the nematode C. elegans.
Current opinion in neurobiology, 2008Co-Authors: Milica A. Margeta, Kang Shen, Brock GrillAbstract:Synapses are specialized sites of cell contact that mediate information flow between neurons and their targets. Genetic screens in the nematode C. elegans have led to the discovery of a number of molecules required for synapse patterning and assembly. Recent studies have demonstrated the importance of guidepost cells in the positioning of preSynaptic sites at specific locations along the axon. Interestingly, these guideposts can promote or inhibit synapse formation, and do so by utilizing transmembrane adhesion molecules or secreted factors that act over relatively larger distances. Once the decision of where to build a preSynaptic terminal has been made, key molecules are recruited to assemble Synaptic vesicles and active zone proteins at that site. Multiple steps of this process are regulated by ubiquitin ligase complexes. Interestingly, some of the molecules involved in preSynaptic assembly also play roles in regulating axon polarity and outgrowth, suggesting that different neurodevelopmental processes are molecularly integrated.
Silvia Arber - One of the best experts on this subject based on the ideXlab platform.
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monoSynaptic rabies virus reveals premotor network organization and Synaptic Specificity of cholinergic partition cells
Neuron, 2010Co-Authors: Marco Tripodi, Anna E Stepien, Silvia ArberAbstract:Movement is the behavioral output of neuronal activity in the spinal cord. Motor neurons are grouped into motor neuron pools, the functional units innervating individual muscles. Here we establish an anatomical rabies virus-based connectivity assay in early postnatal mice. We employ it to study the connectivity scheme of premotor neurons, the neuronal cohorts monoSynaptically connected to motor neurons, unveiling three aspects of organization. First, motor neuron pools are connected to segmentally widely distributed yet stereotypic interneuron populations, differing for pools innervating functionally distinct muscles. Second, depending on subpopulation identity, interneurons take on local or segmentally distributed positions. Third, cholinergic partition cells involved in the regulation of motor neuron excitability segregate into ipsilaterally and bilaterally projecting populations, the latter exhibiting preferential connections to functionally equivalent motor neuron pools bilaterally. Our study visualizes the widespread yet precise nature of the connectivity matrix for premotor interneurons and reveals exquisite Synaptic Specificity for bilaterally projecting cholinergic partition cells.
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Specificity of sensory motor connections encoded by sema3e plxnd1 recognition
Nature, 2009Co-Authors: Eline Pechovrieseling, Yutaka Yoshida, Markus Sigrist, Thomas M Jessell, Silvia ArberAbstract:Reflex circuits are carefully and specifically formed between sensory and motor neurons based on the class of sensory cell and the muscle type innervated by the motor neuron. Pecho-Vrieseling et al. now report that this fine Synaptic Specificity is mediated by selective expression of Sema3e and PlexinD1 by specific motor and sensory neuron populations, respectively. Signalling cascades activated by these molecular repellents affected not only monoSynaptic circuit anatomy, but also circuit function. Reflex circuits are specifically formed between sensory and motor neurons based on the class of sensory cell and the muscle type innervated by the motor neuron. Here, this fine Synaptic Specificity is found to be mediated by selective expression of the class 3 semaphorin Sema3e and its high-affinity receptor plexin D1 (Plxnd1) by specific motor and sensory neuron populations, respectively. Spinal reflexes are mediated by Synaptic connections between sensory afferents and motor neurons1,2,3. The organization of these circuits shows several levels of Specificity. Only certain classes of proprioceptive sensory neurons make direct, monoSynaptic connections with motor neurons4. Those that do are bound by rules of motor pool Specificity: they form strong connections with motor neurons supplying the same muscle, but avoid motor pools supplying antagonistic muscles1,5,6,7. This pattern of connectivity is initially accurate and is maintained in the absence of activity8, implying that wiring Specificity relies on the matching of recognition molecules on the surface of sensory and motor neurons. However, determinants of fine Synaptic Specificity here, as in most regions of the central nervous system, have yet to be defined. To address the origins of Synaptic Specificity in these reflex circuits we have used molecular genetic methods to manipulate recognition proteins expressed by subsets of sensory and motor neurons. We show here that a recognition system involving expression of the class 3 semaphorin Sema3e by selected motor neuron pools, and its high-affinity receptor plexin D1 (Plxnd1) by proprioceptive sensory neurons, is a critical determinant of Synaptic Specificity in sensory–motor circuits in mice. Changing the profile of Sema3e–Plxnd1 signalling in sensory or motor neurons results in functional and anatomical rewiring of monoSynaptic connections, but does not alter motor pool Specificity. Our findings indicate that patterns of monoSynaptic connectivity in this prototypic central nervous system circuit are constructed through a recognition program based on repellent signalling.
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Specificity of sensory–motor connections encoded by Sema3e–Plxnd1 recognition
Nature, 2009Co-Authors: Eline Pecho-vrieseling, Yutaka Yoshida, Markus Sigrist, Thomas M Jessell, Silvia ArberAbstract:Spinal reflexes are mediated by Synaptic connections between sensory afferents and motor neurons. The organization of these circuits shows several levels of Specificity. Only certain classes of proprioceptive sensory neurons make direct, monoSynaptic connections with motor neurons. Those that do are bound by rules of motor pool Specificity: they form strong connections with motor neurons supplying the same muscle, but avoid motor pools supplying antagonistic muscles. This pattern of connectivity is initially accurate and is maintained in the absence of activity, implying that wiring Specificity relies on the matching of recognition molecules on the surface of sensory and motor neurons. However, determinants of fine Synaptic Specificity here, as in most regions of the central nervous system, have yet to be defined. To address the origins of Synaptic Specificity in these reflex circuits we have used molecular genetic methods to manipulate recognition proteins expressed by subsets of sensory and motor neurons. We show here that a recognition system involving expression of the class 3 semaphorin Sema3e by selected motor neuron pools, and its high-affinity receptor plexin D1 (Plxnd1) by proprioceptive sensory neurons, is a critical determinant of Synaptic Specificity in sensory-motor circuits in mice. Changing the profile of Sema3e-Plxnd1 signalling in sensory or motor neurons results in functional and anatomical rewiring of monoSynaptic connections, but does not alter motor pool Specificity. Our findings indicate that patterns of monoSynaptic connectivity in this prototypic central nervous system circuit are constructed through a recognition program based on repellent signalling.
Yutaka Yoshida - One of the best experts on this subject based on the ideXlab platform.
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Expression of the immunoglobulin superfamily cell adhesion molecules in the developing spinal cord and dorsal root ganglion.
PloS one, 2015Co-Authors: Fumiyasu Imai, Yoshihiro Yoshihara, Kensaku Mori, In-jung Kim, Hiroko Fujita, Kei Ichi Katayama, Yutaka YoshidaAbstract:Cell adhesion molecules belonging to the immunoglobulin superfamily (IgSF) control Synaptic Specificity through hetero- or homophilic interactions in different regions of the nervous system. In the developing spinal cord, monoSynaptic connections of exquisite Specificity form between proprioceptive sensory neurons and motor neurons, however, it is not known whether IgSF molecules participate in regulating this process. To determine whether IgSF molecules influence the establishment of Synaptic Specificity in sensory-motor circuits, we examined the expression of 157 IgSF genes in the developing dorsal root ganglion (DRG) and spinal cord by in situ hybridization assays. We find that many IgSF genes are expressed by sensory and motor neurons in the mouse developing DRG and spinal cord. For instance, Alcam, Mcam, and Ocam are expressed by a subset of motor neurons in the ventral spinal cord. Further analyses show that Ocam is expressed by obturator but not quadriceps motor neurons, suggesting that Ocam may regulate sensory-motor Specificity in these sensory-motor reflex arcs. Electrophysiological analysis shows no obvious defects in Synaptic Specificity of monoSynaptic sensory-motor connections involving obturator and quadriceps motor neurons in Ocam mutant mice. Since a subset of Ocam+ motor neurons also express Alcam, Alcam or other functionally redundant IgSF molecules may compensate for Ocam in controlling sensory-motor Specificity. Taken together, these results reveal that IgSF molecules are broadly expressed by sensory and motor neurons during development, and that Ocam and other IgSF molecules may have redundant functions in controlling the Specificity of sensory-motor circuits.
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Specificity of sensory motor connections encoded by sema3e plxnd1 recognition
Nature, 2009Co-Authors: Eline Pechovrieseling, Yutaka Yoshida, Markus Sigrist, Thomas M Jessell, Silvia ArberAbstract:Reflex circuits are carefully and specifically formed between sensory and motor neurons based on the class of sensory cell and the muscle type innervated by the motor neuron. Pecho-Vrieseling et al. now report that this fine Synaptic Specificity is mediated by selective expression of Sema3e and PlexinD1 by specific motor and sensory neuron populations, respectively. Signalling cascades activated by these molecular repellents affected not only monoSynaptic circuit anatomy, but also circuit function. Reflex circuits are specifically formed between sensory and motor neurons based on the class of sensory cell and the muscle type innervated by the motor neuron. Here, this fine Synaptic Specificity is found to be mediated by selective expression of the class 3 semaphorin Sema3e and its high-affinity receptor plexin D1 (Plxnd1) by specific motor and sensory neuron populations, respectively. Spinal reflexes are mediated by Synaptic connections between sensory afferents and motor neurons1,2,3. The organization of these circuits shows several levels of Specificity. Only certain classes of proprioceptive sensory neurons make direct, monoSynaptic connections with motor neurons4. Those that do are bound by rules of motor pool Specificity: they form strong connections with motor neurons supplying the same muscle, but avoid motor pools supplying antagonistic muscles1,5,6,7. This pattern of connectivity is initially accurate and is maintained in the absence of activity8, implying that wiring Specificity relies on the matching of recognition molecules on the surface of sensory and motor neurons. However, determinants of fine Synaptic Specificity here, as in most regions of the central nervous system, have yet to be defined. To address the origins of Synaptic Specificity in these reflex circuits we have used molecular genetic methods to manipulate recognition proteins expressed by subsets of sensory and motor neurons. We show here that a recognition system involving expression of the class 3 semaphorin Sema3e by selected motor neuron pools, and its high-affinity receptor plexin D1 (Plxnd1) by proprioceptive sensory neurons, is a critical determinant of Synaptic Specificity in sensory–motor circuits in mice. Changing the profile of Sema3e–Plxnd1 signalling in sensory or motor neurons results in functional and anatomical rewiring of monoSynaptic connections, but does not alter motor pool Specificity. Our findings indicate that patterns of monoSynaptic connectivity in this prototypic central nervous system circuit are constructed through a recognition program based on repellent signalling.
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Specificity of sensory–motor connections encoded by Sema3e–Plxnd1 recognition
Nature, 2009Co-Authors: Eline Pecho-vrieseling, Yutaka Yoshida, Markus Sigrist, Thomas M Jessell, Silvia ArberAbstract:Spinal reflexes are mediated by Synaptic connections between sensory afferents and motor neurons. The organization of these circuits shows several levels of Specificity. Only certain classes of proprioceptive sensory neurons make direct, monoSynaptic connections with motor neurons. Those that do are bound by rules of motor pool Specificity: they form strong connections with motor neurons supplying the same muscle, but avoid motor pools supplying antagonistic muscles. This pattern of connectivity is initially accurate and is maintained in the absence of activity, implying that wiring Specificity relies on the matching of recognition molecules on the surface of sensory and motor neurons. However, determinants of fine Synaptic Specificity here, as in most regions of the central nervous system, have yet to be defined. To address the origins of Synaptic Specificity in these reflex circuits we have used molecular genetic methods to manipulate recognition proteins expressed by subsets of sensory and motor neurons. We show here that a recognition system involving expression of the class 3 semaphorin Sema3e by selected motor neuron pools, and its high-affinity receptor plexin D1 (Plxnd1) by proprioceptive sensory neurons, is a critical determinant of Synaptic Specificity in sensory-motor circuits in mice. Changing the profile of Sema3e-Plxnd1 signalling in sensory or motor neurons results in functional and anatomical rewiring of monoSynaptic connections, but does not alter motor pool Specificity. Our findings indicate that patterns of monoSynaptic connectivity in this prototypic central nervous system circuit are constructed through a recognition program based on repellent signalling.
Joshua R. Sanes - One of the best experts on this subject based on the ideXlab platform.
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Synaptic Specificity, Recognition Molecules, and Assembly of Neural Circuits
Cell, 2020Co-Authors: Joshua R. Sanes, S. Lawrence ZipurskyAbstract:Developing neurons connect in specific and stereotyped ways to form the complex circuits that underlie brain function. By comparison to earlier steps in neural development, progress has been slow in identifying the cell surface recognition molecules that mediate these Synaptic choices, but new high-throughput imaging, genetic, and molecular methods are accelerating progress. Over the past decade, numerous large and small gene families have been implicated in target recognition, including members of the immunoglobulin, cadherin, and leucine-rich repeat superfamilies. We review these advances and propose ways in which combinatorial use of multifunctional recognition molecules enables the complex neuron-neuron interactions that underlie Synaptic Specificity.
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Type II Cadherins Guide Assembly of a Direction-Selective Retinal Circuit
Cell, 2014Co-Authors: Xin Duan, Arjun Krishnaswamy, Irina De La Huerta, Joshua R. SanesAbstract:Complex retinal circuits process visual information and deliver it to the brain. Few molecular determinants of Synaptic Specificity in this system are known. Using genetic and optogenetic methods, we identified two types of bipolar interneurons that convey visual input from photoreceptors to a circuit that computes the direction in which objects are moving. We then sought recognition molecules that promote selective connections of these cells with previously characterized components of the circuit. We found that the type II cadherins, cdh8 and cdh9, are each expressed selectively by one of the two bipolar cell types. Using loss- and gain-of-function methods, we showed that they are critical determinants of connectivity in this circuit and that perturbation of their expression leads to distinct defects in visually evoked responses. Our results reveal cellular components of a retinal circuit and demonstrate roles of type II cadherins in Synaptic choice and circuit function.
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Many Paths to Synaptic Specificity
Annual review of cell and developmental biology, 2009Co-Authors: Joshua R. Sanes, Masahito YamagataAbstract:The most impressive structural feature of the nervous system is the Specificity of its Synaptic connections. Even after axons have navigated long distances to reach target areas, they must still choose appropriate Synaptic partners from the many potential partners within easy reach. In many cases, axons also select a particular domain of the postSynaptic cell on which to form a synapse. Thus, synapse formation is selective at both cellular and subcellular levels. Unsurprisingly, the nervous system uses multiple mechanisms to ensure proper connectivity; these include complementary labels, coordinated growth of Synaptic partners, sorting of afferents, prohibition or elimination of inappropriate synapses, respecification of targets, and use of short-range guidance mechanisms or intermediate targets. Specification of any circuit is likely to involve integration of multiple mechanisms. Recent studies of vertebrate and invertebrate systems have led to the identification of molecules that mediate a few of these interactions.
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Formation of lamina-specific Synaptic connections.
Current opinion in neurobiology, 1999Co-Authors: Joshua R. Sanes, Masahito YamagataAbstract:In many parts of the vertebrate central nervous system, inputs of distinct types confine their synapses to individual laminae. Such laminar Specificity is a major determinant of Synaptic Specificity. Recent studies of several laminated structures have begun to identify some of the cells (such as guidepost neurons in hippocampus), molecules (such as N-cadherin in optic tectum, semaphorin/collapsin in spinal cord, and ephrins in cerebral cortex), and mechanisms (such as activity-dependent refinement in lateral geniculate) that combine to generate laminar Specificity.
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Topographic maps and molecular gradients
Current opinion in neurobiology, 1993Co-Authors: Joshua R. SanesAbstract:Topographically organized patterns of connectivity occur throughout the central and peripheral nervous systems. It is commonly supposed that gradients of recognition molecules underlie this form of Synaptic Specificity. Recent studies have led to new ideas about how such gradients might arise in the retinotectal system, and initiated molecular analyses of position-dependent gene expression in the peripheral motor system.
Cornelia I Bargmann - One of the best experts on this subject based on the ideXlab platform.
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gfp reconstitution across Synaptic partners grasp defines cell contacts and synapses in living nervous systems
Neuron, 2008Co-Authors: Evan H Feinberg, Kang Shen, Richard D. Fetter, Miri K Vanhoven, Andres Bendesky, George T Wang, Cornelia I BargmannAbstract:The identification of Synaptic partners is challenging in dense nerve bundles, where many processes occupy regions beneath the resolution of conventional light microscopy. To address this difficulty, we have developed GRASP, a system to label membrane contacts and synapses between two cells in living animals. Two complementary fragments of GFP are expressed on different cells, tethered to extracellular domains of transmembrane carrier proteins. When the complementary GFP fragments are fused to ubiquitous transmembrane proteins, GFP fluorescence appears uniformly along membrane contacts between the two cells. When one or both GFP fragments are fused to Synaptic transmembrane proteins, GFP fluorescence is tightly localized to synapses. GRASP marks known Synaptic contacts in C. elegans, correctly identifies changes in mutants with altered Synaptic Specificity, and can uncover new information about Synaptic locations as confirmed by electron microscopy. GRASP may prove particularly useful for defining connectivity in complex nervous systems.
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Hierarchical assembly of preSynaptic components in defined C. elegans synapses
Nature Neuroscience, 2006Co-Authors: Maulik R Patel, Cornelia I Bargmann, Emily K Lehrman, Vivian Y Poon, Justin G Crump, Mei Zhen, Kang ShenAbstract:The preSynaptic regions of axons accumulate Synaptic vesicles, active zone proteins and periactive zone proteins. However, the rules for orderly recruitment of preSynaptic components are not well understood. We systematically examined molecular mechanisms of preSynaptic development in egg-laying synapses of Caenorhabditis elegans , demonstrating that two scaffolding molecules, SYD-1 and SYD-2, have key roles in preSynaptic assembly. SYD-2 (liprin-α) was previously shown to regulate the size and the shape of active zones. We now show that in syd-1 and syd-2 mutants, Synaptic vesicles and numerous other preSynaptic proteins fail to accumulate at preSynaptic sites. SYD-1 and SYD-2 function cell-autonomously at preSynaptic terminals, downstream of Synaptic Specificity molecule SYG-1. SYD-1 is likely to act upstream of SYD-2 to positively regulate its Synaptic assembly activity. These data imply a hierarchical organization of preSynaptic assembly, in which transmembrane Specificity molecules initiate synaptogenesis by recruiting a few key scaffolding proteins, which in turn assemble other preSynaptic components.
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Synaptic Specificity is generated by the Synaptic guidepost protein SYG-2 and its receptor, SYG-1.
Cell, 2004Co-Authors: Kang Shen, Richard D. Fetter, Cornelia I BargmannAbstract:Synaptic connections in the nervous system are directed onto specific cellular and subcellular targets. Synaptic guidepost cells in the C. elegans vulval epithelium drive synapses from the HSNL motor neuron onto adjacent target neurons and muscles. Here, we show that the transmembrane immunoglobulin superfamily protein SYG-2 is a central component of the Synaptic guidepost signal. SYG-2 is expressed transiently by primary vulval epithelial cells during synapse formation. SYG-2 binds SYG-1, the receptor on HSNL, and directs SYG-1 accumulation and synapse formation to adjacent regions of HSNL. syg-1 and syg-2 mutants have defects in Synaptic Specificity; the HSNL neuron forms fewer synapses onto its normal targets and forms ectopic synapses onto inappropriate targets. Misexpression of SYG-2 in secondary epithelial cells causes aberrant accumulation of SYG-1 and Synaptic markers in HSNL adjacent to the SYG-2-expressing cells. Our results indicate that local interactions between immunoglobulin superfamily proteins can determine Specificity during synapse formation.
