The Experts below are selected from a list of 1467 Experts worldwide ranked by ideXlab platform
Stephanie L. Gupton - One of the best experts on this subject based on the ideXlab platform.
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mammalian trim67 functions in brain development and behavior
eNeuro, 2018Co-Authors: Nicholas P. Boyer, Shalini Menon, Caroline Monkiewicz, Sheryl S Moy, Stephanie L. GuptonAbstract:Class I members of the tripartite motif (TRIM) family of E3 ubiquitin ligases evolutionarily appeared just prior to the advent of neuronal like cells and have been implicated in neuronal development from invertebrates to mammals. The single Class I TRIM in Drosophila melanogaster and Caenorhabditis elegans and the mammalian Class I TRIM9 regulate axon branching and guidance in response to the guidance cue Netrin, whereas mammalian TRIM46 establishes the axon initial segment. In humans, mutations in TRIM1 and TRIM18 are implicated in Opitz Syndrome, characterized by midline defects and often intellectual disability. We find that although TRIM67 is the least studied vertebrate Class I TRIM, it is the most evolutionarily conserved. Here we show that mammalian TRIM67 interacts with both its closest paralog TRIM9 and the Netrin Receptor DCC and is differentially enriched in specific brain regions during development and adulthood. We describe the anatomical and behavioral consequences of deletion of murine Trim67. While viable, mice lacking Trim67 exhibit abnormal anatomy of specific brain regions, including hypotrophy of the hippocampus, striatum, amygdala, and thalamus, and thinning of forebrain commissures. Additionally, Trim67-/- mice display impairments in spatial memory, cognitive flexibility, social novelty preference, muscle function, and sensorimotor gating, whereas several other behaviors remain intact. This study demonstrates the necessity for TRIM67 in appropriate brain development and behavior.
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The E3 Ubiquitin Ligase TRIM9 Is a Filopodia Off Switch Required for Netrin-Dependent Axon Guidance.
Developmental Cell, 2015Co-Authors: Shalini Menon, Nicholas P. Boyer, Cortney C. Winkle, Leslie Marie Mcclain, Christopher Carey Hanlin, Dharmendra Pandey, Simon Rothenfußer, Anne Marion Taylor, Stephanie L. GuptonAbstract:Neuronal growth cone filopodia contain guidance Receptors and contribute to axon guidance; however, the mechanism by which the guidance cue Netrin increases filopodia density is unknown. Here, we demonstrate that TRIM9, an E3 ubiquitin ligase that localizes to filopodia tips and binds the Netrin Receptor DCC, interacts with and ubiquitinates the barbed-end polymerase VASP to modulate filopodial stability during Netrin-dependent axon guidance. Studies with murine Trim9(+/+) and Trim9(-/-) cortical neurons, along with a non-ubiquitinatable VASP mutant, demonstrate that TRIM9-mediated ubiquitination of VASP reduces VASP filopodial tip localization, VASP dynamics at tips, and filopodial stability. Upon Netrin treatment, VASP is deubiquitinated, which promotes VASP tip localization and filopodial stability. Trim9 deletion induces axon guidance defects in vitro and in vivo, whereas a gradient of deubiquitinase inhibition promotes axon turning in vitro. We conclude that a gradient of TRIM9-mediated ubiquitination of VASP creates a filopodial stability gradient during axon turning.
Marc Tessier-lavigne - One of the best experts on this subject based on the ideXlab platform.
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Draxin inhibits axonal outgrowth through the Netrin Receptor DCC.
Journal of Neuroscience, 2011Co-Authors: Giasuddin Ahmed, Yohei Shinmyo, Kunimasa Ohta, Shahidul M. Islam, Mahmud Hossain, Iftekhar Bin Naser, M. Asrafuzzaman Riyadh, Sanbing Zhang, Marc Tessier-lavigneAbstract:Draxin, a recently identified axon guidance protein, is essential for the formation of forebrain commissures, and can mediate repulsion of Netrin-stimulated spinal commissural axons. Here, we report that draxin binds multiple Netrin Receptors: DCC (deleted in colorectal cancer), Neogenin, UNC5s (H1, H2, H3), and DSCAM (Down's syndrome cell adhesion molecule). Since draxin and DCC knockouts showed similar phenotype in forebrain commissures formation, we show here the functional importance of draxin/DCC interaction. Draxin interacts with subnanomolar affinity to the Netrin Receptor DCC, in a region of DCC distinct from its Netrin-binding domain. In vitro, neurite outgrowth from cortical and olfactory bulb explants of DCC knock-out mice is significantly less inhibited by draxin, when compared with neurites from explants of wild-type mice. Furthermore, in comparison with wild-type mice, the growth cone collapse in response to draxin is largely abolished in DCC-deficient cortical neurons. In vivo, double heteros of draxin/DCC mice show markedly higher frequency of complete agenesis of corpus callosum than either of the single hetero. These results identify DCC as a convergent Receptor for Netrin and draxin in axon growth and guidance.
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DSCAM Is a Netrin Receptor that Collaborates with DCC in Mediating Turning Responses to Netrin-1
Cell, 2008Co-Authors: Anatoly Nikolaev, Marc Tessier-lavigne, Geetha Suresh, Yufang Zheng, Elke SteinAbstract:During nervous system development, spinal commissural axons project toward and across the ventral midline. They are guided in part by Netrin-1, made by midline cells, which attracts the axons by activating the Netrin Receptor DCC. However, previous studies suggest that additional Receptor components are required. Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds Netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to Netrin-1. Similarly, Xenopus spinal neurons exogenously expressing DSCAM can be attracted by Netrin-1 independently of DCC. These results show that DSCAM is a Receptor that can mediate turning responses to Netrin-1 and support a key role for Netrin/DSCAM signaling in commissural axon guidance in vertebrates.
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Turning of Retinal Growth Cones in a Netrin-1 Gradient Mediated by the Netrin Receptor DCC
Neuron, 1997Co-Authors: José R. De La Torre, Marc Tessier-lavigne, Guo Li Ming, Veit H. Höpker, Mu-ming Poo, Ali Hemmati-brivanlou, Christine E. HoltAbstract:Netrin-1 promotes outgrowth of axons in vitro through the Receptor Deleted in Colorectal Cancer (DCC) and elicits turning of axons within embryonic explants when presented as a point source. It is not known whether Netrin-1 alone can elicit turning nor whether DCC mediates the turning response. We show that Xenopus retinal ganglion cell growth cones orient rapidly toward a pipette ejecting Netrin-1, an effect blocked by antibodies to DCC. In vitro, Netrin-1 induces a complex growth cone morphology reminiscent of that at the optic nerve head, a site of Netrin-1 expression in vivo. These results demonstrate that Netrin-1 can function alone to induce turning, implicate DCC in this response, and support the idea that Netrin-1 contributes to steering axons out of the retina.
Shalini Menon - One of the best experts on this subject based on the ideXlab platform.
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mammalian trim67 functions in brain development and behavior
eNeuro, 2018Co-Authors: Nicholas P. Boyer, Shalini Menon, Caroline Monkiewicz, Sheryl S Moy, Stephanie L. GuptonAbstract:Class I members of the tripartite motif (TRIM) family of E3 ubiquitin ligases evolutionarily appeared just prior to the advent of neuronal like cells and have been implicated in neuronal development from invertebrates to mammals. The single Class I TRIM in Drosophila melanogaster and Caenorhabditis elegans and the mammalian Class I TRIM9 regulate axon branching and guidance in response to the guidance cue Netrin, whereas mammalian TRIM46 establishes the axon initial segment. In humans, mutations in TRIM1 and TRIM18 are implicated in Opitz Syndrome, characterized by midline defects and often intellectual disability. We find that although TRIM67 is the least studied vertebrate Class I TRIM, it is the most evolutionarily conserved. Here we show that mammalian TRIM67 interacts with both its closest paralog TRIM9 and the Netrin Receptor DCC and is differentially enriched in specific brain regions during development and adulthood. We describe the anatomical and behavioral consequences of deletion of murine Trim67. While viable, mice lacking Trim67 exhibit abnormal anatomy of specific brain regions, including hypotrophy of the hippocampus, striatum, amygdala, and thalamus, and thinning of forebrain commissures. Additionally, Trim67-/- mice display impairments in spatial memory, cognitive flexibility, social novelty preference, muscle function, and sensorimotor gating, whereas several other behaviors remain intact. This study demonstrates the necessity for TRIM67 in appropriate brain development and behavior.
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The E3 Ubiquitin Ligase TRIM9 Is a Filopodia Off Switch Required for Netrin-Dependent Axon Guidance.
Developmental Cell, 2015Co-Authors: Shalini Menon, Nicholas P. Boyer, Cortney C. Winkle, Leslie Marie Mcclain, Christopher Carey Hanlin, Dharmendra Pandey, Simon Rothenfußer, Anne Marion Taylor, Stephanie L. GuptonAbstract:Neuronal growth cone filopodia contain guidance Receptors and contribute to axon guidance; however, the mechanism by which the guidance cue Netrin increases filopodia density is unknown. Here, we demonstrate that TRIM9, an E3 ubiquitin ligase that localizes to filopodia tips and binds the Netrin Receptor DCC, interacts with and ubiquitinates the barbed-end polymerase VASP to modulate filopodial stability during Netrin-dependent axon guidance. Studies with murine Trim9(+/+) and Trim9(-/-) cortical neurons, along with a non-ubiquitinatable VASP mutant, demonstrate that TRIM9-mediated ubiquitination of VASP reduces VASP filopodial tip localization, VASP dynamics at tips, and filopodial stability. Upon Netrin treatment, VASP is deubiquitinated, which promotes VASP tip localization and filopodial stability. Trim9 deletion induces axon guidance defects in vitro and in vivo, whereas a gradient of deubiquitinase inhibition promotes axon turning in vitro. We conclude that a gradient of TRIM9-mediated ubiquitination of VASP creates a filopodial stability gradient during axon turning.
David R. Sherwood - One of the best experts on this subject based on the ideXlab platform.
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The Netrin Receptor DCC focuses invadopodia-driven basement membrane transmigration in vivo.
Journal of Cell Biology, 2013Co-Authors: Elliott J. Hagedorn, Meghan A. Morrissey, Joshua W. Ziel, Lara M. Linden, Zheng Wang, Qiuyi Chi, Sam A. Johnson, David R. SherwoodAbstract:Though critical to normal development and cancer metastasis, how cells traverse basement membranes is poorly understood. A central impediment has been the challenge of visualizing invasive cell interactions with basement membrane in vivo. By developing live-cell imaging methods to follow anchor cell (AC) invasion in Caenorhabditis elegans, we identify F-actin–based invadopodia that breach basement membrane. When an invadopodium penetrates basement membrane, it rapidly transitions into a stable invasive process that expands the breach and crosses into the vulval tissue. We find that the Netrin Receptor UNC-40 (DCC) specifically enriches at the site of basement membrane breach and that activation by UNC-6 (Netrin) directs focused F-actin formation, generating the invasive protrusion and the cessation of invadopodia. Using optical highlighting of basement membrane components, we further demonstrate that rather than relying solely on proteolytic dissolution, the AC’s protrusion physically displaces basement membrane. These studies reveal an UNC-40–mediated morphogenetic transition at the cell–basement membrane interface that directs invading cells across basement membrane barriers.
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Cell invasion through basement membrane: The Netrin Receptor DCC guides the way.
Worm, 2013Co-Authors: Meghan A. Morrissey, Elliott J. Hagedorn, David R. SherwoodAbstract:Cell invasion through basement membrane is an essential part of normal development and physiology, and occurs during the pathological progression of human inflammatory diseases and cancer. F-actin-rich membrane protrusions, called invadopodia, have been hypothesized to be the “drill bits” of invasive cells, mediating invasion through the dense, highly cross-linked basement membrane matrix. Though studied in vitro for over 30 y, invadopodia function in vivo has remained elusive. We have recently discovered that invadopodia breach basement membrane during anchor cell invasion in C. elegans, a genetically and visually tractable in vivo invasion event. Further, we found that the Netrin Receptor DCC localizes to the initial site of basement membrane breach and directs invasion through a single gap in the matrix. In this commentary, we examine how the dynamics and structure of AC-invadopodia compare with in vitro invadopodia and how the Netrin Receptor guides invasion through a single basement membrane breach. We end with a discussion of our surprising result that the anchor cell pushes the basement membrane aside, instead of completely dissolving it through proteolysis, and provide some ideas for how proteases and physical displacement may work together to ensure efficient and robust invasion.
Nicholas P. Boyer - One of the best experts on this subject based on the ideXlab platform.
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mammalian trim67 functions in brain development and behavior
eNeuro, 2018Co-Authors: Nicholas P. Boyer, Shalini Menon, Caroline Monkiewicz, Sheryl S Moy, Stephanie L. GuptonAbstract:Class I members of the tripartite motif (TRIM) family of E3 ubiquitin ligases evolutionarily appeared just prior to the advent of neuronal like cells and have been implicated in neuronal development from invertebrates to mammals. The single Class I TRIM in Drosophila melanogaster and Caenorhabditis elegans and the mammalian Class I TRIM9 regulate axon branching and guidance in response to the guidance cue Netrin, whereas mammalian TRIM46 establishes the axon initial segment. In humans, mutations in TRIM1 and TRIM18 are implicated in Opitz Syndrome, characterized by midline defects and often intellectual disability. We find that although TRIM67 is the least studied vertebrate Class I TRIM, it is the most evolutionarily conserved. Here we show that mammalian TRIM67 interacts with both its closest paralog TRIM9 and the Netrin Receptor DCC and is differentially enriched in specific brain regions during development and adulthood. We describe the anatomical and behavioral consequences of deletion of murine Trim67. While viable, mice lacking Trim67 exhibit abnormal anatomy of specific brain regions, including hypotrophy of the hippocampus, striatum, amygdala, and thalamus, and thinning of forebrain commissures. Additionally, Trim67-/- mice display impairments in spatial memory, cognitive flexibility, social novelty preference, muscle function, and sensorimotor gating, whereas several other behaviors remain intact. This study demonstrates the necessity for TRIM67 in appropriate brain development and behavior.
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The E3 Ubiquitin Ligase TRIM9 Is a Filopodia Off Switch Required for Netrin-Dependent Axon Guidance.
Developmental Cell, 2015Co-Authors: Shalini Menon, Nicholas P. Boyer, Cortney C. Winkle, Leslie Marie Mcclain, Christopher Carey Hanlin, Dharmendra Pandey, Simon Rothenfußer, Anne Marion Taylor, Stephanie L. GuptonAbstract:Neuronal growth cone filopodia contain guidance Receptors and contribute to axon guidance; however, the mechanism by which the guidance cue Netrin increases filopodia density is unknown. Here, we demonstrate that TRIM9, an E3 ubiquitin ligase that localizes to filopodia tips and binds the Netrin Receptor DCC, interacts with and ubiquitinates the barbed-end polymerase VASP to modulate filopodial stability during Netrin-dependent axon guidance. Studies with murine Trim9(+/+) and Trim9(-/-) cortical neurons, along with a non-ubiquitinatable VASP mutant, demonstrate that TRIM9-mediated ubiquitination of VASP reduces VASP filopodial tip localization, VASP dynamics at tips, and filopodial stability. Upon Netrin treatment, VASP is deubiquitinated, which promotes VASP tip localization and filopodial stability. Trim9 deletion induces axon guidance defects in vitro and in vivo, whereas a gradient of deubiquitinase inhibition promotes axon turning in vitro. We conclude that a gradient of TRIM9-mediated ubiquitination of VASP creates a filopodial stability gradient during axon turning.