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Advances in Anatomy, Embryology and Cell Biology Heide Schatten The Centrosome and its Functions and Dysfunctions Advances in Anatomy, Embryology and Cell Biology Volume 235 Editor-in-Chief Peter Sutovsky, Division of Animal Sciences and Department of Obstetrics, Gynecology and Women’s Health University of Missouri Columbia, MO, USA Series Editors Z. Kmiec, Department of Histology and Immunology Medical University of Gdansk Gdansk, Poland Michael J. Schmeisser, Institute of Microscopic Anatomy and Neurobiology University Medical Center of the Johannes Gutenberg University Mainz, Germany Jean-Pierre Timmermans, Laboratory of Cell Biology and Histology/Core Facility Biomedical Microscopic Imaging, Department of Veterinary Sciences University of Antwerp Wilrijk, Belgium Sven Schumann, Inst, f. Mikroskop. Anatomie u. Neurobio Johannes Gutenberg University of Mainz Mainz, Rheinland-Pfalz, Germany Pei-Shiue Tsai, School of Veterinary Medicine National Taiwan University Taipei, Taiwan Advances in Anatomy, Embryology and Cell Biology publishes critical reviews and state-of-the-art research in the areas of anatomy, developmental and cellular biology. Founded in 1891, this book series has a long standing tradition of publishing focused and condensed information on a given topic with a special emphasis on biomedical and translational aspects. The series is open to both contributed volumes (each collecting 7 to 15 focused reviews written by leading experts) and single-authored or multi-authored monographs (providing a comprehensive overview of their topic of research). Advances in Anatomy, Embryology and Cell Biology is indexed in BIOSIS, Medline, SCImago, SCOPUS. Heide Schatten The Centrosome and its Functions and Dysfunctions Heide Schatten Department of Veterinary Pathobiology University of Missouri-Columbia Columbia, USA ISSN 0301-5556 ISSN 2192-7065 (electronic) Advances in Anatomy, Embryology and Cell Biology ISBN 978-3-031-20847-8 ISBN 978-3-031-20848-5 (eBook) https://doi.org/10.1007/978-3-031-20848-5 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface The centrosome field has seen enormous progress during the past few decades which spans the large areas of cell biology with new information on cell cycle con- trols and cellular health; immunology with centrosomes being essential for the formation of the immunological synapse; neurobiology with new insights into centrosome dysfunctions leading to disorders and disease; stem cell biology with fate-determining distribution of centrosomal material during asymmetric cell division; cancer biology with huge insights into the role of centrosomes in disease ini- tiation, progression, and manifestation; reproductive biology with essential centrosome functions in oocytes, during fertilization and embryo development in which centrosome dysfunctions can be related back to abnormal centrosomal material in the meiotic spindle of oocytes; and several others that will be highlighted in the specific chapters of this book. Fast and significant advances have been made when it was clearly recognized that this small membrane-free organelle serves essential central and multiple functions that have highly relevant implications for cellular health. Detailed insights have now been gained into the importance of the molecular integrity of centrosomes for normal cell functions and the consequences of centrosome instability during aging as well as the importance of primary cilia–centrosome interactions for cellular signaling. The wide range of vital centrosome functions includes guiding the movement of cell organelles and macromolecular assemblies using its highly dynamic microtubule organization; direct or indirect functions further include serving as critical communication centers to coordinate and link specific signal transduction pathways and playing a role in proteolytic activities. The centrosome’s functions further include a role in ciliogenesis, cell polarity and migration, formation of the immunological synapse, DNA damage control, and others. It is remarkable that centrosome research had stagnated for decades after its orig- inal highly appreciated discovery almost 150 years ago. It took new methodological and functional approaches to fully understand its significance in modern times. Prior to the new appreciation facilitated by the development of new molecular methodologies including new molecular characterizations and especially new imaging v vi Preface modalities the centrosome had been called “mysterious,” amorphous,” and various other names. New methods including new imaging and molecular methods were essential to identify the complex structure and multiple functions of this highly dynamic centrosome organelle. While the centrosome is best known for its functions as the principal microtubule organizing center (MTOC) of the metazoan cell and core of an enormously complex transport system with microtubule minus ends anchored at the centrosome core a new wave of centrosome research, new appreciation, and a renaissance of the centrosome field began when new experimental tools, new methodological approaches, and new technologies became available which included new imaging modalities such as fluorescence microscopy using specific centrosome markers, live cell imaging, followed more recently by super-resolution fluorescence microscopy, new genetic approaches/manipulations, and various others. Through extensive and vig- orous new research, it became abundantly clear that centrosomes play major roles in orchestrating multiple cellular functions, and it was further shown that a wide range of dysfunctions are implicated in numerous disorders and diseases. I hope that this monograph will stimulate further advances in centrosome research and contribute new insights and appreciation for the role of centrosomes in the basic, biomedical, and clinical sciences. I am most grateful and would like to express my sincere thanks to Dr. Peter Sutovsky for inviting this monograph, for his own contributions to the field, and for the many years of most fruitful interactions as a treasured colleague and friend and highly respected and distinguished colleague. I am further indebted to the publisher with special thanks to Dr. Ulrike Träger, Dr. Eliana Acosta, Ulrike Dächert, Tanja Weyandt, and associates for all the excellent help and care during all stages of the project—help and care that is so much appreciated. It is a special pleasure and timely to write this monograph The Centrosome and its Functions and Dysfunctions depicting areas of centrosome biology that have impacted the field significantly. I was fortunate to have had great and most inspiring mentors including Daniel Mazia and Hans Ris as well as numerous outstanding col- leagues for stimulating and most valuable discussions and feedback. My sincere thanks to all those who shared with me the appreciation for centrosomes. Columbia, MO, USA Heide Schatten Contents 1 Cell and Molecular Biology of Centrosome Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 The Centrosome Cycle within the Cell Cycle . . . . . . . . . . . . . . . . . . . . . 17 3 Centrosome as Center for Proteolytic Activity and Dysfunctions Associated with Pathogenesis of Human Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4 Centrosome Dysfunctions in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 5 Virus Exploitation (Hijacking) of Centrosomes . . . . . . . . . . . . . . . . . . . 51 6 Centrosomes in Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 7 Transitions from Centrosomal to Non- centrosomal Microtubule Organization During Cellular Polarization . . . . . . . . . . . . . . . . . . . . . . 75 8 External and Environmental Effects on Centrosomes . . . . . . . . . . . . . . 81 9 Centrosomes and Centrosome Equivalents in Other Systems . . . . . . . 85 10 Non-centrosomal Microtubule Organization in Plant Cells . . . . . . . . 105 vii Chapter 1 Cell and Molecular Biology of Centrosome Structure and Function 1.1 Introduction The centrosome field has seen enormous progress during the past few decades which spans the large areas of cell biology with new information on cell cycle con- trols and cellular health; immunology with centrosomes being essential for the formation of the immunological synapse; neurobiology with new insights into centrosome dysfunctions leading to disorders and disease; stem cell biology with fate-determining distribution of centrosomal material during asymmetric cell division; cancer biology with huge insights into the role of centrosomes in disease ini- tiation, progression, and manifestation; reproductive biology with essential centrosome functions in oocytes, during fertilization and embryo development in which centrosome dysfunctions can be related back to abnormal centrosomal material in the meiotic spindle of oocytes; and several others that will be highlighted in the specific chapters of this book. More detailed insight has been gained into the importance of the molecular integrity of centrosomes for normal cell functions and the consequences of centrosome instability during aging as well as the importance of primary cilia-centrosome interactions for cellular signaling. Major progress has been made during the past few years by cell biologists and scientists in numerous other fields to build on our knowledge of the centrosome’s essential functions in health and dysfunctions in disorders and disease which has contributed immensely to determine the underlying mechanisms leading to altered states of cellular dysfunctions, disorders, and disease (reviewed in Schatten 2008; Schatten and Sun 2018) which is now being used to target dysfunctional centrosomes for therapeutic purposes. Targeting centrosome dysfunctions to find new therapies is a promising approach which has especially gained attention in cancer biology where centrosome dysfunctions have been well explored and new therapies are being proposed. It includes targeting supernumerary cancer cell centrosomes to © The Author(s), under exclusive license to Springer Nature 1 Switzerland AG 2022 H. Schatten, The Centrosome and its Functions and Dysfunctions, Advances in Anatomy, Embryology and Cell Biology 235, https://doi.org/10.1007/978-3-031-20848-5_1 2 1 Cell and Molecular Biology of Centrosome Structure and Function specifically inhibit cancer cell survival and tumor growth without affecting healthy non-cancer cells which includes preventing cancer-specific centrosome clustering and other approaches to restore centrosome integrity and centrosome functions. These aspects and others are addressed in the specific chapters of this book. 1.2 Historical Perspectives The centrosome field has seen significant advances during the past few decades, which accelerated substantially when it was recognized that this small membrane- free organelle serves essential central and multiple functions that have highly relevant implications for cellular health. While centrosomes had been discovered almost 150 years ago (Flemming 1875; Van Beneden 1876) and brilliantly explored by Theodore Boveri (1901, 1914; reviewed in Schatten 2008, Schatten and Sun 2018) centrosomes became underap- preciated for many decades in part because of the lack of appropriate imaging methods and in part because molecular methodologies had not yet been developed. The appreciation for centrosome research had stagnated when electron microscopy (EM) did not reveal a clear centrosome structure and only osmiophilic material was imaged with the most powerful imaging technology, that is EM, at the time. The lack of good imaging capabilities hindered progress of centrosome research for quite some time. Centrioles, on the other hand, located within the osmiophilic mass appeared clearly distinguishable with EM and more attention was paid to centrioles than to the material surrounding the clearly visible, well structured, and prominent centrioles. The prediction by Walther Flemming (1875, 1891) that the discovery of the centrosome would be as important as the discovery of the nucleus appeared all but forgotten. As EM had not revealed structural details of centrosomes, the centrosome has been called “mysterious,” “amorphous,” and various other names while new methods including new imaging and molecular methods were essential to identify the complex structure of the centrosome. The appreciation for centrosomes was rekin- dled with progress in immunofluorescence microscopy and the detection of centrosomes or centrosomal components with specific antibodies. A human autoimmune antibody called 5051 was used to gain new insights into centrosome localization and functions; subsequently, specific centrosome proteins could be identified through specific antibody labeling which made it possible to determine centrosome localization as well as specific functions and dysfunctions. In subsequent years, rapid and significant progress has been made to determine and characterize its nature, diverse molecular compositions, and functions/dysfunctions in health and disease (reviewed in Schatten 2008; Schatten and Sun 2018). A breakthrough discovery was the identification of gamma-tubulin (Joshi and Zhou 2001) that specifically localized to centrosomes and was extensively used for new discoveries of centrosome characteristics. Further new imaging modalities led to rapid progress in determining centrosome structure and functions of mammalian somatic cell centrosomes (previously reviewed in detail in Schatten 2008; Schatten and Sun 2018;