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- ArticleMutant MRPS5 affects mitoribosomal accuracy and confers stress‐related behavioral alterations
- Rashid Akbergenov1,†,
- Stefan Duscha1,†,
- Ann‐Kristina Fritz2,3,†,
- Reda Juskeviciene1,†,
- Naoki Oishi4,10,
- Karen Schmitt5,
- Dimitri Shcherbakov1,
- Youjin Teo1,
- Heithem Boukari1,
- Pietro Freihofer1,
- Patricia Isnard‐Petit6,
- Björn Oettinghaus7,
- Stephan Frank7,
- Kader Thiam6,
- Hubert Rehrauer8,
- Eric Westhof9,
- Jochen Schacht4,
- Anne Eckert5,
- David Wolfer2,3 and
- Erik C Böttger (boettger{at}imm.uzh.ch)*,1
- 1Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland
- 2Anatomisches Institut, Universität Zürich, Zürich, Switzerland
- 3Institut für Bewegungswissenschaften und Sport, ETH Zürich, Zürich, Switzerland
- 4Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA
- 5Transfaculty Research Platform Molecular and Cognitive Neurosciences, Universitäre Psychiatrische Kliniken Basel, Basel, Switzerland
- 6GenOway, Lyon Cedex 07, France
- 7Neuro‐ und Ophthalmopathologie, Universitätsspital Basel, Basel, Switzerland
- 8Functional Genomics Center Zurich, ETH Zürich und Universität Zürich, Zürich, Switzerland
- 9Institut de biologie moléculaire et cellulaire du CNRS, Université de Strasbourg, Strasbourg, France
- 10Present Address: Department of Otolaryngology – Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan
- ↵*Corresponding author. Tel: +41 44 634 26 60; Fax: +41 44 634 49 06; E‐mail: boettger{at}imm.uzh.ch
↵† These authors contributed equally to this work
Mitochondrial mistranslation due to mutations in the mitochondrial 12S rRNA was proposed to cause hearing deficits. This study establishes a mouse model for mitochondrial mistranslation based on mutation of the mitoribosomal protein MRPS5, which recapitulates the suggested pathomechanism of the A1555G 12S rRNA mutation.
Synopsis
An experimental model of mitochondrial mistranslation based on the mutation V336Y in mitoribosomal protein MRPS5 recapitulates the suggested pathomechanism of the A1555G mutation in mitochondrial 12S rRNA.
Accuracy of mitochondrial protein synthesis can be assessed by in organello translation of MT‐CO1.
Mutation V336Y in MRPS5 confers mitoribosomal misreading.
MRPS5 V336Y knock‐in mice reproduce the hearing‐related deficit in the absence of non‐cochlear pathology that characterizes the A1555G mutation.
Further assessment of the in vivo model points to a key role for mitochondrial function in behavioral and physiological adaptations.
EMBO Reports (2018) e46193
- Received March 28, 2018.
- Revision received August 21, 2018.
- Accepted August 24, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- ArticleThe dual role of the centrosome in organizing the microtubule network in interphase
- Maria P Gavilan1,†,
- Pablo Gandolfo1,†,
- Fernando R Balestra1,
- Francisco Arias1,
- Michel Bornens2 and
- Rosa M Rios (rosa.rios{at}cabimer.es)*,1
- 1Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla‐CSIC‐Universidad Pablo de Olavide, Seville, Spain
- 2UMR144 CNRS‐Institut Curie, Paris Cedex 05, France
- ↵*Corresponding author. Tel: +34 954467996; E‐mail: rosa.rios{at}cabimer.es
↵† These authors contributed equally to this work
The activity of microtubule‐organizing centers during interphase is regulated in a hierarchical manner. The centrosome controls Golgi apparatus activity, and both of them inhibit γ‐tubulin‐dependent MT nucleation from cytoplasmic aggregates.
Synopsis
During interphase, microtubules can be generated from a variety of microtubule‐organizing centers (MTOCs) the activity of which is regulated in a hierarchical manner. The centrosome (CTR) controls Golgi apparatus (GA) activity, and both of them inhibit MT nucleation from cytoplasmic aggregates (cMTOCs). When all MTOCs are inactive, individual MTs can still form in a γ‐tubulin dependent manner.
Canonical γ‐TuRC receptors are essential for Golgi and cytoplasmic MT nucleation but they are dispensable for the centrosome that employs additional mechanisms.
The centrosome negatively regulates alternative MTOCs, thereby limiting the total number of MTs during interphase.
EMBO Reports (2018) e45942
- Received February 9, 2018.
- Revision received August 27, 2018.
- Accepted August 29, 2018.
- © 2018 The Authors
- Scientific ReportNetrin‐1/DCC‐mediated PLCγ1 activation is required for axon guidance and brain structure development
- Du‐Seock Kang1,2,
- Yong Ryoul Yang1,
- Cheol Lee1,
- BumWoo Park1,
- Kwang IL Park1,
- Jeong Kon Seo3,
- Young Kyo Seo1,
- HyungJoon Cho1,
- Cocco Lucio4 and
- Pann‐Ghill Suh (pgsuh{at}unist.ac.kr)*,1
- 1School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea
- 2College of Life Science & Bioengineering, Korea Advanced Institute of Science & Technology (KAIST), Daejeon, Korea
- 3UNIST Central Research Facility, Ulsan National Institute of Science and Technology, Ulsan, Korea
- 4Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- ↵*Corresponding author. Tel: +82 52 217 2621; E‐mail: pgsuh{at}unist.ac.kr
Netrin‐1 activates PLCγ1 via Src kinase, which is crucial for axon guidance and corpus callosum and mDA system development.
Synopsis
Netrin‐1 activates PLCγ1 via Src kinase, which is crucial for axon guidance and corpus callosum and mDA system development.
PLCγ1 promotes axon extension and guidance by mediating netrin‐1/DCC signaling.
Netrin‐1 activates the lipase activity of PLCγ1 through phosphorylation of the Y783‐residue by Src kinase.
Disruption of PLCγ1 signaling adversely affects corpus callosum structural and mDA system development.
EMBO Reports (2018) e46250
- Received April 9, 2018.
- Revision received August 11, 2018.
- Accepted August 23, 2018.
- © 2018 The Authors
- Scientific ReportSIRT2‐mediated inactivation of p73 is required for glioblastoma tumorigenicity
- Kosuke Funato1,2,†,
- Tomoatsu Hayashi1,†,
- Kanae Echizen1,
- Lumi Negishi1,
- Naomi Shimizu1,
- Ryo Koyama‐Nasu1,
- Yukiko Nasu‐Nishimura1,
- Yasuyuki Morishita3,
- Viviane Tabar2,
- Tomoki Todo4,
- Yasushi Ino4,
- Akitake Mukasa4,
- Nobuhito Saito4 and
- Tetsu Akiyama (akiyama{at}iam.u-tokyo.ac.jp)*,1
- 1Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo‐ku, Tokyo, Japan
- 2Department of Neurosurgery, Memorial Sloan‐Kettering Cancer Center, New York, NY, USA
- 3Department of Human Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo‐ku, Tokyo, Japan
- 4Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Bunkyo‐ku, Tokyo, Japan
- ↵*Corresponding author. Tel: +81 3 5841 7834; Fax: +81 3 5841 8482; E‐mail: akiyama{at}iam.u-tokyo.ac.jp
↵† These authors contributed equally to this work
SIRT2 targets the tumor suppressor p73, thereby deacetylating its C‐terminus and suppressing its transcriptional activity. SIRT2‐mediated inactivation of p73 is crucial for the tumorigenicity of glioblastoma cells.
Synopsis
SIRT2 targets the tumor suppressor p73, thereby deacetylating its C‐terminus and suppressing its transcriptional activity. SIRT2‐mediated inactivation of p73 is crucial for the tumorigenicity of glioblastoma cells.
The lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of glioblastoma cells.
SIRT2 targets and regulates the transcriptional activity of the tumor suppressor p73.
SIRT2‐mediated inactivation of p73 is critical for the proliferation and tumorigenicity of glioblastoma cells.
EMBO Reports (2018) e45587
- Received December 8, 2017.
- Revision received August 16, 2018.
- Accepted August 21, 2018.
- © 2018 The Authors
- Scientific ReportSingle‐cell transcriptomics reveals distinct inflammation‐induced microglia signatures
- Carole Sousa1,2,3,
- Anna Golebiewska1,
- Suresh K Poovathingal2,4,
- Tony Kaoma5,
- Yolanda Pires‐Afonso1,3,
- Silvia Martina2,
- Djalil Coowar2,
- Francisco Azuaje5,
- Alexander Skupin2,6,
- Rudi Balling2,
- Knut Biber7,8,
- Simone P Niclou1,9 and
- Alessandro Michelucci (alessandro.michelucci{at}lih.lu)*,1,2
- 1NORLUX Neuro‐Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
- 2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch‐Belval, Luxembourg
- 3Doctoral School of Science and Technology, University of Luxembourg, Esch‐sur‐Alzette, Luxembourg
- 4Single Cell Analytics & Microfluidics Core, Vlaams Instituut voor Biotechnologie‐KU Leuven, Leuven, Belgium
- 5Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
- 6National Centre for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA, USA
- 7Section Molecular Psychiatry, Department for Psychiatry and Psychotherapy, Laboratory of Translational Psychiatry, Medical Center ‐ University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- 8Section Medical Physiology, Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- 9Department of Biomedicine, KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
- ↵*Corresponding author. Tel: +352 26970 263; E‐mail: alessandro.michelucci{at}lih.lu
Using single‐cell transcriptomics and multicolour flow cytometry this study presents comprehensive profiles of microglia in LPS‐injected mice, providing insight into microglia heterogeneity, and establishing a resource for the identification of specific phenotypes in CNS disorders.
Synopsis
Using single‐cell transcriptomics and multicolour flow cytometry this study presents comprehensive profiles of microglia in LPS‐injected mice, providing insight into microglia heterogeneity, and establishing a resource for the identification of specific phenotypes in CNS disorders.
Microglia homeostatic signatures are mainly lost upon acute systemic inflammation.
Inflammation‐induced microglia segregate into two distinct reactive states.
Inflammation‐induced microglia signatures are distinct from neurodegenerative disease‐associated profiles.
EMBO Reports (2018) e46171
- Received March 23, 2018.
- Revision received August 17, 2018.
- Accepted August 22, 2018.
- © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- Scientific ReportOpposing kinesin complexes queue at plus tips to ensure microtubule catastrophe at cell ends
- John C Meadows (J.C.Meadows{at}warwick.ac.uk)*,1,†,
- Liam J Messin1,†,
- Anton Kamnev1,
- Theresa C Lancaster1,
- Mohan K Balasubramanian1,
- Robert A Cross1 and
- Jonathan BA Millar (J.Millar{at}warwick.ac.uk)*,1
- 1Division of Biomedical Sciences, Centre for Mechanochemical Cell Biology, Warwick Medical School, University of Warwick, Coventry, UK
- ↵*
Corresponding author. Tel: +44 24 76150414; E‐mail: J.C.Meadows{at}warwick.ac.uk
Corresponding author. Tel: +44 24 76150414; E‐mail: J.Millar{at}warwick.ac.uk
↵† These authors contributed equally to this work
Spatially regulated competition between the de‐stabilizing Kinesin‐8 and the stabilizing Kinesin‐7 complex at the microtubule plus tip regulates the length of interphase microtubules in fission yeast.
Synopsis
During interphase, the de‐stabilising Klp5/Klp6/Mcp1 (Kinesin‐8) complex accumulates behind the stabilising Tea2/Tea1/Tip1 (Kinesin‐7) complex at microtubule plus tips. When microtubules encounter the cell end, Kinesin‐8 invades the space occupied by Kinesin‐7 to trigger microtubule catastrophe.
Mcp1 is an interphase specific component of the fission yeast Klp5/Klp6 (Kinesin‐8) complex.
Mcp1 is required for Kinesin‐8‐mediated microtubule de‐stabilisation but not the processivity of the motor complex.
Klp5/Klp6/Mcp1 accumulates behind Tea2/Tea1/Tip1 (Kinesin‐7) complex, which blocks Kinesin‐8 access to microtubule plus tips until the microtubule reaches the cell end.
Competition between Kinesin‐7 and Kinesin‐8 ensures microtubule catastrophe occurs at cell ends.
EMBO Reports (2018) e46196
- Received March 28, 2018.
- Revision received August 21, 2018.
- Accepted August 23, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- ArticleVesicle sub‐pool organization at inner hair cell ribbon synapses
- Rituparna Chakrabarti1,2,3,4,
- Susann Michanski1,2,3,5 and
- Carolin Wichmann (carolin.wichmann{at}med.uni-goettingen.de)*,1,2,3
- 1Molecular Architecture of Synapses Group, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
- 2Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany
- 3Collaborative Research Center 889 “Cellular Mechanisms of Sensory Processing”, Göttingen, Germany
- 4Göttingen Graduate School for Neurosciences, Biophysics and Molecular Biosciences, University of Göttingen, Göttingen, Germany
- 5Georg‐August University School of Science, Göttingen, Germany
- ↵*Corresponding author. Tel: +49 551 3961128; E‐mail: carolin.wichmann{at}med.uni-goettingen.de
Distinct sub‐pools of ribbon‐associated and membrane‐proximal vesicles govern exocytosis at murine cochlear inner hair cells. Based on these findings, a vesicle route in the course of exocytosis is proposed for ribbon synapses.
Synopsis
Distinct vesicular sub‐pools are present at inner hair cell ribbon synapses. These sub‐pools of ribbon‐associated and membrane‐proximal vesicles govern exocytosis at murine cochlear inner hair cells. Based on the findings, a vesicle route in the course of exocytosis is proposed for ribbon synapses.
Near‐to‐native 3D‐ultrastructure of resting wild‐type synapses revealed vesicle sub‐pools determined via the associated filament‐number and the structures they attach to.
Prolonged activity triggers an increase of vesicles interconnected to each other and simultaneously to the distal ribbon part. At the membrane, a shift towards more single‐tethered vesicles occurs.
In the otoferlin mutant pachanga vesicle sub‐pools were investigated under reduced sustained release. During activity, the filament‐connectivity between vesicles and the ribbon was less complex compared to wild‐type, but multiple‐tethered and docked vesicles accumulated at active zone membranes possibly due to impaired release site clearance.
During exocytosis, vesicles travel to the AZ‐membrane, where they prepare via single‐ and multiple tethers for docking and fusion.
EMBO Reports (2018) e44937
- Received July 31, 2017.
- Revision received August 7, 2018.
- Accepted August 21, 2018.
- © 2018 The Authors
