The Centrosome and its Functions and Dysfunctions

115 Pages·2022·3.809 MB·English

by  Heide Schatten

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
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The series is open to both contributed volumes (each collecting 7 to 15 focused
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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
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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 for-
mation 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 divi-
sion; 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 mate-
rial 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 func-
tions 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 cellu-
lar signaling.
The wide range of vital centrosome functions includes guiding the movement of
cell organelles and macromolecular assemblies using its highly dynamic microtu-
bule 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 immuno-
logical 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 meth-
odologies 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 cen-
trosome 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 imag-
ing, 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 for-
mation 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 divi-
sion; 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 mate-
rial 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 centro-
some 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 centro-
somes 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 rele-
vant 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 meth-
ods 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 centro-
some 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 meth-
ods 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 centro-
somes 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 dis-
covery was the identification of gamma-tubulin (Joshi and Zhou 2001) that specifi-
cally 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 centro-
somes (previously reviewed in detail in Schatten 2008; Schatten and Sun 2018;