Ciliogenesis and the DNA Damage Response: a Stressful Relationship Colin A
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Par6c Is at the Mother Centriole and Controls Centrosomal Protein
860 Research Article Par6c is at the mother centriole and controls centrosomal protein composition through a Par6a-dependent pathway Vale´rian Dormoy, Kati Tormanen and Christine Su¨ tterlin* Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697-2300, USA *Author for correspondence ([email protected]) Accepted 3 December 2012 Journal of Cell Science 126, 860–870 ß 2013. Published by The Company of Biologists Ltd doi: 10.1242/jcs.121186 Summary The centrosome contains two centrioles that differ in age, protein composition and function. This non-membrane bound organelle is known to regulate microtubule organization in dividing cells and ciliogenesis in quiescent cells. These specific roles depend on protein appendages at the older, or mother, centriole. In this study, we identified the polarity protein partitioning defective 6 homolog gamma (Par6c) as a novel component of the mother centriole. This specific localization required the Par6c C-terminus, but was independent of intact microtubules, the dynein/dynactin complex and the components of the PAR polarity complex. Par6c depletion resulted in altered centrosomal protein composition, with the loss of a large number of proteins, including Par6a and p150Glued, from the centrosome. As a consequence, there were defects in ciliogenesis, microtubule organization and centrosome reorientation during migration. Par6c interacted with Par3 and aPKC, but these proteins were not required for the regulation of centrosomal protein composition. Par6c also associated with Par6a, which controls protein recruitment to the centrosome through p150Glued. Our study is the first to identify Par6c as a component of the mother centriole and to report a role of a mother centriole protein in the regulation of centrosomal protein composition. -
Establishment of the Early Cilia Preassembly Protein Complex
Establishment of the early cilia preassembly protein PNAS PLUS complex during motile ciliogenesis Amjad Horania,1, Alessandro Ustioneb, Tao Huangc, Amy L. Firthd, Jiehong Panc, Sean P. Gunstenc, Jeffrey A. Haspelc, David W. Pistonb, and Steven L. Brodyc aDepartment of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110; bDepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; cDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and dDepartment of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033 Edited by Kathryn V. Anderson, Sloan Kettering Institute, New York, NY, and approved December 27, 2017 (received for review September 9, 2017) Motile cilia are characterized by dynein motor units, which preas- function of these proteins is unknown; however, missing dynein semble in the cytoplasm before trafficking into the cilia. Proteins motor complexes in the cilia of mutants and cytoplasmic locali- required for dynein preassembly were discovered by finding human zation (or absence in the cilia proteome) suggest a role in the mutations that result in absent ciliary motors, but little is known preassembly of dynein motor complexes. Studies in C. reinhardtii about their expression, function, or interactions. By monitoring show motor components in the cell body before transport to ciliogenesis in primary airway epithelial cells and MCIDAS-regulated flagella (22–25). However, the expression, interactions, and induced pluripotent stem cells, we uncovered two phases of expres- functions of preassembly proteins, as well as the steps required sion of preassembly proteins. An early phase, composed of HEATR2, for preassembly, are undefined. -
Reconstructions of Centriole Formation and Ciliogenesis in Mammalian Lungs
J. Cell Sci. 3, 207-230 (1968) 207 Printed in Great Britain RECONSTRUCTIONS OF CENTRIOLE FORMATION AND CILIOGENESIS IN MAMMALIAN LUNGS S. P. SOROKIN Department of Anatomy, Harvard Medical School, Boston, Massachusetts 02115, U.S.A. SUMMARY This study presents reconstructions of the processes of centriolar formation and ciliogenesis based on evidence found in electron micrographs of tissues and organ cultures obtained chiefly from the lungs of foetal rats. A few observations on living cultures supplement the major findings. In this material, centrioles are generated by two pathways. Those centrioles that are destined to participate in forming the achromatic figure, or to sprout transitory, rudimentary (primary) cilia, arise directly off the walls of pre-existing centrioles. In pulmonary cells of all types this direct pathway operates during interphase. The daughter centrioles are first recognizable as annular structures (procentrioles) which lengthen into cylinders through acropetal deposition of osmiophilic material in the procentriolar walls. Triplet fibres develop in these walls from singlet and doublet fibres that first appear near the procentriolar bases and thereafter extend apically. When little more than half grown, the daughter centrioles are released into the cyto- plasm, where they complete their maturation. A parent centriole usually produces one daughter at a time. Exceptionally, up to 8 have been observed to develop simultaneously about 1 parent centriole. Primary cilia arise from directly produced centrioles in differentiating pulmonary cells of all types throughout the foetal period. In the bronchial epithelium they appear before the time when the ciliated border is generated. Fairly late in foetal life, centrioles destined to become kinetosomes in ciliated cells of the epithelium become assembled from masses of fibrogranular material located in the apical cytoplasm. -
Ninein, a Microtubule Minus-End Anchoring Protein 3015 Analysis As Described Previously (Henderson Et Al., 1994)
Journal of Cell Science 113, 3013-3023 (2000) 3013 Printed in Great Britain © The Company of Biologists Limited 2000 JCS1634 Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein Mette M. Mogensen1,*, Azer Malik1, Matthieu Piel2, Veronique Bouckson-Castaing2 and Michel Bornens2 1Department of Anatomy and Physiology, MSI/WTB complex, Dow Street, University of Dundee, Dundee, DD1 5EH, UK 2Institute Curie, UMR 144-CNRS, 26 Rue d’Ulm, 75248 Paris Cedex 05, France *Author for correspondence (e-mail: [email protected]) Accepted 14 June; published on WWW 9 August 2000 SUMMARY The novel concept of a centrosomal anchoring complex, epithelial cells, where the vast majority of the microtubule which is distinct from the γ-tubulin nucleating complex, has minus-ends are associated with apical non-centrosomal previously been proposed following studies on cochlear sites, suggests that it is not directly involved in microtubule epithelial cells. In this investigation we present evidence nucleation. Ninein seems to play an important role in the from two different cell systems which suggests that the positioning and anchorage of the microtubule minus-ends centrosomal protein ninein is a strong candidate for the in these epithelial cells. Evidence is presented which proposed anchoring complex. suggests that ninein is released from the centrosome, Ninein has recently been observed in cultured fibroblast translocated with the microtubules, and is responsible for cells to localise primarily to the post-mitotic mother the anchorage of microtubule minus-ends to the apical centriole, which is the focus for a classic radial microtubule sites. We propose that ninein is a non-nucleating array. -
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242 S-M Ho et al. Regulation of centrosome 24:2 83–96 Research duplication by BPA analogues Bisphenol A and its analogues disrupt centrosome cycle and microtubule dynamics in prostate cancer Shuk-Mei Ho1,2,3,4, Rahul Rao1, Sarah To1,5,6, Emma Schoch1 and Pheruza Tarapore1,2,3 1Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio, USA 2Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio, USA Correspondence 3Cincinnati Cancer Center, Cincinnati, Ohio, USA should be addressed 4Cincinnati Veteran Affairs Hospital Medical Center, Cincinnati, Ohio, USA to S-M Ho or P Tarapore 5Center for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia Email 6Monash University, Clayton, Victoria, Australia [email protected] or [email protected] Abstract Humans are increasingly exposed to structural analogues of bisphenol A (BPA), as Key Words BPA is being replaced by these compounds in BPA-free consumer products. We have f endocrine-disrupting previously shown that chronic and developmental exposure to BPA is associated with chemicals increased prostate cancer (PCa) risk in human and animal models. Here, we examine f bisphenol A analogues whether exposure of PCa cells (LNCaP, C4-2) to low-dose BPA and its structural analogues f BPA (BPS, BPF, BPAF, TBBPA, DMBPA and TMBPA) affects centrosome amplification (CA), f BPS a hallmark of cancer initiation and progression. We found that exposure to BPA, BPS, f BPF DMBPA and TBBPA, in descending order, increased the number of cells with CA, in a non- f TBBPA Endocrine-Related Cancer Endocrine-Related monotonic dose–response manner. -
Is Cep70, a Centrosomal Protein with New Roles in Breast Cancer Dissemination and Metastasis, a Facilitator of Epithelial-Mesenchymal Transition?
Is Cep70, a centrosomal protein with new roles in breast cancer dissemination and metastasis, a facilitator of epithelial-mesenchymal transition? Pedro A. Lazo 1,2 1 Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, Salamanca, Spain 2 Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain Running title: Cep70 and EMT Disclosures: None declared. Contact address: [email protected] 1 Introduction Microtubules are driving mechanisms of chromosomes, intracellular organelle movement, and cell shape and motility. Microtubules are organized on centrosomes, which are assembled in microtubule-organizing centers (MTOC). In mitosis there is no nuclear envelope and centromeres associated to microtubules are mainly involved in chromosome redistribution into daughter cells. In differentiated cells the microtubule- organizing centers are dispersed in the cytoplasm (non centrosomal (ncMTOC)) and interact with the minus end of microtubules through γ-tubulin. 1 However, it is not known if the microtubule contribution to tumor biology is only by facilitating tumor aneuploidy. During tumor dissemination, a process not linked to cell division, important changes take place in cell shape and motility. Microtubules are very dynamic because of their inherent structural instability, and this plasticity facilitates their reorganization during the epithelial-mesenchymal -
Assembly of Centrosomal Proteins and Microtubule Organization Depends on PCM-1
JCBArticle Assembly of centrosomal proteins and microtubule organization depends on PCM-1 Alexander Dammermann and Andreas Merdes Wellcome Trust Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh EH9 3JR, UK he protein PCM-1 localizes to cytoplasmic granules treatment of cells with the microtubule inhibitor nocodazole. known as “centriolar satellites” that are partly enriched Inhibition or depletion of PCM-1 function further disrupted T around the centrosome. We inhibited PCM-1 function the radial organization of microtubules without affecting using a variety of approaches: microinjection of antibodies microtubule nucleation. Loss of microtubule organization into cultured cells, overexpression of a PCM-1 deletion was also observed after centrin or ninein depletion. Our mutant, and specific depletion of PCM-1 by siRNA. All data suggest that PCM-1–containing centriolar satellites are Downloaded from approaches led to reduced targeting of centrin, pericentrin, involved in the microtubule- and dynactin-dependent recruit- and ninein to the centrosome. Similar effects were seen ment of proteins to the centrosome, of which centrin and upon inhibition of dynactin by dynamitin, and after prolonged ninein are required for interphase microtubule organization. jcb.rupress.org Introduction Microtubule organization is essential for directional intra- the centrosomal surface or subsequently released and anchored cellular transport, for the modulation of cell morphology in other places of the cell (Mogensen, 1999). The initial step and locomotion, and for the formation of the spindle apparatus of microtubule nucleation is dependent on the function of during cell division. With the exception of plants, most cells 25S ring complexes of the protein ␥-tubulin and associated on December 31, 2017 organize their microtubule network using specialized structures, proteins (Zheng et al., 1995). -
Microtubule Regulation in Cystic Fibrosis Pathophysiology
MICROTUBULE REGULATION IN CYSTIC FIBROSIS PATHOPHYSIOLOGY By: SHARON MARIE RYMUT Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Thomas J Kelley Department of Pharmacology CASE WESTERN RESERVE UNIVERSITY August 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/ dissertation of Sharon Marie Rymut candidate for the Doctor of Philosophy degree* Dissertation Advisor: Thomas J Kelley Committee Chair: Paul N MacDonald Committee Member: Ruth E Siegel Committee Member: Craig A Hodges Committee Member: Danny Manor Committee Member: Rebecca J Darrah Date of Defense: April 29, 2015 * We also certify that written approval has been obtained for any proprietary material contained therein. ii Dedication There are five chapters in this dissertation. To Mom, Dad, Joe, Marie and Susan, I dedicate one chapter to each of you. You can fight about which chapter you want later. iii Table of Contents Table of Contents................................................................................................................iv List of Tables .................................................................................................................... vii List of Figures .................................................................................................................. viii Acknowledgements ............................................................................................................. x List of Abbreviations ....................................................................................................... -
Ciliary Dyneins and Dynein Related Ciliopathies
cells Review Ciliary Dyneins and Dynein Related Ciliopathies Dinu Antony 1,2,3, Han G. Brunner 2,3 and Miriam Schmidts 1,2,3,* 1 Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Mathildenstrasse 1, 79106 Freiburg, Germany; [email protected] 2 Genome Research Division, Human Genetics Department, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 KL Nijmegen, The Netherlands; [email protected] 3 Radboud Institute for Molecular Life Sciences (RIMLS), Geert Grooteplein Zuid 10, 6525 KL Nijmegen, The Netherlands * Correspondence: [email protected]; Tel.: +49-761-44391; Fax: +49-761-44710 Abstract: Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel Citation: Antony, D.; Brunner, H.G.; developments in the field. -
Putative Roles of Cilia in Polycystic Kidney Disease☆
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1812 (2011) 1256–1262 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Review Putative roles of cilia in polycystic kidney disease☆ Paul Winyard a, Dagan Jenkins b,⁎ a Nephro-Urology Unit, UCL Institute of Child Health, 30 Guilford St, London, WC1N 1EH, UK b Molecular Medicine Unit, UCL Institute of Child Health, 30 Guilford St, London, WC1N 1EH, UK article info abstract Article history: The last 10 years has witnessed an explosion in research into roles of cilia in cystic renal disease. Cilia are Received 26 November 2010 membrane-enclosed finger-like projections from the cell, usually on the apical surface or facing into a lumen, Received in revised form 18 April 2011 duct or airway. Ten years ago, the major recognised functions related to classical “9+2” cilia in the respiratory Accepted 29 April 2011 and reproductive tracts, where co-ordinated beating clears secretions and assists fertilisation respectively. Available online 8 May 2011 Primary cilia, which have a “9+0” arrangement lacking the central microtubules, were anatomical curiosities but several lines of evidence have implicated them in both true polycystic kidney disease and other cystic Keywords: Cilia renal conditions: ranging from the homology between Caenorhabditis elegans proteins expressed on sensory Development cilia to mammalian polycystic kidney disease (PKD) 1 and 2 proteins, through the discovery that orpk cystic Wnt mice have structurally abnormal cilia to numerous recent studies wherein expression of nearly all cyst- Hedgehog associated proteins has been reported in the cilia or its basal body. -
The Transformation of the Centrosome Into the Basal Body: Similarities and Dissimilarities Between Somatic and Male Germ Cells and Their Relevance for Male Fertility
cells Review The Transformation of the Centrosome into the Basal Body: Similarities and Dissimilarities between Somatic and Male Germ Cells and Their Relevance for Male Fertility Constanza Tapia Contreras and Sigrid Hoyer-Fender * Göttingen Center of Molecular Biosciences, Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology-Developmental Biology, Faculty of Biology and Psychology, Georg-August University of Göttingen, 37077 Göttingen, Germany; [email protected] * Correspondence: [email protected] Abstract: The sperm flagellum is essential for the transport of the genetic material toward the oocyte and thus the transmission of the genetic information to the next generation. During the haploid phase of spermatogenesis, i.e., spermiogenesis, a morphological and molecular restructuring of the male germ cell, the round spermatid, takes place that includes the silencing and compaction of the nucleus, the formation of the acrosomal vesicle from the Golgi apparatus, the formation of the sperm tail, and, finally, the shedding of excessive cytoplasm. Sperm tail formation starts in the round spermatid stage when the pair of centrioles moves toward the posterior pole of the nucleus. The sperm tail, eventually, becomes located opposed to the acrosomal vesicle, which develops at the anterior pole of the nucleus. The centriole pair tightly attaches to the nucleus, forming a nuclear membrane indentation. An Citation: Tapia Contreras, C.; articular structure is formed around the centriole pair known as the connecting piece, situated in the Hoyer-Fender, S. The Transformation neck region and linking the sperm head to the tail, also named the head-to-tail coupling apparatus or, of the Centrosome into the Basal in short, HTCA. -
Transient Ciliogenesis Involving Bardet-Biedl Syndrome Proteins Is a Fundamental Characteristic of Adipogenic Differentiation
Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation Vincent Mariona,1, Corinne Stoetzela, Dominique Schlichta, Nadia Messaddeqb, Michael Kochb, Elisabeth Floric, Jean Marc Dansea, Jean-Louis Mandelb,d, and He´ le` ne Dollfusa aLaboratoire Physiopathologie des Syndromes Rares He´re´ ditaires, AVENIR-Inserm, EA3949, Faculte´deMe´ decine de Strasbourg, Universite´Louis Pasteur, 11 rue Humann, 67085 Strasbourg, France; bInstitut de Ge´ne´ tique et de Biologie Mole´culaire et Cellulaire, Inserm U596, CNRS, UMR7104; Universite´Louis Pasteur, Strasbourg, Illkirch, F-67400 France; cService de Cytoge´ne´ tique, Hoˆpitaux Universitaires de Strasbourg, Avenue Molie`re, Strasbourg, France; and dChaire de Ge´ne´ tique Humaine, Colle`ge de France, Illkirch, F-67400 France Communicated by Pierre Chambon, Institut de Ge´ne´ tique et de Biologie Mole´culaire et Cellulaire, Illkirch-Cedex, France, December 10, 2008 (received for review September 4, 2008) Bardet-Biedl syndrome (BBS) is an inherited ciliopathy generally pocytes in a process described as adipogenesis (14). At this cross- associated with severe obesity, but the underlying mechanism road, several pathways antagonize each other: the antiadipogenic remains hypothetical and is generally proposed to be of neuroen- Wnt and Hh pathways are potent inhibitors of adipogenesis, whose docrine origin. In this study, we show that while the proliferating activities need to be repressed before the cells can undergo final preadipocytes or mature adipocytes are nonciliated in culture, a differentiation, whereas the peroxisome proliferator-activated re- typical primary cilium is present in differentiating preadipocytes. ceptor-␥ (PPAR␥) and CCAAT-enhancer-binding proteins (c/ This transient cilium carries receptors for Wnt and Hedgehog EBP␣,-) are potent pro-adipogenic factors (15–17).