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489 results on '"Peles, Elior"'

1. Coiling of cellular protrusions around extracellular fibers

Author

Sadhu, Raj Kumar, Hernandez-Padilla, Christian, Eisenbach, Yael Eshed, Zhang, Lixia, Vishwasrao, Harshad D, Behkam, Bahareh, Shroff, Hari, Iglič, Aleš, Peles, Elior, Nain, Amrinder S., and Gov, Nir S

Subjects
Physics - Biological Physics, Condensed Matter - Soft Condensed Matter
Abstract

Protrusions at the leading-edge of a cell play an important role in sensing the extracellular cues, during cellular spreading and motility. Recent studies provided indications that these protrusions wrap (coil) around the extra-cellular fibers. The details of this coiling process, and the mechanisms that drive it, are not well understood. We present a combined theoretical and experimental study of the coiling of cellular protrusions on fibers of different geometry. Our theoretical model describes membrane protrusions that are produced by curved membrane proteins that recruit the protrusive forces of actin polymerization, and identifies the role of bending and adhesion energies in orienting the leading-edges of the protrusions along the azimuthal (coiling) direction. Our model predicts that the cell's leading-edge coils on round fibers, but the coiling ceases for a fiber of elliptical (flat) cross-section. These predictions are verified by 3D visualization and quantitation of coiling on suspended fibers using Dual-View light-sheet microscopy (diSPIM). Overall, we provide a theoretical framework supported by high spatiotemporal resolution experiments capable of resolving coiling of cellular protrusions around extracellular fibers of varying diameters., Comment: 21 pages, 14 figures

Published
2022

6. TDP-43 maximizes nerve conduction velocity by repressing a cryptic exon for paranodal junction assembly in Schwann cells.

Author

Chang, Kae-Jiun, Agrawal, Ira, Vainshtein, Anna, Ho, Wan Yun, Xin, Wendy, Tucker-Kellogg, Greg, Susuki, Keiichiro, Peles, Elior, Ling, Shuo-Chien, and Chan, Jonah R

Subjects
Schwann cell, TDP-43, cell biology, mouse, myelination, neuroscience, node of Ranvier, Biochemistry and Cell Biology
Abstract

TDP-43 is extensively studied in neurons in physiological and pathological contexts. However, emerging evidence indicates that glial cells are also reliant on TDP-43 function. We demonstrate that deletion of TDP-43 in Schwann cells results in a dramatic delay in peripheral nerve conduction causing significant motor deficits in mice, which is directly attributed to the absence of paranodal axoglial junctions. By contrast, paranodes in the central nervous system are unaltered in oligodendrocytes lacking TDP-43. Mechanistically, TDP-43 binds directly to Neurofascin mRNA, encoding the cell adhesion molecule essential for paranode assembly and maintenance. Loss of TDP-43 triggers the retention of a previously unidentified cryptic exon, which targets Neurofascin mRNA for nonsense-mediated decay. Thus, TDP-43 is required for neurofascin expression, proper assembly and maintenance of paranodes, and rapid saltatory conduction. Our findings provide a framework and mechanism for how Schwann cell-autonomous dysfunction in nerve conduction is directly caused by TDP-43 loss-of-function.

Published
2021

7. TRIM46 Is Required for Microtubule Fasciculation In Vivo But Not Axon Specification or Axon Initial Segment Formation.

Author

Melton, Allison J., Palfini, Victoria L., Yuki Ogawa, Oses Prieto, Juan A., Vainshtein, Anna, Burlingame, Alma L., Peles, Elior, and Rasband, Matthew N.

Subjects
TRIM proteins, KNOCKOUT mice, ACTION potentials, NERVOUS system, MICROTUBULE-associated proteins
Abstract

Vertebrate nervous systems use the axon initial segment (AIS) to initiate action potentials and maintain neuronal polarity. The microtubule-associated protein tripartite motif containing 46 (TRIM46) was reported to regulate axon specification, AIS assembly, and neuronal polarity through the bundling, or fasciculation, of microtubules in the proximal axon. However, these claims are based on TRIM46 knockdown in cultured neurons. To investigate TRIM46 function in vivo, we examined male and female TRIM46 knock-out mice. Contrary to previous reports, we find that TRIM46 is dispensable for axon specification and AIS formation. TRIM46 knock-out mice are viable, have normal behavior, and have normal brain structure. Thus, TRIM46 is not required for AIS formation, axon specification, or nervous system function. However, we confirm that TRIM46 is required for microtubule fasciculation. We also show TRIM46 enrichment in the first ~100 µm of axon occurs independently of ankyrinG (AnkG) in vivo, although AnkG is required to restrict TRIM46 only to the AIS. Our results highlight the need for further investigation of the mechanisms by which the AIS and microtubules interact to shape neuronal structure and function. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism.

Author

Peñagarikano, Olga, Lázaro, María T, Lu, Xiao-Hong, Gordon, Aaron, Dong, Hongmei, Lam, Hoa A, Peles, Elior, Maidment, Nigel T, Murphy, Niall P, Yang, X William, Golshani, Peyman, and Geschwind, Daniel H

Subjects
Paraventricular Hypothalamic Nucleus, Neurons, Animals, Animals, Newborn, Mice, Knockout, Humans, Mice, Mutant Strains, Disease Models, Animal, Oxytocin, Membrane Proteins, Nerve Tissue Proteins, Behavior, Animal, Social Behavior, Autistic Disorder, Mental Health, Genetics, Autism, Basic Behavioral and Social Science, Behavioral and Social Science, Intellectual and Developmental Disabilities (IDD), Neurosciences, Pediatric, Brain Disorders, 5.1 Pharmaceuticals, 1.1 Normal biological development and functioning, Underpinning research, Development of treatments and therapeutic interventions, Aetiology, 2.1 Biological and endogenous factors, Neurological, Biological Sciences, Medical and Health Sciences
Abstract

Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.

Published
2015

10. Three Mechanisms Assemble Central Nervous System Nodes of Ranvier

Author

Susuki, Keiichiro, Chang, Kae-Jiun, Zollinger, Daniel R, Liu, Yanhong, Ogawa, Yasuhiro, Eshed-Eisenbach, Yael, Dours-Zimmermann, María T, Oses-Prieto, Juan A, Burlingame, Alma L, Seidenbecher, Constanze I, Zimmermann, Dieter R, Oohashi, Toshitaka, Peles, Elior, and Rasband, Matthew N

Subjects
Biomedical and Clinical Sciences, Neurosciences, Multiple Sclerosis, Neurodegenerative, Brain Disorders, Autoimmune Disease, Neurological, Action Potentials, Animals, Axons, Cell Adhesion Molecules, Central Nervous System, Cytoskeleton, Extracellular Matrix, Mice, Mice, Knockout, Myelin Sheath, Proteoglycans, Ranvier's Nodes, Sodium Channels, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Rapid action potential propagation in myelinated axons requires Na⁺ channel clustering at nodes of Ranvier. However, the mechanism of clustering at CNS nodes remains poorly understood. Here, we show that the assembly of nodes of Ranvier in the CNS involves three mechanisms: a glia-derived extracellular matrix (ECM) complex containing proteoglycans and adhesion molecules that cluster NF186, paranodal axoglial junctions that function as barriers to restrict the position of nodal proteins, and axonal cytoskeletal scaffolds (CSs) that stabilize nodal Na⁺ channels. We show that while mice with a single disrupted mechanism had mostly normal nodes, disruptions of the ECM and paranodal barrier, the ECM and CS, or the paranodal barrier and CS all lead to juvenile lethality, profound motor dysfunction, and significantly reduced Na⁺ channel clustering. Our results demonstrate that ECM, paranodal, and axonal cytoskeletal mechanisms ensure robust CNS nodal Na⁺ channel clustering.

Published
2013

23. Antibody-directed extracellular proximity biotinylation reveals Contactin-1 regulates axo-axonic innervation of axon initial segments

Author

Ogawa, Yuki, primary, Lim, Brian C., additional, George, Shanu, additional, Oses-Prieto, Juan A., additional, Rasband, Joshua M., additional, Eshed-Eisenbach, Yael, additional, Nair, Supna, additional, Boato, Francesco, additional, Peles, Elior, additional, Burlingame, Alma L., additional, Aelst, Linda Van, additional, and Rasband, Matthew N., additional

Published
2023
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25. LGI3/2-ADAM23 interactions cluster Kv1 channels in myelinated axons to regulate refractory period

Author

Kozar-Gillan, Nina, Velichkova, Atanaska, Kanatouris, George, Eshed-Eisenbach, Yael, Steel, Gavin, Jaegle, Martine, Aunin, Eerik, Peles, Elior, Torsney, Carole, Meijer, Dies N., Kozar-Gillan, Nina, Velichkova, Atanaska, Kanatouris, George, Eshed-Eisenbach, Yael, Steel, Gavin, Jaegle, Martine, Aunin, Eerik, Peles, Elior, Torsney, Carole, and Meijer, Dies N.

Abstract

Along myelinated axons, Shaker-type potassium channels (Kv1) accumulate at high density in the juxtaparanodal region, directly adjacent to the paranodal axon-glia junctions that flank the nodes of Ranvier. However, the mechanisms that control the clustering of Kv1 channels, as well as their function at this site, are still poorly understood. Here we demonstrate that axonal ADAM23 is essential for both the accumulation and stability of juxtaparanodal Kv1 complexes. The function of ADAM23 is critically dependent on its interaction with its extracellular ligands LGI2 and LGI3. Furthermore, we demonstrate that juxtaparanodal Kv1 complexes affect the refractory period, thus enabling high-frequency burst firing of action potentials. Our findings not only reveal a previously unknown molecular pathway that regulates Kv1 channel clustering, but they also demonstrate that the juxtaparanodal Kv1 channels that are concealed below the myelin sheath, play a significant role in modifying axonal physiology.

Published
2023

29. LGI3/2-ADAM23 interactions cluster Kv1 channels in myelinated axons to fine-tune axonal properties

Author

Kozar-Gillan, Nina, Velichkova, Atanaska, Kanatouris, George, Eshed-Eisenbach, Yael, Steel, Gavin, Jaegle, Martine, Aunin, Eerik, Peles, Elior, Torsney, Carole, and Meijer, Dies N.

Abstract

Along myelinated axons, Shaker-type potassium channels (Kv1) accumulate at high density in the juxtaparanodal region, directly adjacent to the paranodal axon–glia junctions that flank the nodes of Ranvier. However, the mechanisms that control the clustering of Kv1 channels, as well as their function at this site, are still poorly understood. Here we demonstrate that axonal ADAM23 is essential for both the accumulation and stability of juxtaparanodal Kv1 complexes. The function of ADAM23 is critically dependent on its interaction with its extracellular ligands LGI2 and LGI3. Furthermore, we demonstrate that juxtaparanodal Kv1 complexes affect the refractory period, thus enabling high-frequency burst firing of action potentials. Our findings not only reveal a previously unknown molecular pathway that regulates Kv1 channel clustering, but they also demonstrate that the juxtaparanodal Kv1 channels that are concealed below the myelin sheath, play a significant role in modifying axonal physiology.

Published
2023

31. Coiling of cellular protrusions around extracellular fibers

Author

Sadhu, Raj Kumar, primary, Hernandez-Padilla, Christian, additional, Eisenbach, Yael Eshed, additional, Zhang, Lixia, additional, Vishwasrao, Harshad D, additional, Behkam, Bahareh, additional, Shroff, Hari, additional, Igli\v{c}, Ale\v{s}, additional, Peles, Elior, additional, Nain, Amrinder, additional, and Gov, Nir, additional

Published
2022
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37. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder

Author

Lossos, Alexander, Elazar, Nimrod, Lerer, Israela, Schueler-Furman, Ora, Fellig, Yakov, Glick, Benjamin, Zimmerman, Bat-El, Azulay, Haim, Dotan, Shlomo, Goldberg, Sharon, Gomori, John M., Ponger, Penina, Newman, J. P., Marreed, Hodaifah, Steck, Andreas J., Schaeren-Wiemers, Nicole, Mor, Nofar, Harel, Michal, Geiger, Tamar, Eshed-Eisenbach, Yael, Meiner, Vardiella, and Peles, Elior

Published
2015
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39. Erratum to: A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement

Author

Rebelo, Adriana P, primary, Cortese, Andrea, additional, Abraham, Amit, additional, Eshed-Eisenbach, Yael, additional, Shner, Gal, additional, Vainshtein, Anna, additional, Buglo, Elena, additional, Camarena, Vladimir, additional, Gaidosh, Gabriel, additional, Shiekhattar, Ramin, additional, Abreu, Lisa, additional, Courel, Steve, additional, Burns, Dennis K, additional, Bai, Yunhong, additional, Bacon, Chelsea, additional, Feely, Shawna M E, additional, Castro, Diana, additional, Peles, Elior, additional, Reilly, Mary M, additional, Shy, Michael E, additional, and Zuchner, Stephan, additional

Published
2021
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40. Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects

Author

Repudi, Srinivasarao, primary, Steinberg, Daniel J, additional, Elazar, Nimrod, additional, Breton, Vanessa L, additional, Aquilino, Mark S, additional, Saleem, Afifa, additional, Abu-Swai, Sara, additional, Vainshtein, Anna, additional, Eshed-Eisenbach, Yael, additional, Vijayaragavan, Bharath, additional, Behar, Oded, additional, Hanna, Jacob J, additional, Peles, Elior, additional, Carlen, Peter L, additional, and Aqeilan, Rami I, additional

Published
2021
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41. A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement

Author

Rebelo, Adriana P, primary, Cortese, Andrea, additional, Abraham, Amit, additional, Eshed-Eisenbach, Yael, additional, Shner, Gal, additional, Vainshtein, Anna, additional, Buglo, Elena, additional, Camarena, Vladimir, additional, Gaidosh, Gabriel, additional, Shiekhattar, Ramin, additional, Abreu, Lisa, additional, Courel, Steve, additional, Burns, Dennis K, additional, Bai, Yunhong, additional, Bacon, Chelsea, additional, Feely, Shawna M E, additional, Castro, Diana, additional, Peles, Elior, additional, Reilly, Mary M, additional, Shy, Michael E, additional, and Zuchner, Stephan, additional

Published
2021
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