Centrosomes in spindle organization and chromosome segregation: a mechanistic view

Abstract

Centrosomes are complex structures, which are embedded into the opposite poles of the mitotic spindle of most animals, acting as microtubule organizing centres. Surprisingly, in several biological systems, such as flies, chicken, or human cells, centrosomes are not essential for cell division. Nonetheless, they ensure faithful chromosome segregation. Moreover, mis-functioning centrosomes can act in a dominant-negative manner, resulting in erroneous mitotic progression. Here, I review the mechanisms by which centrosomes contribute to proper spindle organization and faithful chromosome segregation under physiological conditions and discuss how errors in centrosome function impair transmission of the genomic material in a pathological setting.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Abbreviations

ASPM:

Abnormal spindle-like microcephaly-associated protein

Cdk5rap2:

Cyclin-dependent kinase 5 regulatory-associated protein 2

CENP:

Centromere-associated protein

CEP:

Centrosomal protein

C-Nap1:

Centrosomal Nek2-associated protein 1

CPAP:

Centrosomal P4.1-associated protein

CRISPR:

Clustered regularly interspaced short palindromic repeats

EGFR:

Epidermal growth factor receptor

Mad2:

Mitotic arrest deficient 2

MCAK:

Mitotic centromere-associated protein

MCPH1:

Microcephaly 1

Nek:

NIMA-related kinase

NuMA:

Nuclear mitotic apparatus protein

Plk:

Polo-like kinase

PTEN:

Phosphatase and tensin homolog

RNAi:

RNA interference

Sas-4:

Spindle assembly abnormal protein 4

VEGF:

Vascular endothelial growth factor

WDR62:

WD40 repeat protein 62

References

  1. Arquint C, Nigg EA (2014) STIL microcephaly mutations interfere with APC/C-mediated degradation and cause centriole amplification. Curr Biol 24:351–360. doi:10.1016/j.cub.2013.12.016

    CAS  PubMed  Article  Google Scholar 

  2. Azimzadeh J, Wong ML, Downhour DM et al (2012) Centrosome loss in the evolution of planarians. Science 335:461–463. doi:10.1126/science.1214457

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  3. Bahe S, Stierhof Y-D, Wilkinson CJ et al (2005) Rootletin forms centriole-associated filaments and functions in centrosome cohesion. J Cell Biol 171:27–33. doi:10.1083/jcb.200504107

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  4. Bakhoum SF, Genovese G, Compton DA (2009) Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr Biol 19:1937–1942. doi:10.1016/j.cub.2009.09.055

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  5. Barr AR, Kilmartin JV, Gergely F (2010) CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response. J Cell Biol 189:23–39. doi:10.1083/jcb.200912163

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  6. Basto R, Brunk K, Vinogradova T et al (2008) Centrosome amplification can initiate tumorigenesis in flies. Cell 133:1032–1042. doi:10.1016/j.cell.2008.05.039

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  7. Basto R, Lau J, Vinogradova T et al (2006) Flies without centrioles. Cell 125:1375–1386. doi:10.1016/j.cell.2006.05.025

    CAS  PubMed  Article  Google Scholar 

  8. Beck B, Driessens G, Goossens S et al (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478:399–403. doi:10.1038/nature10525

    CAS  PubMed  Article  Google Scholar 

  9. Bertran MT, Sdelci S, Regué L et al (2011) Nek9 is a Plk1-activated kinase that controls early centrosome separation through Nek6/7 and Eg5. EMBO J 30:2634–2647. doi:10.1038/emboj.2011.179

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  10. Blangy A, Lane HA, d'Hérin P et al (1995) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83:1159–1169

    CAS  PubMed  Article  Google Scholar 

  11. Bornens M (2012) The centrosome in cells and organisms. Science 335:422–426. doi:10.1126/science.1209037

    CAS  PubMed  Article  Google Scholar 

  12. Boveri TH (1914) Zur Frage der Entstehung Maligner Tumoren. Gustav Fischer, Jena

    Google Scholar 

  13. Bringmann H, Hyman AA (2005) A cytokinesis furrow is positioned by two consecutive signals. 436:731–734. doi: 10.1038/nature03823

  14. Buffin E, Emre D, Karess RE (2007) Flies without a spindle checkpoint. Nat Cell Biol 9:565–572. doi:10.1038/ncb1570

    CAS  PubMed  Article  Google Scholar 

  15. Canman JC, Cameron LA, Maddox PS, et al (2003) Determining the position of the cell division plane. 424:1074–1078. doi: 10.1038/nature01860

  16. Carazo-Salas RE, Guarguaglini G, Gruss OJ et al (1999) Generation of GTP-bound Ran by RCC1 is required for chromatin-induced mitotic spindle formation. Nature 400:178–181. doi:10.1038/22133

    CAS  PubMed  Article  Google Scholar 

  17. Castellanos E, Dominguez P, Gonzalez C (2008) Centrosome dysfunction in drosophila neural stem cells causes tumors that are not due to genome instability. Curr Biol 18:1209–1214. doi:10.1016/j.cub.2008.07.029

    CAS  PubMed  Article  Google Scholar 

  18. Chen J-F, Zhang Y, Wilde J et al (2014) Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size. Nat Commun 5:3885. doi:10.1038/ncomms4885

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Chmátal L, Yang K, Schultz RM, Lampson MA (2015) Spatial regulation of kinetochore microtubule attachments by destabilization at spindle poles in Meiosis I. Curr Biol 25:1835–1841. doi:10.1016/j.cub.2015.05.013

    PubMed  Article  CAS  Google Scholar 

  20. Cimini D, Cameron LA, Salmon ED (2004) Anaphase spindle mechanics prevent mis-segregation of merotelically oriented chromosomes. Curr Biol 14:2149–2155. doi:10.1016/j.cub.2004.11.029

    CAS  PubMed  Article  Google Scholar 

  21. Cimini D, Wan X, Hirel CB, Salmon ED (2006) Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr Biol 16:1711–1718. doi:10.1016/j.cub.2006.07.022

    CAS  PubMed  Article  Google Scholar 

  22. Conduit PT, Brunk K, Dobbelaere J et al (2010) Centrioles regulate centrosome size by controlling the rate of Cnn incorporation into the PCM. Curr Biol 20:2178–2186. doi:10.1016/j.cub.2010.11.011

    CAS  PubMed  Article  Google Scholar 

  23. Cosenza MR, Krämer A (2015) Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues. In press

  24. Crasta K, Ganem NJ, Dagher R, et al (2012) DNA breaks and chromosome pulverization from errors in mitosis. 482:53–58. doi: 10.1038/nature10802

  25. Drechsler H, McHugh T, Singleton MR et al (2014) The Kinesin-12 Kif15 is a processive track-switching tetramer. Elife 3:e01724

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  26. Fish JL, Kosodo Y, Enard W et al (2006) Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. Proc Natl Acad Sci USA 103:10438–10443. doi:10.1073/pnas.0604066103

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  27. Floriot S, Vesque C, Rodriguez S et al (2015) C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle. Nat Commun 6:6894. doi:10.1038/ncomms7894

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  28. Fodde R, Kuipers J, Rosenberg C et al (2001) Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3:433–438. doi:10.1038/35070129

    CAS  PubMed  Article  Google Scholar 

  29. Foley EA, Kapoor TM (2013) Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat Rev MolCell Biol 14:25–37. doi:10.1038/nrm3494

  30. Fry AM, Mayor T, Meraldi P et al (1998a) C-Nap1, a novel centrosomal coiled-coil protein and candidate substrate of the cell cycle-regulated protein kinase Nek2. J Cell Biol 141:1563–1574

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  31. Fry AM, Meraldi P, Nigg EA (1998b) A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators. EMBO J 17:470–481. doi:10.1093/emboj/17.2.470

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  32. Ganem NJ, Godinho SA, Pellman D (2009) A mechanism linking extra centrosomes to chromosomal instability. 460:278–282. doi: 10.1038/nature08136

  33. Gasic I, Nerurkar P, Meraldi P (2015) Centrosome age regulates kinetochore microtubule stability and biases chromosome mis-segregation. Elife 4:e07909. doi:10.7554/eLife.07909

    Article  Google Scholar 

  34. Giansanti MG, Gatti M, Bonaccorsi S (2001) The role of centrosomes and astral microtubules during asymmetric division of Drosophila neuroblasts. Development 128:1137–1145

    CAS  PubMed  Google Scholar 

  35. Gilmore EC, Walsh CA (2013) Genetic causes of microcephaly and lessons for neuronal development. Wiley Interdiscip Rev Dev Biol 2:461–478. doi:10.1002/wdev.89

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  36. Godinho SA, Picone R, Burute M et al (2014) Oncogene-like induction of cellular invasion from centrosome amplification. Nature 510:167–171. doi:10.1038/nature13277

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  37. Goshima G, Mayer M, Zhang N et al (2008) Augmin: a protein complex required for centrosome-independent microtubule generation within the spindle. J Cell Biol 181:421–429. doi:10.1083/jcb.200711053

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  38. Greenan G, Brangwynne CP, Jaensch S et al (2010) Centrosome size sets mitotic spindle length in Caenorhabditis elegans embryos. Curr Biol 20:353–358. doi:10.1016/j.cub.2009.12.050

    CAS  PubMed  Article  Google Scholar 

  39. Gregan J, Polakova S, Zhang L et al (2011) Merotelic kinetochore attachment: causes and effects. Trends Cell Biol 21:374–381. doi:10.1016/j.tcb.2011.01.003

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  40. Gruber R, Zhou Z, Sukchev M et al (2011) MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway. Nat Cell Biol 13:1325–1334. doi:10.1038/ncb2342

    CAS  PubMed  Article  Google Scholar 

  41. Hayward D, Metz J, Pellacani C, Wakefield JG (2014) Synergy between multiple microtubule-generating pathways confers robustness to centrosome-driven mitotic spindle formation. Dev Cell 28:81–93. doi:10.1016/j.devcel.2013.12.001

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  42. Heald R, Tournebize R, Blank T, et al (1996) Self-organization of microtubules into bipolar spindles around artificial chromosomes in Xenopus egg extracts. 382:420–425. doi: 10.1038/382420a0

  43. Heald R, Tournebize R, Habermann A et al (1997) Spindle assembly in Xenopus egg extracts: respective roles of centrosomes and microtubule self-organization. J Cell Biol 138:615–628

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  44. Hinchcliffe EH, Miller FJ, Cham M et al (2001) Requirement of a centrosomal activity for cell cycle progression through G1 into S phase. Science 291:1547–1550. doi:10.1126/science.291.5508.1547

    CAS  PubMed  Article  Google Scholar 

  45. Holland AJ, Cleveland DW (2012) Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep 13:501–514. doi:10.1038/embor.2012.55

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  46. Hyman AA (1989) Centrosome movement in the early divisions of Caenorhabditis elegans: a cortical site determining centrosome position. J Cell Biol 109:1185–1193

    CAS  PubMed  Article  Google Scholar 

  47. Januschke J, Llamazares S, Reina J, Gonzalez C (2011) Drosophila neuroblasts retain the daughter centrosome. Nat Commun 2:243. doi:10.1038/ncomms1245

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  48. Januschke J, Reina J, Llamazares S et al (2013) Centrobin controls mother-daughter centriole asymmetry in Drosophila neuroblasts. Nat Cell Biol 15:241–248. doi:10.1038/ncb2671

    CAS  PubMed  Article  Google Scholar 

  49. Kaplan KB, Burds AA, Swedlow JR et al (2001) A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat Cell Biol 3:429–432. doi:10.1038/35070123

    CAS  PubMed  Article  Google Scholar 

  50. Kaseda K, McAinsh AD, Cross RA (2012) Dual pathway spindle assembly increases both the speed and the fidelity of mitosis. Biol Open 1:12–18. doi:10.1242/bio.2011012

    PubMed Central  PubMed  Article  Google Scholar 

  51. Kashina AS, Baskin RJ, Cole DG, et al (1996) A bipolar kinesin. 379:270–272. doi: 10.1038/379270a0

  52. Keller LC, Wemmer KA, Marshall WF (2010) Influence of centriole number on mitotic spindle length and symmetry. Cytoskeleton (Hoboken) 67:504–518. doi:10.1002/cm.20462

    CAS  Google Scholar 

  53. Kellogg DR, Moritz M, Alberts BM (1994) The centrosome and cellular organization. Annu Rev Biochem 63:639–674. doi:10.1146/annurev.bi.63.070194.003231

    CAS  PubMed  Article  Google Scholar 

  54. Khodjakov AL, Cole RW, Oakley BR, Rieder CL (2000) Centrosome-independent mitotic spindle formation in vertebrates. Curr Biol 10:59–67

    CAS  PubMed  Article  Google Scholar 

  55. Khodjakov AL, Rieder CL (2001) Centrosomes enhance the fidelity of cytokinesis in vertebrates and are required for cell cycle progression. J Cell Biol 153:237–242

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  56. Kitagawa D, Kohlmaier G, Keller D et al (2011) Spindle positioning in human cells relies on proper centriole formation and on the microcephaly proteins CPAP and STIL. J Cell Sci 124:3884–3893. doi:10.1242/jcs.089888

    CAS  PubMed  Article  Google Scholar 

  57. Kiyomitsu T, Cheeseman IM (2012) Chromosome- and spindle-pole-derived signals generate an intrinsic code for spindle position and orientation. Nat Cell Biol 14:311–317. doi:10.1038/ncb2440

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  58. Knowlton AL, Lan W, Stukenberg PT (2006) Aurora B is enriched at merotelic attachment sites, where it regulates MCAK. Curr Biol 16:1705–1710. doi:10.1016/j.cub.2006.07.057

    CAS  PubMed  Article  Google Scholar 

  59. Kochanski RS, Borisy GG (1990) Mode of centriole duplication and distribution. J Cell Biol 110:1599–1605

    CAS  PubMed  Article  Google Scholar 

  60. Kotak S, Gönczy P (2013) Mechanisms of spindle positioning: cortical force generators in the limelight. Curr Opin Cell Biol 25:741–748. doi:10.1016/j.ceb.2013.07.008

    CAS  PubMed  Article  Google Scholar 

  61. Kulukian A, Fuchs E (2013) Spindle orientation and epidermal morphogenesis. Philos Trans R Soc Lond, B, Biol Sci 368:20130016. doi:10.1098/rstb.2013.0016

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  62. Kwon M, Godinho SA, Chandhok NS et al (2008) Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev 22:2189–2203. doi:10.1101/gad.1700908

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  63. Lampson MA, Renduchitala K, Khodjakov AL, Kapoor TM (2004) Correcting improper chromosome-spindle attachments during cell division. Nat Cell Biol 6:232–237. doi:10.1038/ncb1102

    CAS  PubMed  Article  Google Scholar 

  64. Lange BM, Gull K (1995) A molecular marker for centriole maturation in the mammalian cell cycle. J Cell Biol 130:919–927

    CAS  PubMed  Article  Google Scholar 

  65. Lavia P (2015) The GTPase RAN regulates multiple steps of the centrosome life cycle. In press

  66. Levy DL, Heald R (2012) Mechanisms of intracellular scaling. Annu Rev Cell Dev Biol 28:113–135. doi:10.1146/annurev-cellbio-092910-154158

    CAS  PubMed  Article  Google Scholar 

  67. Lin Y-C, Chang C-W, Hsu W-B et al (2013) Human microcephaly protein CEP135 binds to hSAS-6 and CPAP, and is required for centriole assembly. EMBO J 32:1141–1154. doi:10.1038/emboj.2013.56

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  68. Lingle WL, Lutz WH, Ingle JN et al (1998) Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity. Proc Natl Acad Sci USA 95:2950–2955

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  69. Logarinho E, Maffini S, Barisic M et al (2012) CLASPs prevent irreversible multipolarity by ensuring spindle-pole resistance to traction forces during chromosome alignment. Nat Cell Biol 14:295–303. doi:10.1038/ncb2423

    CAS  PubMed  Article  Google Scholar 

  70. Lu MS, Johnston CA (2013) Molecular pathways regulating mitotic spindle orientation in animal cells. Development 140:1843–1856. doi:10.1242/dev.087627

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  71. Maiato H, Rieder CL, Khodjakov AL (2004) Kinetochore-driven formation of kinetochore fibers contributes to spindle assembly during animal mitosis. J Cell Biol 167:831–840. doi:10.1083/jcb.200407090

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  72. Mardin BR, Isokane M, Cosenza MR et al (2013) EGF-induced centrosome separation promotes mitotic progression and cell survival. Dev Cell 25:229–240. doi:10.1016/j.devcel.2013.03.012

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  73. Mardin BR, Lange C, Baxter JE et al (2010) Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction. Nat Cell Biol 12:1166–1176. doi:10.1038/ncb2120

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  74. Mardin BR, Schiebel E (2012) Breaking the ties that bind: new advances in centrosome biology. J Cell Biol 197:11–18. doi:10.1083/jcb.201108006

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  75. Marthiens V, Rujano MA, Pennetier C et al (2013) Centrosome amplification causes microcephaly. Nat Cell Biol 15:731–740. doi:10.1038/ncb2746

    CAS  PubMed  Article  Google Scholar 

  76. Martin C-A, Ahmad I, Klingseisen A et al (2014) Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet 46:1283–1292. doi:10.1038/ng.3122

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  77. Mayer TU, Kapoor TM, Haggarty SJ et al (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971–974

    CAS  PubMed  Article  Google Scholar 

  78. Mazia D (1961) The cell. In: Brachet J, Mirsky AE (eds) Mitosis and the physiology of cell division. Academic, New York and London, pp 77–412

    Google Scholar 

  79. Mchedlishvili N, Wieser S, Holtackers R et al (2012) Kinetochores accelerate centrosome separation to ensure faithful chromosome segregation. J Cell Sci 125:906–918. doi:10.1242/jcs.091967

    CAS  PubMed  Article  Google Scholar 

  80. Mogensen MM, Malik A, Piel M et al (2000) Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein. J Cell Sci 113(Pt 17):3013–3023

    CAS  PubMed  Google Scholar 

  81. Morin X, Bellaïche Y (2011) Mitotic spindle orientation in asymmetric and symmetric cell divisions during animal development. Dev Cell 21:102–119. doi:10.1016/j.devcel.2011.06.012

    CAS  PubMed  Article  Google Scholar 

  82. Moutinho-Pereira S, Stuurman N, Afonso O et al (2013) Genes involved in centrosome-independent mitotic spindle assembly in Drosophila S2 cells. Proc Natl Acad Sci USA 110:19808–19813. doi:10.1073/pnas.1320013110

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  83. Nam H-J, Naylor RM, van Deursen JM (2015) Centrosome dynamics as a source of chromosomal instability. Trends Cell Biol 25:65–73. doi:10.1016/j.tcb.2014.10.002

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  84. Nam H-J, van Deursen JM (2014) Cyclin B2 and p53 control proper timing of centrosome separation. Nat Cell Biol 16:538–549. doi:10.1038/ncb2952

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  85. Nano M, Basto R (2015) The Janus soul of centrosomes: a paradoxical role in disease? In press

  86. Nicholas AK, Khurshid M, Désir J et al (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42:1010–1014. doi:10.1038/ng.682

    CAS  PubMed  Article  Google Scholar 

  87. Nigg EA, Stearns T (2011) The centrosome cycle: Centriole biogenesis, duplication and inherent asymmetries. Nat Cell Biol 13:1154–1160. doi:10.1038/ncb2345

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  88. Noatynska A, Gotta M, Meraldi P (2012) Mitotic spindle (DIS)orientation and DISease: cause or consequence? J Cell Biol 199:1025–1035. doi:10.1083/jcb.201209015

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  89. O'Connell KF, Caron C, Kopish KR et al (2001) The C. elegans zyg-1 gene encodes a regulator of centrosome duplication with distinct maternal and paternal roles in the embryo. Cell 105:547–558

    PubMed  Article  Google Scholar 

  90. Ohba T, Nakamura M, Nishitani H, Nishimoto T (1999) Self-organization of microtubule asters induced in Xenopus egg extracts by GTP-bound Ran. Science 284:1356–1358

    CAS  PubMed  Article  Google Scholar 

  91. Panic M, Hata S, Neuner A, Schiebel E (2015) The centrosomal linker and microtubules provide dual levels of spatial coordination of centrosomes. PLoS Genet 11:e1005243. doi:10.1371/journal.pgen.1005243

    PubMed Central  PubMed  Article  Google Scholar 

  92. Paridaen JTML, Wilsch-Bräuninger M, Huttner WB (2013) Asymmetric inheritance of centrosome-associated primary cilium membrane directs ciliogenesis after cell division. Cell 155:333–344. doi:10.1016/j.cell.2013.08.060

    CAS  PubMed  Article  Google Scholar 

  93. Pease JC, Tirnauer JS (2011) Mitotic spindle misorientation in cancer—out of alignment and into the fire. J Cell Sci 124:1007–1016. doi:10.1242/jcs.081406

    CAS  PubMed  Article  Google Scholar 

  94. Pfau SJ, Amon A (2012) Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep 13:515–527. doi:10.1038/embor.2012.65

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  95. Piel M, Meyer P, Khodjakov AL et al (2000) The respective contributions of the mother and daughter centrioles to centrosome activity and behavior in vertebrate cells. J Cell Biol 149:317–330

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  96. Piel M, Nordberg J, Euteneuer U, Bornens M (2001) Centrosome-dependent exit of cytokinesis in animal cells. Science 291:1550–1553. doi:10.1126/science.291.5508.1550

    CAS  PubMed  Article  Google Scholar 

  97. Pihan GA, Purohit A, Wallace J et al (1998) Centrosome defects and genetic instability in malignant tumors. Cancer Res 58:3974–3985

    CAS  PubMed  Google Scholar 

  98. Poulson ND, Lechler T (2010) Robust control of mitotic spindle orientation in the developing epidermis. J Cell Biol 191:915–922. doi:10.1083/jcb.201008001

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  99. Rapley J, Baxter JE, Blot J et al (2005) Coordinate regulation of the mother centriole component nlp by nek2 and plk1 protein kinases. Mol Cell Biol 25:1309–1324. doi:10.1128/MCB.25.4.1309-1324.2005

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  100. Rappaport R (1961) Experiments concerning the cleavage stimulus in sand dollar eggs. J Exp Zool 148:81–89

    CAS  PubMed  Article  Google Scholar 

  101. Rieder CL, Borisy GG (1982) The Centrosome Cycle in PtK2 Cells: Asymmetric distribution and structural changes in the pericentriolar material. Biol Cell 44:117–132

    Google Scholar 

  102. Rosenblatt J, Cramer LP, Baum B, McGee KM (2004) Myosin II-dependent cortical movement is required for centrosome separation and positioning during mitotic spindle assembly. Cell 117:361–372

    CAS  PubMed  Article  Google Scholar 

  103. Silkworth WT, Nardi IK, Paul R et al (2012) Timing of centrosome separation is important for accurate chromosome segregation. Mol Biol Cell 23:401–411. doi:10.1091/mbc.E11-02-0095

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  104. Silkworth WT, Nardi IK, Scholl LM, Cimini D (2009) Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS ONE 4:e6564. doi:10.1371/journal.pone.0006564

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  105. Siller KH, Doe CQ (2009) Spindle orientation during asymmetric cell division. Nat Cell Biol 11:365–374. doi:10.1038/ncb0409-365

    CAS  PubMed  Article  Google Scholar 

  106. Sir J-H, Barr AR, Nicholas AK et al (2011) A primary microcephaly protein complex forms a ring around parental centrioles. Nat Genet 43:1147–1153. doi:10.1038/ng.971

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  107. Sir J-H, Pütz M, Daly O et al (2013) Loss of centrioles causes chromosomal instability in vertebrate somatic cells. J Cell Biol 203:747–756. doi:10.1083/jcb.201309038

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  108. Sturgill EG, Ohi R (2013) Kinesin-12 differentially affects spindle assembly depending on its microtubule substrate. Curr Biol 23:1280–1290. doi:10.1016/j.cub.2013.05.043

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  109. Tajbakhsh S, Gonzalez C (2009) Biased segregation of DNA and centrosomes—moving together or drifting apart? Nat Rev Mol Cell Biol 10:804–810. doi:10.1038/nrm2784

    CAS  PubMed  Article  Google Scholar 

  110. Tan CH, Gasic I, Huber-Reggi SP et al (2015) The equatorial position of the metaphase plate ensures symmetric cell divisions. Elife 4:e05124. doi:10.7554/eLife.05124

    Google Scholar 

  111. Tanenbaum ME, Macůrek L, Galjart N, Medema RH (2008) Dynein, Lis1 and CLIP-170 counteract Eg5-dependent centrosome separation during bipolar spindle assembly. EMBO J 27:3235–3245. doi:10.1038/emboj.2008.242

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  112. Tanenbaum ME, Macůrek L, Janssen A et al (2009) Kif15 cooperates with eg5 to promote bipolar spindle assembly. Curr Biol 19:1703–1711. doi:10.1016/j.cub.2009.08.027

    CAS  PubMed  Article  Google Scholar 

  113. Tanenbaum ME, Medema RH (2010) Mechanisms of centrosome separation and bipolar spindle assembly. Dev Cell 19:797–806. doi:10.1016/j.devcel.2010.11.011

    CAS  PubMed  Article  Google Scholar 

  114. Tang C-JC, Lin S-Y, Hsu W-B et al (2011) The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation. EMBO J 30:4790–4804. doi:10.1038/emboj.2011.378

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  115. Thoma CR, Toso A, Gutbrodt KL et al (2009) VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol 11:994–1001. doi:10.1038/ncb1912

    CAS  PubMed  Article  Google Scholar 

  116. Thompson SL, Compton DA (2011) Chromosome missegregation in human cells arises through specific types of kinetochore-microtubule attachment errors. Proc Natl Acad Sci USA 108:17974–17978. doi:10.1073/pnas.1109720108

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  117. Toso A, Winter JR, Garrod AJ et al (2009) Kinetochore-generated pushing forces separate centrosomes during bipolar spindle assembly. J Cell Biol 184:365–372. doi:10.1083/jcb.200809055

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  118. Toyoshima F, Matsumura S, Morimoto H et al (2007) PtdIns(3,4,5)P3 regulates spindle orientation in adherent cells. Dev Cell 13:796–811. doi:10.1016/j.devcel.2007.10.014

    CAS  PubMed  Article  Google Scholar 

  119. Toyoshima F, Nishida E (2007) Integrin-mediated adhesion orients the spindle parallel to the substratum in an EB1- and myosin X-dependent manner. EMBO J 26:1487–1498. doi:10.1038/sj.emboj.7601599

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  120. van Ree JH, Nam H-J, van Deursen JM (2015) Mitotic kinase cascades orchestrating timely disjunction and movement of centrosomes maintain chromosomal stability and prevent cancer. In press

  121. Vanneste D, Takagi M, Imamoto N, Vernos I (2009) The role of Hklp2 in the stabilization and maintenance of spindle bipolarity. Curr Biol 19:1712–1717. doi:10.1016/j.cub.2009.09.019

    CAS  PubMed  Article  Google Scholar 

  122. Wang X, Tsai J-W, Imai JH et al (2009) Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461:947–955. doi:10.1038/nature08435

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  123. Wilde A, Zheng Y (1999) Stimulation of microtubule aster formation and spindle assembly by the small GTPase Ran. Science 284:1359–1362

    CAS  PubMed  Article  Google Scholar 

  124. Williams SE, Beronja S, Pasolli HA, Fuchs E (2011) Asymmetric cell divisions promote Notch-dependent epidermal differentiation. 470:353–358. doi: 10.1038/nature09793

  125. Wong YL, Anzola JV, Davis RL et al (2015) Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4. Science 348:1155–1160. doi:10.1126/science.aaa5111

    CAS  PubMed  Article  Google Scholar 

  126. Woods CG, Basto R (2014) Microcephaly. Curr Biol 24:R1109–11. doi:10.1016/j.cub.2014.09.063

    CAS  PubMed  Article  Google Scholar 

  127. Yamashita YM, Mahowald AP, Perlin JR, Fuller MT (2007) Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315:518–521. doi:10.1126/science.1134910

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  128. Yang J, Gao J, Adamian M et al (2005) The ciliary rootlet maintains long-term stability of sensory cilia. Mol Cell Biol 25:4129–4137. doi:10.1128/MCB.25.10.4129-4137.2005

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  129. Ye AA, Deretic J, Hoel CM et al (2015) Aurora A kinase contributes to a pole-based error correction pathway. Curr Biol 25:1842–1851. doi:10.1016/j.cub.2015.06.021

    CAS  PubMed  Article  Google Scholar 

  130. Yu TW, Mochida GH, Tischfield DJ et al (2010) Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 42:1015–1020. doi:10.1038/ng.683

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  131. Zhang C-Z, Spektor A, Cornils H et al (2015) Chromothripsis from DNA damage in micronuclei. Nature 522:179–184. doi:10.1038/nature14493

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  132. Zhang Y, Foreman O, Wigle DA et al (2012) USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. J Clin Invest 122:4362–4374. doi:10.1172/JCI63084

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  133. Zou C, Li J, Bai Y et al (2005) Centrobin: a novel daughter centriole-associated protein that is required for centriole duplication. J Cell Biol 171:437–445. doi:10.1083/jcb.200506185

    PubMed Central  CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

I thank M. Gotta (Univ. of Geneva, Switzerland) and the Meraldi lab members for critical discussions of the manuscript. P.M. is funded by an SNF-project grant and the University of Geneva.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Patrick Meraldi.

Additional information

Responsible Editor: Daniela Cimini and Giulia Guarguaglini

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Meraldi, P. Centrosomes in spindle organization and chromosome segregation: a mechanistic view. Chromosome Res 24, 19–34 (2016). https://doi.org/10.1007/s10577-015-9508-2

Download citation

Keywords

  • bipolar spindle
  • mitosis
  • chromosomal instability
  • spindle orientation
  • bipolar spindle assembly