meet ing report

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Exploring the pole: an EMBO conference on centrosomes and spindle pole bodiesSue L. Jaspersen and Tim Stearns

the centrosome and spindle pole body community gathered for its triennial meeting from 12–16 September, 2008 at emBL in Heidelberg (germany).

Sue L. Jaspersen is at the Stowers Institute for Medical Research, Kansas City, MO 64110 USA and in the Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160 USA. Tim Stearns is in the Department of Biology, Stanford University, Stanford, CA 94305 USA and in the Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA. e-mail: slj@stowers-institute.org and stearns@stanford.edu

Sponsored by the EMBO, the conference on centrosomes and spindle pole bodies was organized by Trisha Davis, Susan Dutcher, Michael Knop, Robert Palazzo, Elmar Schiebel and Kip Sluder. This was the fourth meeting in a series that started in 1996 and, as with the previous meetings1–3, was an occasion to cel-ebrate present accomplishments and contem-plate the future. Below we summarize some of the major themes that emerged.

Centrosome 101Microtubules and their constellation of asso-ciated proteins and structures are strongly conserved components of all eukaryotic cells. One of the universal themes in the microtubule cytoskeleton is the use of specific structures to organize microtubules into useful arrays. The centrosome of animal cells and the spindle pole body of fungi are the two best characterized microtubule-organizing structures and were the topic of this meeting. The centrosome contains a pair of centrioles surrounded by a matrix of proteins involved in microtubule nucleation and other centrosome functions. This matrix of proteins is usually referred to as pericentriolar material (PCM), although many of the components of PCM are also found at other sites of microtubule organization in dif-ferentiated cell types.

Centrioles are short, cylindrical structures in which the walls of the cylinder are made up of nine specialized triplet microtubules. This elegant nine-fold symmetry is absolutely conserved and gives centrioles their characteristic ‘pinwheel’ appearance in cross-section. Separate from their role as a focus of PCM, centrioles also nucleate the ciliary axoneme, imparting their nine-fold sym-metry to this structure as well. A centriole at the base of a cilium is referred to as a basal body.

The centrosome, with its pair of centrioles, duplicates once per cell cycle at the G1/S tran-sition so that a cell will have exactly two cen-trosomes during mitosis. Centrioles reproduce semi-conservatively; the pairs separate and each ‘mother’ centriole grows a new ‘daughter’ cen-triole from its side. The centrosome has a mutu-alistic relationship with the mitotic spindle, helping to form the poles of the spindle, while at the same time using that spindle to segregate equally to the sister cells of a division. This equal segregation of one centrosome per cell ensures that each cell has the potential to grow a cilium, which is imparted by the mother centriole.

Most fungi have lost the capacity to make centrioles and cilia but have evolved a morpho-logically distinct structure, known as the spindle pole body (SPB), to serve as their primary site of microtubule nucleation. The functional orthol-ogy of the SPB to the centrosome is reflected in the conservation of some of the important components, and genetic and biochemical anal-ysis of SPBs have provided valuable insight into centrosome regulation and function.

Centrosome partsThe rate-limiting step in understanding the centrosome has been the definition of its

constituent proteins, and the identification of those that are key functional components, as opposed to hangers-on that use the centro-some as a cellular assembly point. At the first meeting twelve years ago, John Kilmartin’s mass-spectrometry analysis of the SPB4 was a prescient first glimpse of the cornucopia of centrosome proteins that would soon emerge from similar work on centrosomes, centrioles and cilia. Whereas we once had the sense of having hold of only the trunk, leg or tail of the proverbial centrosomal elephant, new results are revealing a much more complete picture of the organelle as a whole.

Jens Andersen described a refinement of the original mass-spectrometry analysis of mamma-lian centrosomes5, using SILAC stable isotope labelling technology to increase coverage and specificity of results from impure centrosome material. Jean Cohen presented a compilation of centriole and cilia proteomic data from across the eukaryotic world and an associated web-based analysis tool. In these and other proteomic studies, the same proteins come up repeatedly, suggesting that, by analogy to genetic screens, we are close to saturation for identification of new components. However, lest one become sanguine about this prospect, Hannah Müller’s proteomic analysis of centrosomes, isolated from rapidly dividing Drosophila embryos, found only limited overlap with the list of known centro-some proteins from other systems. Perhaps this reflects differences in analysis techniques or important biological changes in centrosome components in the rapidly dividing embryo.

Genetic analysis has also made an important contribution to identifying centrosome com-ponents and their interactions. The keynote

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address from Tony Hyman stressed the power of RNA interference (RNAi) in Caenorhabditis elegans and mammalian cells as a tool for iden-tifying important components and determining their function. Combining the ability to observe early embryonic divisions of C. elegans with whole-genome RNAi, Hyman and his worm-ophile colleagues have discovered several of the key players, including SAS-4 and SAS-6. He described recent work revealing an unexpected connection between centrosome size and spindle length, which was independent of microtubule nucleation. In addition, his group combined a mammalian RNAi screen6 with tagging of pro-teins in BACs7 to identify interaction networks among mammalian centrosome components.

Similar RNAi screens have been performed in Drosophila melanogaster cultured cells8,9. Naomi Stevens described three genes, ana1, ana2 and ana3, that are involved in centrosome duplication and whose duplication results in anastral spindles. Ana2 is structurally similar to SAS-5, and like SAS-5 is required for centri-ole formation. Chad Pearson used basal body proteome data from Tetrahymena10 to identify Poc1 as a conserved centriole component that is also required for centrosome duplication and ciliogenesis in human cells. Using human centrin as the bait in a yeast two-hybrid screen, Michel Bornens identified hPoc5, the human orthologue of a protein originally identified in Chlamydomonas as a component of centrioles11.

Interestingly, hPoc5 contains Sfi1-like repeats, which were originally discovered as Cdc31/cen-trin-binding motifs in the Saccharomyces cerevi-siae SPB component Sfi1. Recruitment of hPoc5 to the distal lumen of centrioles, where centrin 2/3 are located, occurs late in G2 and involves binding to its interacting partner, hPoc19, which is recruited earlier in the cell cycle.

Centrosome pathwaysOne of the deeper mysteries of centrosome biology is how the initiation of new centrioles is controlled. As each centriole is potentially a distinct centrosome, controlling initiation is the key event in centrosome number control. Although new centrioles typically grow from the

G1/Scartwheel formationcentriole assembly

SZY-20

Mps1SCF

Cdk2-cyclinA/E

SAS-6 SAS-6-PSAS-5

SPD-2ZYG-1/Plk4 APC

SAS-4/CPAPBld10/Cep135

Scentriole

elongationM

centrioledisengagement,

cytokinesis

SeparasePlk1

G2 and Mcentriole

maturation & separation

Recruitment of PCM, appendage,γ-TuRC, hPoc5, spindle pole proteins

BoraPlk1Aurora-A

Figure 1 Centriole duplication pathway. Schematic representation of the major steps in centrosome duplication, as well as structural and regulatory proteins. We have combined results from several systems, and the details may differ in specific systems (for reviews of the centriole cycle and its cell-cycle control, see refs 18, 29–31). At the end of mitosis, each of the two engaged centrioles within each pair become disengaged by the action of the separase protease and Plk1. The older of the centrioles in each pair is marked with distal and sub-distal appendages, and the two centrioles remain linked by cohesion fibres. Centriole duplication is initiated at the disengaged centrioles during G1/S by SPD-2, as well as the kinases Mps1 and Cdk2–cyclinA/E. A key regulatory step in centriole duplication is activation of the kinase ZYG–1/Plk4; this involves control of its kinase activity, localization to the centrosome and, ultimately, proteolysis by the SCF ubiquitylation complex. Active ZYG–1/Plk4 can phosphorylate SAS-6, a component of the cartwheel structure at the base of nascent centrioles. Recruitment of SAS-6, SAS-5 and Bld10/Cep135 drive formation of the cartwheel, which imparts a nine-fold symmetry on the forming centriole. During S phase, centriole duplication continues by recruitment of SAS-4/CPAP. Levels of CPAP are tightly controlled during the cell cycle by APC-mediated proteolysis, perhaps restricting centriole assembly. Daughter centrioles continue to elongate during G2 and early M phase after activation of Aurora A at the centrosome, which is regulated by Plk1 and Bora. The centrin-binding protein hPoc5 is also recruited to the centrosome. The new mother centriole matures by addition of components of distal and subdistal appendages. The cohesion link between the two mother centrioles is broken, allowing the centrosomes to move to opposite sides of the nucleus. As mitosis begins, γ-tubulin ring complex (γ-TuRC) and other PCM components are recruited to the centrosomes, along with mitotic spindle pole proteins. The two mitotic centrosomes nucleate microtubules and help to form the mitotic spindle on which both chromosomes and centrosomes will segregate to the two daughter cells. At the end of mitosis, separase and Plk1 trigger centriole disengagement, allowing the centrioles to duplicate in the G1/S phase, and completing the cycle.

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side of an existing centriole, Alexey Khodjakov’s group has shown that generic mammalian cells can produce centrioles de novo12, a property they share with some single-cell organisms and specialized mammalian cell types. However, the presence of an existing centriole prevents this de novo pathway. Khodjakov used laser ablation to show that a mother centriole can only make a new centriole after removal of its daughter. This is consistent with experiments described by Tim Stearns showing that in mammalian cells, the protease separase and the kinase Plk1 act to disengage the mother and daughter centrioles at the end of mitosis, and that this is required for duplication in the next cell cycle.

A confluence of results from several systems has identified Polo-like kinase 4 (Plk4) as the likely trigger for centriole formation in animal cells13. Monica Bettencourt-Dias and Stefan Duensing both showed that the levels of Plk4 are controlled by proteolysis in Drosophila and mammalian cells, respectively. In both cell types, depletion of components of the SCF (for Skp1–Cullin–Fbox) ubiquitin-ligase complex results in more Plk4 and formation of extra cen-trioles. Interestingly, Michel Bornens reported centrosomal accumulation of Plk4 during mito-sis and described a Plk4 autophosphorylation event that stimulates degradation of the protein; however, this seems to be independent of SCF-mediated degradation. It is still not known how Plk4 carries out its centriole-initiating magic, but it seems likely that its level, localization and activity are tightly controlled.

An early event in new centriole growth is formation of the cartwheel, a nine-fold sym-metrical structure at the base of the centriole. Masafumi Hirono discussed his findings on mutants of bld12 and bld10, the Chlamydomonas orthologues of SAS-6 and Cep135; these two proteins seem to be essential components of the cartwheel, probably defining its nine-fold sym-metry14,15. SAS-6 is at the centre of the cartwheel, and loss of SAS-6 results in centrioles with non-nine numbers of triplet microtubules. Pierre Gönczy reported that SAS-6 is phosphorylated by ZYG-1 in C. elegans. ZYG-1 is a kinase related to Plk4, and SAS-6 mutants that mimic phos-phorylation at the ZYG-1 site can bypass the requirement for the kinase, supporting the idea that SAS-6 is the key target of ZYG-1 for centro-some duplication and is a central point of regu-lation of centriole assembly. Kevin O’Connell showed that a conserved RNA-binding protein, SZY-20 (known as PM20 in humans), acts antag-onistically to ZYG-1 and regulates centrosome

size16, although the nature of the connection to the RNA world is not clear.

Another conserved component originally identified in C. elegans is SAS-4, thought to be required to add centriolar microtubules to the base structure17. Susan Dutcher’s genetic and electron microscopic analysis of basal body duplication in Chlamydomonas indicates that spokes emanating from the central hub first form an amorphous pinwheel before the cart-wheel appears, perhaps as SAS-4 is recruited18. Tang Tang presented evidence that levels of the human orthologue CPAP are tightly regulated during the cell cycle by proteolysis mediated by the anaphase-promoting complex (APC). Tang, Gönczy and Erich Nigg all noted that overex-pression of CPAP results in growth of micro-tubule extensions from the end of the centriole, extending its length. Alex Dammermann identi-fied a protein, HYLS-1, that interacts with SAS-4 and found that it is required for cilium, but not centriole, formation. In humans with hydroe-thalus syndrome, a mutation in HYLS-1 impairs cilia assembly, adding this disease to the known ciliopathies.

When the analysis of centriole and basal body assembly from several different organisms is combined, a picture of the stepwise centrosome assembly pathway begins to emerge (Fig. 1).

Centrosomes and cell cycle signalingCentrosome function is intimately tied to cell-cycle progression, with characteristic changes occurring in each phase of the cycle. Conserved cell-cycle regulatory kinases, such as the cyclin-dependent kinases (Cdks), polo-like kinases (Plks) and Mps1, control the function and duplication of SPBs in fungi, and centrosomes in metazoan cells. As a start to developing a more complete understanding of the role of phosphor-ylation at the centrosome, Mark Winey described an ambitious proteomics approach to examine phosphorylation of all of the core components of the S. cerevisiase SPB, whereas Harold Fisk focused on Mps1 phosphorylation of centrin as a control point for centriole duplication.

At the entry to mitosis in animal cells, more PCM is recruited to centrosomes, and this recruitment requires the activity of Plk1 and Aurora A. Isabelle Vernos described experiments in frog egg extracts to define the role of Aurora A kinase activity at the centrosome19. Jens Lüders talked about the connection between Plk1 and γ−tubulin recruitment through the attachment factor GCP-WD/Nedd1. Bringing some of these threads together, Erich Nigg described recent

results from his lab, showing that Plk1 and Bora cooperate to regulate the centrosomal levels of Aurora A during mitotic entry in cultured cells20. This is at least conceptually similar to the situation in Schizosaccharomyces pombe, described by Iain Hagan, in which recruitment of the polo kinase Plo1 to the SPB is important for mitotic entry.

The results discussed above support the view of the centrosome as a crucial signal transduc-tion hub. This is perhaps most clearly true in S. cerevisiase, where a surveillance system known as the spindle-positioning checkpoint (SPOC) monitors alignment of the mitotic spindle at the bud neck and delays cell-cycle progression until correct spindle orientation is achieved. The target of the SPOC is the mitotic exit network (MEN), and the ultimate target of the MEN pathway is the Cdc14 phosphatase, which antagonizes Cdk1–cyclinB activity. The SPB serves as a scaffold for regulatory proteins and a sensor for spindle alignment. Simonetta Piatti’s analysis of the E3 ubiquitin ligases Dma1 and Dma2 suggested a new mechanism control-ling the SPOC, whereas Gislene Pereira focused on the dynamic association of Bub2 and Bfa1 with the SPB in cells with mis-aligned spindles and how this is controlled by phosphorylation21. Elmar Schiebel also discussed the important role that phosphorylation has in this path-way, through analysis of Cdk1 regulation of MEN components. Kathy Gould reported that phosphorylation of Clp1, the Cdc14 ortholog in S. pombe, promotes binding to Rad24 and cytoplasmic retention during anaphase22. At least some MEN proteins have orthologues in higher eukaryotes, so an important future direc-tion will be to elucidate their role in cell-cycle progression. Also, the intimate association of SPBs and centrosomes with the nuclear enve-lope seems to be important for regulating cen-trosome function and duplication, as discussed by Sue Jaspersen on the basis of their studies on the evolutionarily conserved SUN proteins.

Cell divisions: some more equal than othersSeveral recent studies have highlighted the role that spindle alignment and centrosome distri-bution play during developmentally important asymmetric cell divisions, including in adult stem cells, the germ line and the immune sys-tem. Yukiko Yamashita examined why adult stem cells lose their ability to divide with increas-ing age during spermatogenesis in Drosophila. These cells usually divide with the older centro-some anchored near the stem-cell niche, but she

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found that the number of male germ stem cells with mis-oriented centrosomes increases with time23. These cells also transiently arrested in the cell cycle, explaining their decreased ability to proliferate, and perhaps reflecting a checkpoint similar to that described above for yeast.

Correct positioning of the mitotic spindle and centrosomes is important to maintain cellular identity, and defects in this process can result in uncontrolled cell division. This was described and discussed by Cayetano Gonzalez and Jordan Raff, who used a transplantation system to study tumorigenesis in flies. It has often been observed that cancer cells have extra centrosomes, and sometimes undergo multipolar divisions, which might lead to some of the genetic instability observed in such cells. Indeed, this is one of the touchstones of the centrosome field, first proposed by Theodor Boveri 100 years ago24. However, the results from Gonzalez and Raff are most consistent with centrosome abnor-malities resulting in defects in asymmetric cell division and thus resulting in over-proliferation of stem cells25,26. Steve Doxsey presented results suggesting that similar mechanisms might be at work in vertebrates. He found that interfer-ing with the function of centrosome proteins in zebrafish caused phenotypes similar to those described for ciliary proteins. Further analysis in mammalian cells indicated that interfering with IFT88, an intraflagellar transport protein, resulted in misoriented spindles. This led to the hypothesis that some of the phenotypes in cili-opathies might be due to defective cell division plane orientation.

Cytokinesis failure is often cited as a mecha-nism responsible for generating the many cells with extra centrosomes observed in tumours. However, Kip Sluder presented evidence sug-gesting that cytokinesis failure is unlikely to be the culprit in this case. In a heroic effort of time-lapse imaging, the Sluder lab treated cultured mammalian cells with cytochalasin to induce cytokinesis failure, then observed cells over the course of several cell cycles. Although they could frequently recover tetraploid cells, most cells did not contain extra centrosomes, and the tetra-ploid cells did not proliferate. This suggests that centrosome amplification in tumour cells must involve other steps, or perhaps multiple rounds of cleavage failure. Susana Godinho’s analysis of centrosome clustering in Drosophila S2 cells and mammalian cancer cell lines indicates that even when extra centrosomes are present, cells cope by clustering centrosomes into poles of functional bipolar spindle27. Remarkably, her results suggest

that targeting centrosome clustering mechanisms might be a way to specifically kill cancer cells.

Coming full circleIt is particularly satisfying to see a result that clearly answers a long-standing question. David Agard’s presentation on the structure of the γ-tubulin complex from yeast did just that, providing a molecular understanding of nuclea-tion, the process that led most investigators to the centrosome in the first place. Microtubule nucleation at the centrosome involves γ-tubulin and associated proteins. The γ-tubulin complex purified from animal cells is ring-shaped, with a size and diameter that suggest that it nucleates a microtubule by directly templating it. A vexing problem has been that yeast cells lack some of the γ-tubulin complex associated proteins and also lack a soluble ring complex. Combining purified yeast proteins, from a collaboration with Trisha Davis’ lab, and electron microscopy, Agard showed that the simple combination of γ-tubulin, its two closest binding partners Spc97 and Spc98, and the linker protein Spc110 will form a ring in vitro, with appropriate dimensions for micro-tubule nucleation. It is fitting, perhaps, that a detailed understanding of γ-tubulin comes from a study of the yeast proteins, given that γ−tubulin was originally identified by Berl Oakley and col-leagues in a genetic screen in Aspergillus28.

In conclusion, our understanding of these complex organelles, which both control microtu-bule nucleation, and serve as important hubs for cell signaling, has increased dramatically since the first centrosome and SPB conference twelve years ago. What was then a relative cell biological backwater has now become what Tony Hyman called “perhaps the most advanced organelle with respect to combining genomics, proteomics and cell biology”. No longer an enigma, the cen-trosome is now at the center of some of the most important issues in biology, with the attendant burning questions about its structure, function, and duplication. Searching for the answers to these questions will keep us busy until we meet again in 2011 in Barcelona.

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