Twenty Ways of Looking at a Centrosome

Book Reviews 309

Twenty Ways of Looking at a Centrosome The Centrosome in Cell Replication and Early Development Edited by R.E. Palazzo and G.P. Schatten San Diego, CA: Academic Press (2000). 470 pp. $129.95

Most cell biologists would admit that the centrosome has an ineffable quality. Discovered at the end of the nineteenth century, it was dubbed the “dynamic center of the cell” and considered to hold the keys to understanding mitosis, fertilization, morphogenesis, and cancer. It is easy to see why the centrosome seemed to promise a direct route to the essence of these problems. Like the chromosomes, the centrosome is duplicated once each cell division, and the heart of the centrosome, the centriole, is duplicated with new elements formed adjacent to and in strict geometric relation to old ones. Puzzling out this intriguing pattern of replication has been a significant challenge, generating much writing about the “mystery” of the centrosome. In recent years, there has been progress in the molecular characterization of the centrosome which has lifted many mysteries but also lead to some new ones. Thus, after more than 100 years of study, one can still, with some seriousness, ask: “what does the centrosome do?” The Centrosome in Cell Replication and Early Development edited by R.E. Palazzo and G.P. Schatten provides, in twenty chapters, different perspectives on the current state of the answer. One of the difficulties for providing a cohesive answer on centrosome function is their remarkable morphological diversity. In animal cells, the centrosome is the main microtubule organizing center (MTOC) of the cell. It is composed of the centrioles, an orthogonally arranged pair of cylinders composed of nine triplet microtubules, and the surrounding amorphous pericentriolar material (PCM). In fungi, an analogous structure is the spindle pole body (SPB). Although superficially they have no visible similarity, SPBs and centrosomes perform essentially the same function. It is important to note that some centrosome functions are divisible. Many microtubule structures, such as those in higher plants, are organized by MTOCs that lack centrioles. Likewise the centrioles can be split off from the PCM, morphed into basal bodies, and used to template ciliary or flagellar axonemes. To encompass this diversity, the book takes a Noah’s Ark approach, presenting a parade of centrosomes and MTOCs from different organisms, including all of the important model systems except plants. In spite of their morphological diversity, there are common themes at the molecular level. Where this is understood, the book presents the general principals that extend across species. This is particularly well done in the chapters on ␥-tubulin. Two chapters also do a nice job of comparing and contrasting the morphology of centrosomes in different organisms. In addition, the book has excellent chapters that cover a wide variety of extramitotic centrosome topics such as centrosome reduction in meiosis, centrosome function in cytokinesis/mitotic exit, and the

centrosome-dependent controls on cell morphology during development. Any serious understanding of how centrosomes work will depend on having a complete parts list and knowledge of how the parts fit together. One of the big successes for assembling this parts list was the identification of ␥-tubulin and the realization of its key role in microtubule nucleation. ␥-tubulin is a distinct tubulin found in the PCM and on the outer surfaces of the SPB. Two chapters describe genetic studies on ␥-tubulin. Although these experiments nicely support the notion that ␥-tubulin nucleates microtubules, they highlight aspects of ␥-tubulin function that are less well understood. For example, although ␥-tubulin interacts with ␣-tubulin in polymerized microtubules, the genetic data raises the possibility that ␥-tubulin might also interact with ␤-tubulin at some point during the assembly process. Another excellent chapter reviews the biochemical properties of ␥-tubulin. This includes the partitioning of ␥-tubulin into different complexes (one of which is the ␥-tubulin ring complex found at the centrosome), and a discussion of the two radically different models proposed to explain the role of ␥-tubulin in microtubule nucleation. The next step in building the centrosome wiring diagram is to define how the nucleating activity is integrated into the general structure of centrosomes. Two chapters lay out how far along this effort has advanced for the budding yeast SPB. In budding yeast, most if not all of the core components of the SPB have been identified. Enough is known about the interactions among SPB components to propose a general model of its molecular architecture. Notably, this includes the identification of the conserved proteins that link ␥-tubulin to the core SPB structure. The matter-of-fact presentation of all this data on SPB structure almost masks the extent of the achievement. For the yeast SPB, it is becoming impossible to savor any real sense of mystery because this sense is rapidly being overwhelmed by prosaic fact. Progress has also been made toward defining the molecular architecture of animal centrosomes, but here fewer parts are known and there is controversy over key issues. Perhaps the most significant controversy is whether centrosomes in animals are required at all for mitosis, as was generally assumed to be the case. However, several findings have challenged the notion of the centrosome’s essential mitotic function. In some systems, spindles can be assembled without centrosomes, and, in others, mitosis can proceed if they are destroyed by laser ablation. The book discusses the important experiments and presents what has emerged as the current consensus: that centrosomes are not absolutely required for mitosis, but they promote both its speed and accuracy. Having established that 100 years of research on animal centrosomes is in fact important, the book turns back to questions about their architecture. By contrast with the unity of the yeast SPB, animal centrosomes are composed of two distinct structures: centrioles and the surrounding PCM. An enduring mystery has been the relationship between these two elements. The discovery that the ␥-tubulin nucleating sites are associated with the PCM and not with the centriole, triggered doubts about whether the centriole has a significant role in the

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centrosome’s job as an MTOC. One view was that the centriole was just along for the ride, possibly en route for a task in meiosis. However, the tide may be turning against the centriole nihilists. Recent studies show that the PCM has a definable fibrous structure that may be functionally linked to the centriole. Although the precise role of the centriole in mitosis is not settled, the evidence for each perspective is clearly presented. Much of the mystique of the centrosome is tied to its duplication. There was a remarkably longstanding controversy over whether the centrosome contained its own nucleic acid genome. The issue is primarily of historical importance as it is now clear that it does not. The chapter recounting the dispute nevertheless makes for instructive reading as it captures both the power of attractive models and the painstaking work required to overturn them when they happen to be incorrect. Even without centrosome genomes, the book still has much to report on the current understanding of centrosome duplication, the signaling molecules that regulate it, and its potential abnormal control in cancer. A key factor for recent progress has been the refinement of in vitro centrosome duplication systems. The use of these systems has lead to an understanding of the cyclins and CDKs that control centrosome duplication in animals. One important idea that has emerged is that a licensing event may occur during S phase that makes the centrosome competent to reproduce. Licensing may then be followed by a subsequent event(s) such as Cdk2 phosphorylation that triggers duplication. Thus, the first visible structure in centriole duplication may in fact represent a late step in a process begun during the previous cell cycle. Even though the nature of the proposed licensing event remains obscure, the experimental approaches being taken to characterize it are well described (for example, see the parthenogenesis assay in chapter 1). In addition to its work in dividing cells, the centrosome has many other jobs. It controls key aspects of cell morphology necessary for normal development. It is important for establishing the position of mitotic spindles during polarized cell divisions and for organizing the cortical cytoskeleton in oocytes. The book contains lucid chapters that cover all of these topics; those on worms and fruit flies are particularly interesting. The completed genome sequence for many of these organisms is enabling systematic genetic approaches that are already accelerating the pace of discovery. Overall, this is an excellent book that has clear discussions of all facets of the many-sided centrosome. It is the successor to the 1992 Academic Press book The Centrosome, which, in informal web annotations, is referred to as the centrosome “bible.” Like any book on a fast-moving topic, important new literature has come out since the book went to press (e.g. ␦- and ⑀-tubulins from animals and the potential for centrioles to regulate cytokinesis). The book is pitched to researchers working in the general areas of mitosis and development and, as such, I think most laboratories working on these topics will want to have it. Although the book succeeds in both scope and depth, it falls somewhat short on synthesis. A foreword or introductory chapter providing a general perspective would have made the book more accessible to the novice reader. Nevertheless, the book does provide a vantage point to take stock of how much

the “mysterious” centrosome has been demystified by real progress. A molecular basis for many centrosome functions is rapidly emerging. To the detriment of poetic description, the successes in hand show that the centrosome is no longer an indecipherable cause. David Pellman Departments of Pediatric Oncology The Dana-Farber Cancer Institute and Pediatric Hematology/Oncology The Children’s Hospital Harvard Medical School 44 Binney Street Boston, Massachusetts 02115

Navigating by Landmarks Landmark Papers in Cell Biology Edited by Joseph G. Gall and J. Richard McIntosh Cold Spring Harbor, NY, and Bethesda, MD: American Society for Cell Biology and Cold Spring Harbor Laboratory Press (2001). 532 pp. $45.00

The past 40 years in cell biology have seen so many profound intellectual and technical advancements that the paths of discovery through any one area are often difficult to recall. For today’s college students, who never knew a world without genetic engineering or personal computers, the evolution of ideas leading to our current understanding of cell function can be particularly hard to imagine. With Landmark Papers in Cell Biology, readers gain some perspective on the tremendous advances of this time. To mark the 40th anniversary of the American Society for Cell Biology, Gall and McIntosh have gathered 42 papers that punctuated this period in seven broad areas of cell biology: genome organization and replication, transcription, nuclear envelope and nuclear import, mitosis and cell cycle control, cell membrane and extracellular matrix, protein synthesis and membrane traffic, and cytoskeleton. Within each area, articles are presented in chronological order, and for each article, the editors have written a brief review to provide historical context for the paper. This book helps retrace, albeit in a terse way, some of the most important intellectual avenues in cell biology research, and marks key milestones with which all cell and molecular biology students and researchers should be familiar. In Landmark Papers, the growth of understanding in cell biology can be traced between related discoveries. Papers on genome organization and replication illustrate how biology progresses through a combination of intellectual and technical leaps, with some rare publications accomplishing both. For example, after the semiconservative nature of DNA replication was demonstrated in 1957 using 3H-thymidine and autoradiography in plant cells (Taylor et al., Proc. Natl. Acad. Sci. USA 43, 122– 128), essentially the same technique revealed the existence of multiple origins of DNA replication in mamma-