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Timothy E. Kennedy - One of the best experts on this subject based on the ideXlab platform.

  • Guiding synaptic plasticity: Novel roles for netrin‐1 in synaptic plasticity and memory formation in the adult brain
    The Journal of Physiology, 2020
    Co-Authors: Stephen D. Glasgow, Edward S. Ruthazer, Timothy E. Kennedy
    Abstract:

    Adult neural plasticity engages mechanisms that change synapse structure and function, yet many of the underlying events bear a striking similarity to processes that occur during the initial establishment of neural circuits during development. It is a long-standing hypothesis that the molecular mechanisms critical for neural development may also regulate synaptic plasticity related to learning and memory in adults. Netrins were initially described as chemoattractant guidance cues that direct cell and Axon Migration during embryonic development, yet they continue to be expressed by neurons in the adult brain. Recent findings have identified roles for netrin-1 in synaptogenesis during postnatal maturation, and in synaptic plasticity in the adult mammalian brain, regulating AMPA glutamate receptor trafficking at excitatory synapses. These findings provide an example of a conserved developmental guidance cue that is expressed by neurons in the adult brain and functions as a key regulator of activity-dependent synaptic plasticity. Notably, in humans, genetic polymorphisms in netrin-1 and its receptors have been linked to neurodevelopmental and neurodegenerative disorders. The molecular mechanisms associated with the synaptic function of netrin-1 therefore present new therapeutic targets for neuropathologies associated with memory dysfunction. Here, we summarize recent findings that link netrin-1 signalling to synaptic plasticity, and discuss the implications of these discoveries for the neurobiological basis of memory consolidation.

  • Making Connections: Guidance Cues and Receptors at Nonneural Cell–Cell Junctions
    Cold Spring Harbor Perspectives in Biology, 2017
    Co-Authors: Ian V. Beamish, Lindsay Hinck, Timothy E. Kennedy
    Abstract:

    The field of Axon guidance was revolutionized over the past three decades by the identification of highly conserved families of guidance cues and receptors. These proteins are essential for normal neural development and function, directing cell and Axon Migration, neuron-glial interactions, and synapse formation and plasticity. Many of these genes are also expressed outside the nervous system in which they influence cell Migration, adhesion and proliferation. Because the nervous system develops from neural epithelium, it is perhaps not surprising that these guidance cues have significant nonneural roles in governing the specialized junctional connections between cells in polarized epithelia. The following review addresses roles for ephrins, semaphorins, netrins, slits and their receptors in regulating adherens, tight, and gap junctions in nonneural epithelia and endothelia.

  • Rat C6 glioma cell motility and glioma growth are regulated by netrin and netrin receptors unc5B and DCC
    journal of Cancer Therapeutics and Research, 2013
    Co-Authors: Margaret Durko, Timothy E. Kennedy, Zaf Koty, Lixia Zhu, Nathalie Marcal, Josephine Nalbantoglu
    Abstract:

    Abstract Background: Cell Migration plays a key role in tumor invasion and metastasis. Deleted in colorectal cancer (DCC) and the unc5 homologues are receptors for secreted netrins that regulate cell and Axon Migration,

  • Autocrine Netrin Function Inhibits Glioma Cell Motility and Promotes Focal Adhesion Formation
    PLoS ONE, 2011
    Co-Authors: Andrew A. Jarjour, Margaret Durko, Nathalie Marcal, Masoud Shekarabi, Tamarah L. Luk, Timothy E. Kennedy
    Abstract:

    Deregulation of mechanisms that control cell motility plays a key role in tumor progression by promoting tumor cell dissemination. Secreted netrins and their receptors, Deleted in Colorectal Cancer (DCC), neogenin, and the UNC5 homologues, regulate cell and Axon Migration, cell adhesion, and tissue morphogenesis. Netrin and netrin receptor expression have previously been shown to be disrupted in invasive tumors, including glioblastoma. We determined that the human glioblastoma cell lines U87, U343, and U373 all express neogenin, UNC5 homologues, and netrin-1 or netrin-3, but only U87 cells express DCC. Using transfilter Migration assays, we demonstrate DCC-dependent chemoattractant Migration of U87 cells up a gradient of netrin-1. In contrast, U343 and U373 cells, which do not express DCC, were neither attracted nor repelled. Ectopic expression of DCC by U343 and U373 cells resulted in these cells becoming competent to respond to a gradient of netrin-1 as a chemoattractant, and also slowed their rate of spontaneous Migration. Here, in addition to netrins' well-characterized chemotropic activity, we demonstrate an autocrine function for netrin-1 and netrin-3 in U87 and U373 cells that slows Migration. We provide evidence that netrins promote the maturation of focal complexes, structures associated with cell movement, into focal adhesions. Consistent with this, netrin, DCC, and UNC5 homologues were associated with focal adhesions, but not focal complexes. Disrupting netrin or DCC function did not alter cell proliferation or survival. Our findings provide evidence that DCC can slow cell Migration, and that neogenin and UNC5 homologues are not sufficient to substitute for DCC function in these cells. Furthermore, we identify a role for netrins as autocrine inhibitors of cell motility that promote focal adhesion formation. These findings suggest that disruption of netrin signalling may disable a mechanism that normally restrains inappropriate cell Migration.

  • Netrins: versatile extracellular cues with diverse functions.
    Development, 2011
    Co-Authors: Karen Lai Wing Sun, James P. Correia, Timothy E. Kennedy
    Abstract:

    Netrins are secreted proteins that were first identified as guidance cues, directing cell and Axon Migration during neural development. Subsequent findings have demonstrated that netrins can influence the formation of multiple tissues, including the vasculature, lung, pancreas, muscle and mammary gland, by mediating cell Migration, cell-cell interactions and cell-extracellular matrix adhesion. Recent evidence also implicates the ongoing expression of netrins and netrin receptors in the maintenance of cell-cell organisation in mature tissues. Here, we review the mechanisms involved in netrin signalling in vertebrate and invertebrate systems and discuss the functions of netrin signalling during the development of neural and non-neural tissues.

William G. Wadsworth - One of the best experts on this subject based on the ideXlab platform.

  • the roles of multiple unc 40 dcc receptor mediated signals in determining neuronal asymmetry induced by the unc 6 netrin ligand
    Genetics, 2009
    Co-Authors: William G. Wadsworth
    Abstract:

    The polarization of post-mitotic neurons is poorly understood. Preexisting spatially asymmetric cues, distributed within the neuron or as extracellular gradients, could be required for neurons to polarize. Alternatively, neurons might have the intrinsic ability to polarize without any preestablished asymmetric cues. In Caenorhabditis elegans, the UNC-40 (DCC) receptor mediates responses to the extracellular UNC-6 (netrin) guidance cue. For the HSN neuron, an UNC-6 ventral-dorsal gradient asymmetrically localizes UNC-40 to the ventral HSN surface. There an Axon forms, which is ventrally directed by UNC-6. In the absence of UNC-6, UNC-40 is equally distributed and the HSN Axon travels anteriorly in response to other cues. However, we find that a single amino acid change in the UNC-40 ectodomain causes randomly oriented asymmetric UNC-40 localization and a wandering Axon phenotype. With UNC-6, there is normal UNC-40 localization and Axon Migration. A single UNC-6 amino acid substitution enhances the mutant phenotypes, whereas UNC-6 second-site amino acid substitutions suppress the phenotypes. We propose that UNC-40 mediates multiple signals to polarize and orient asymmetry. One signal triggers the intrinsic ability of HSN to polarize and causes randomly oriented asymmetry. Concurrently, another signal biases the orientation of the asymmetry relative to the UNC-6 gradient. The UNC-40 ectodomain mutation activates the polarization signal, whereas different forms of the UNC-6 ligand produce UNC-40 conformational changes that allow or prohibit the orientation signal.

  • Assembly and tissue functions of early embryonic laminins and netrins.
    Current Opinion in Cell Biology, 2004
    Co-Authors: Peter D. Yurchenco, William G. Wadsworth
    Abstract:

    Vertebrate laminins and netrins share N-terminal domain structure, but appear to be only distantly related. Both families can be divided into different subfamilies on the basis of structural considerations. Recent observations suggest that specific laminin and netrin members have developmental functions that are highly conserved across species. Vertebrate laminin-1 (α1β1γ1) and laminin-10 (α5β1γ1), like the two Caenorhabditis elegans laminins, are embryonically expressed and are essential for basement membrane assembly. Basement membrane assembly is a cooperative process in which laminins polymerize through their LN domains and anchor to the cell surface through their G domains; this leads to cell signaling through integrins and dystroglycan (and possibly other receptors) recruited to the adherent laminin. Netrins may associate with this network through heterotypic LN domain interactions. Vertebrate netrin-1, like invertebrate UNC-6/netrins, is well known as an extracellular guidance cue that directs Axon Migration towards or away from the ventral midline. It also regulates cell adhesions and Migrations, probably as a basement membrane component. Although sharing structural features, these two vertebrate protein families are quite distinct, having both retained members that mediate the ancestral developmental functions.

Elizabeth C Engle - One of the best experts on this subject based on the ideXlab platform.

  • wildervanck s syndrome and mirror movements a congenital disorder of Axon Migration
    Journal of Neurology, 2012
    Co-Authors: Tobias Hogen, Eva Riedel, Ralf Bruning, Hannah H Chang, Elizabeth C Engle, Waiman Chan
    Abstract:

    Cell outgrowth and Migration in the developing nervous system result from guidance cues, whose molecular bases and clinical correlates are only partly known. We describe a patient with brain stem malformation, paroxysmal left sided lacrimation when eating (“crocodile tears”) and mirror movements in addition to Wildervanck’s cervico-oculo-acusticus (COA) syndrome, which encompasses Klippel–Feil anomaly, congenital hearing loss and Duane’s syndrome. The unique symptom constellation has not been reported in that combination before and can be discussed in the context of congenital disordered Axonal Migration based on dysfunction of signalling pathways. However, mutations in some recently discovered genes, associated with single findings also present in our patient, were not found. Therefore, we suppose that the disturbance of an as yet unknown regulatory factor may explain the congenital malformation syndrome of our patient. In general, only a few human disorders have yet been found to result from defects in Axon guidance. Nevertheless, disorders of Axon guidance can certainly be regarded as a new category of neurodevelopmental disorders.

Masatoshi Takeichi - One of the best experts on this subject based on the ideXlab platform.

  • The cadherin superfamily in neuronal connections and interactions
    Nature Reviews Neuroscience, 2007
    Co-Authors: Masatoshi Takeichi
    Abstract:

    The organization of neuronal circuits involves a number of processes that require cell–cell recognition and contacts. Cadherins are a family of cell–cell adhesion molecules comprising more than 100 members in vertebrates, which are grouped into subfamilies including classic cadherins, Flamingo/CELSRs and protocadherins, and are thought to have roles in various steps of neuronal cell interactions. N-cadherin and other vertebrate classic cadherins are essential not only for early morphogenesis of neural tissues but also for correct Axon Migration towards target areas, and for the extension of neuronal dendrites. Drosophila melanogaster N-cadherin ( D N-cadherin) has been shown to be crucial for the formation of Axonal connections with target neurons in both the visual and olfactory systems, and also for confining dendritic arborizations to specific glomeruli in these systems. The activity of D N-cadherin during the Axon targeting seems to be controlled by cytoplasmic proteins including leukocyte antigen-related-receptor protein tyrosine phosphatase (LAR). Flamingo, a seven-pass transmembrane cadherin, is required for the correct targeting of retinal Axons in visual circuits in D. melanogaster . A vertebrate homologue of Flamingo, CELSR2, regulates dendritic arbor patterning in the cerebellum, and another homologue, CELSR3, is important for Axon tract formation. Some protocadherins, which show a large diversification due to a unique gene organization, seem to be involved in synapse formation and neuronal survival. However, the biological roles of this subfamily remain largely unknown. In conclusion, members of the cadherin superfamily control Axon–target recognition and connections, as well as other types of neuronal interactions in a subfamily-specific manner. The cadherin superfamily has roles in the development and organization of complex neuronal circuits. Takeichi explores the evidence from invertebrate and vertebrate studies for the involvement in these processes of different cadherin subfamilies, including classic cadherins, Flamingo/CELSRs and the protocadherins. Neural development and the organization of complex neuronal circuits involve a number of processes that require cell–cell interaction. During these processes, Axons choose specific partners for synapse formation and dendrites elaborate arborizations by interacting with other dendrites. The cadherin superfamily is a group of cell surface receptors that is comprised of more than 100 members. The molecular structures and diversity within this family suggest that these molecules regulate the contacts or signalling between neurons in a variety of ways. In this review I discuss the roles of three subfamilies — classic cadherins, Flamingo/CELSRs and protocadherins — in the regulation of neuronal recognition and connectivity.

  • αn catenin deficiency causes defects in Axon Migration and nuclear organization in restricted regions of the mouse brain
    Developmental Dynamics, 2006
    Co-Authors: Masato Uemura, Masatoshi Takeichi
    Abstract:

    αN-catenin is a cadherin-binding protein, widely expressed in the nervous system; and it plays a crucial role in cadherin-mediated cell-cell adhesion. Here we report the effects of αN-catenin gene deficiency on brain morphogenesis. In addition to the previously reported phenotypes, we found that some of the Axon tracts did not normally develop, in particular, Axons of the anterior commissure failed to cross the midline, migrating, rather, to ectopic places. In restricted nuclei, a population of neurons was missing or their laminar arrangement was distorted. The ventricular structures were also deformed. These results indicate that αN-catenin has diverse roles in the organization of the central nervous system, but only in limited portions of the brain. Developmental Dynamics 235:2559–2566, 2006. © 2006 Wiley-Liss, Inc.

  • αN‐catenin deficiency causes defects in Axon Migration and nuclear organization in restricted regions of the mouse brain
    Developmental Dynamics, 2006
    Co-Authors: Masato Uemura, Masatoshi Takeichi
    Abstract:

    αN-catenin is a cadherin-binding protein, widely expressed in the nervous system; and it plays a crucial role in cadherin-mediated cell-cell adhesion. Here we report the effects of αN-catenin gene deficiency on brain morphogenesis. In addition to the previously reported phenotypes, we found that some of the Axon tracts did not normally develop, in particular, Axons of the anterior commissure failed to cross the midline, migrating, rather, to ectopic places. In restricted nuclei, a population of neurons was missing or their laminar arrangement was distorted. The ventricular structures were also deformed. These results indicate that αN-catenin has diverse roles in the organization of the central nervous system, but only in limited portions of the brain. Developmental Dynamics 235:2559–2566, 2006. © 2006 Wiley-Liss, Inc.

  • Restricted expression of N- and R-cadherin on neurites of the developing chicken CNS
    The Journal of Neuroscience, 1992
    Co-Authors: Christoph Redies, Hiroyuki Inuzuka, Masatoshi Takeichi
    Abstract:

    The expression of two cadherins, N- and R-cadherin, was mapped in the CNS of chicken embryos of 6–11 d incubation, focusing on the sensory and motor fiber systems. In the spinal cord, the laterally located fibers of the dorsal funiculus express N-cadherin while the medially located fibers do not. These two fiber systems have a different course within the CNS but associate to form the spinal dorsal roots. In the hindbrain, N-cadherin is expressed by the descending trigeminal (general somatic sensory) tract, which is contiguous with the N- cadherin-positive zone of the dorsal funiculus of the spinal cord. R- cadherin is not expressed by sensory fibers, but is expressed by the visceral motor system of the vagus and glossopharyngeal nerves, which are N-cadherin negative. The motor neurites expressing R-cadherin have a different course within the brain than the sensory neurites expressing N-cadherin, although they form the common sensory/motor roots of the vagus nerve at the surface of the brain. The possibility that N-cadherin provides a guidance cue for sensory Axon Migration within the CNS by a homophilic adhesion mechanism was investigated in vitro. Explants from sensory spinal ganglia expressing N-cadherin were placed on N-cadherin-transfected neuroblastoma cells, and Axon outgrowth was visualized. Results showed that the sensory Axons defasciculate and closely follow the cell-cell boundaries between transfected cells where high levels of N-cadherin are expressed. These results show that the two cadherins, like members of the immunoglobulin superfamily of molecules, are expressed in a topographically restricted fashion during chick brain development. They furthermore suggest that N- cadherin expression by neurites may play a role in guiding these neurites along CNS paths that express the same molecule.

James M. Kramer - One of the best experts on this subject based on the ideXlab platform.

  • The Nc1/Endostatin Domain of Caenorhabditis elegans Type Xviii Collagen Affects Cell Migration and Axon Guidance
    Journal of Cell Biology, 2001
    Co-Authors: Brian D. Ackley, Jennifer R. Crew, Harri Elamaa, Tania Pihlajaniemi, Calvin J. Kuo, James M. Kramer
    Abstract:

    Type XVIII collagen is a homotrimeric basement membrane molecule of unknown function, whose COOH-terminal NC1 domain contains endostatin (ES), a potent antiangiogenic agent. The Caenorhabditis elegans collagen XVIII homologue, cle-1, encodes three developmentally regulated protein isoforms expressed predominantly in neurons. The CLE-1 protein is found in low amounts in all basement membranes but accumulates at high levels in the nervous system. Deletion of the cle-1 NC1 domain results in viable fertile animals that display multiple cell Migration and Axon guidance defects. Particular defects can be rescued by ectopic expression of the NC1 domain, which is shown to be capable of forming trimers. In contrast, expression of monomeric ES does not rescue but dominantly causes cell and Axon Migration defects that phenocopy the NC1 deletion, suggesting that ES inhibits the promigratory activity of the NC1 domain. These results indicate that the cle-1 NC1/ES domain regulates cell and Axon Migrations in C. elegans.

  • the nc1 endostatin domain of caenorhabditis elegans type xviii collagen affects cell Migration and Axon guidance
    Journal of Cell Biology, 2001
    Co-Authors: Brian D. Ackley, Jennifer R. Crew, Harri Elamaa, Tania Pihlajaniemi, Calvin J. Kuo, James M. Kramer
    Abstract:

    Type XVIII collagen is a homotrimeric basement membrane molecule of unknown function, whose COOH-terminal NC1 domain contains endostatin (ES), a potent antiangiogenic agent. The Caenorhabditis elegans collagen XVIII homologue, cle-1, encodes three developmentally regulated protein isoforms expressed predominantly in neurons. The CLE-1 protein is found in low amounts in all basement membranes but accumulates at high levels in the nervous system. Deletion of the cle-1 NC1 domain results in viable fertile animals that display multiple cell Migration and Axon guidance defects. Particular defects can be rescued by ectopic expression of the NC1 domain, which is shown to be capable of forming trimers. In contrast, expression of monomeric ES does not rescue but dominantly causes cell and Axon Migration defects that phenocopy the NC1 deletion, suggesting that ES inhibits the promigratory activity of the NC1 domain. These results indicate that the cle-1 NC1/ES domain regulates cell and Axon Migrations in C. elegans.