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First published online March 29, 2004
doi: 10.1242/10.1242/jcs.01128

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The arithmetic of centrosome biogenesis

Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges/Lausanne, Switzerland

View larger version (140K): [in a new window]   Fig. 1. Boveri's discovery. One of Boveri's slides showing a one-cell stage metaphase embryo of the parasitic nematode Parascaris equorum, coloured with Heidenhain's iron haematoxylin method. Reproduced with permission from The American Society for Cell Biology (Gall, 1996). Centrioles appear as prominent dark structures in the centre of each spindle pole. The centrosome is said to have been first spotted by Fleming in 1875 and Van Beneden in 1876, but was extensively studied and named by Boveri a few years thereafter (referenced in Schatten et al., 2000).

View larger version (170K): [in a new window]   Fig. 2. Centriole structure. Structural features of centrioles in vertebrates [A: side view, B: cross-section; reproduced with permission from Elsevier (Paintrand et al., 1992)], D. melanogaster (C: cross-section; courtesy of Patrick O'Farell) and C. elegans (D: cross-section; courtesy of Thomas Müller-Reichert). Bar, 100 nm. (A,B) In vertebrates, centrioles have nine sets of triplet microtubules (B, bracket) and are 150 nm in diameter and 400 nm long. Note that the long axis of the daughter centriole bisects the mother centriole. Note also that the mother centriole bears elaborate appendages on its distal end (A, arrows; only sub-distal appendages are visible in this picture). In many cells, the mother centriole serves as a basal body for the primary cilium, with the appendages anchoring the basal body to the plasma membrane (reviewed by Preble et al., 2000). However, appendages are also present in cells that do not grow primary cilia (Paintrand et al., 1992), where they may have a distinct anchoring function (Piel et al., 2000). Some proteins, including cenexin (Lange and Gull, 1995), ninein (Ou et al., 2002), OFD-2 (Nakagawa et al., 2001), CEP110 (Ou et al., 2002) or -tubulin (Chang et al., 2003) are specific of appendages, and can thus serve to distinguish mother and daughter centrioles using immunofluorescence or GFP fusion proteins. (C,D) Centrioles with nine sets of doublet microtubules in D. melanogaster embryos (C, bracket) and nine sets of singlet microtubles in early C. elegans embryos (D, bracket). In both species, centrioles are 100x100 nm in size (Moritz et al., 1995; Vidwans et al., 1999; Wolf et al., 1978). D. melanogaster centrioles have singlet microtubules in the early embryo (Moritz et al., 1995), doublet microtubules during later embryogenesis (Vidwans et al., 1999) and doublet or triplet microtubules in sperm cells (discussed by Callaini et al., 1999). C. elegans centrioles have singlet microtubules both in the early embryo and in sperm cells (Wolf et al., 1978). Although sub-distal appendages have not been described in C. elegans, they are absent from D. melanogaster embryonic cells, but present in somatic cells (Rothwell and Sullivan, 2000). The apparent absence of appendages in embryos of both species indicates that they are not essential for centrosome duplication.

View larger version (50K): [in a new window]   Fig. 3. The canonical centrosome duplication cycle. Cells in early G1 phase have a single centrosome, which comprises a pair of perpendicular centrioles (dark rectangle: mother centriole; grey rectangle: daughter centriole) and surrounding PCM (shaded disk). Usually at the G1-to-S transition, the two parental centrioles loose their arrangement and split slightly from each other (A). During S phase, a new daughter centriole (white rectangle) forms perpendicular to the proximal side of each parental centriole (B) and elongates (C). The two newly formed centriole pairs then disconnect fully (D), as does the PCM (E). Steps D and E involves the Nek2 kinase and its substrate C-Nap1. A working model posits that C-Nap1 connects centrioles within a pair during the bulk of the cell cycle and is phosphorylated by Nek2 in G2 phase, resulting in disconnection of parental centrioles and generation of two distinct centrosomes (Fry, 2002). Full acquisition of appendages on daughter centrioles is achieved by the end of the subsequent cell cycle (F, shown for daughter centriole from previous duplication round).

View larger version (67K): [in a new window]   Fig. 4. C. elegans centrioles and PCM. SAS-4 or TAC-1 staining in sperm (A,E), oocyte (B,F) and one-cell stage telophase embryo (C and D, G and H). SAS-4 and TAC-1 are shown in red, DNA in blue and microtubules in green (shown only in D,H). The outline of sperm cells and oocytes is indicated. Bars, 10 µm. (A) In sperm, the centrosome is reduced to a pair of centrioles during sperm maturation (A, arrow). Owing to their small size, the two units of the pair cannot be distinguished. Although -tubulin has been reported to localize to sperm centrioles (Kirkham et al., 2003), our staining conditions did not allow us to detect a focus of TAC-1 nor other PCM components in mature sperm. Regardless, PCM material potentially provided by the sperm would probably be negligible in comparison to the contribution of the oocyte. (B,F) In the oocyte, centrioles are lacking, but PCM and centriolar components are present diffusely in the cytoplasm. Note the somatic sheath cell nucleus on the top-left in B. (C,D,G,H) After fertilization, a centrosome is reconstituted from a paternally contributed pair of centrioles and maternally contributed PCM components. This reconstituted centrosome then enters the canonical duplication cycle. Splitting of centrioles occurs already during mitosis in embryonic systems where cells oscillate between M and S phase (Callaini and Riparbelli, 1990; Kirkham et al., 2003; Leidel and Gönczy, 2003). Therefore, centrioles of the posterior (right-most centrosome) are sufficiently distant from one another in telophase embryos to be recognized separately (C, right arrow and inset). Note that the two centrioles of the anterior centrosome are not yet distinguishable as individual units at this stage (C, left arrow) (see also Leidel and Gönczy, 2003; O'Connell et al., 2001).

View larger version (24K): [in a new window]   Fig. 5. Diversity of parental requirement for centrosome formation in the zygote. In all cases displayed, PCM components (shaded disk) are contributed from maternal stores. In C. elegans and X. laevis, the sperm contributes a pair of centrioles (black rectangles), which recruits PCM components from maternal stores to reconstitute one centrosome in the zygote (Karsenti et al., 1984; Wolf et al., 1978). In D. melanogaster and humans, the sperm contributes a single centriole (reviewed by Callaini et al., 1999; Manandhar et al., 2000). This is due to the lack of centrosome duplication prior to meiosis II in insects and to the disappearance of one centriole during sperm maturation in primates. In both cases, the single centriole must duplicate twice prior to mitosis to give rise to four centrioles, two in each centrosome. In mice and in many parthenogenetic species, no centrioles are present in the embryo at fertilization. This results from the disappearance of both centrioles during sperm maturation in the mouse (Manandhar et al., 1999) and from the absence of a male gamete altogether in parthenogenetic species (reviewed by Callaini et al., 1999). In both the mouse and parthenogenetic species, the non-centrosomal pathway of spindle assembly presumably ensures bipolarity during mitosis (reviewed by Karsenti and Vernos, 2001). In the clam S. solidissima, a pair of centrioles is also contributed maternally, but it is silenced in the zygote and does not nucleate microtubules or duplicate (Wu and Palazzo, 1999).

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