Aurora kinase A (AURKA) is an important mitotic kinase involved in the G2/M transition, centrosome maturation and separation, and spindle formation in somatic cells. We used transgenic models that specifically overexpress in mouse oocytes either wild-type (WT-AURKA) or a catalytically inactive (kinase-dead) (KD-AURKA) AURKA to gain new insights regarding the role of AURKA during oocyte maturation. AURKA activation occurs shortly after hCG administration that initiates maturation in vivo. Although AURKA activity is increased in WT-AURKA oocytes, resumption of meiosis is not observed in the absence of hCG administration. Control oocytes contain one to three microtubule organizing centers (MTOCs; centrosome equivalent) at prophase I. At the time of germinal vesicle breakdown (GVBD), the first visible marker of resumption of meiosis, the MTOC number increases. In WT-AURKA oocytes, the increase in MTOC number occurs prematurely but transiently without GVBD, whereas the increase in MTOC number does not occur in control and KD-AURKA oocytes. AURKA activation is biphasic with the initial activation not requiring CDC25B-CDK1 activity, whereas full activation, which is essential for the increase in MTOCs number, depends on CDK1 activity. AURKA activity also influences spindle length and regulates, independent of its protein kinase activity, the amount of MTOC associated with gamma-tubulin. Both WT-AURKA and KD-AURKA transgenic mice have normal fertility during first 6 mo of life. These results suggest that although AURKA is not a trigger kinase for G2/M transition in mouse oocytes, it regulates MTOC number and spindle length, and, independent of its protein kinase activity, gamma-tubulin recruitment to MTOCs.

Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic

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Terada Y, Uetake Y, Kuriyama R. Interaction of Aurora-A and centrosomin at the microtubule-nucleating site in Drosophila and mammalian cells. J Cell Biol 2003;162:757 763 PubMed PMC

Kufer TA, Sillje HH, Korner R, Gruss OJ, Meraldi P, Nigg EA. Human TPX2 is required for targeting Aurora-A kinase to the spindle. J Cell Biol 2002;158:617 623 PubMed PMC

De Luca M, Lavia P, Guarguaglini G. A functional interplay between Aurora-A, Plk1 and TPX2 at spindle poles: Plk1 controls centrosomal localization of Aurora-A and TPX2 spindle association. Cell Cycle 2006;5:296 303 PubMed

Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M, Hatakeyama K, Saya H. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell 2003;114:585 598 PubMed

Hoar K, Chakravarty A, Rabino C, Wysong D, Bowman D, Roy N, Ecsedy JA. MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol 2007;27:4513 4525 PubMed PMC

Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 2003;278:51786 51795 PubMed

Mori D, Yano Y, Toyo-oka K, Yoshida N, Yamada M, Muramatsu M, Zhang D, Saya H, Toyoshima YY, Kinoshita K, Wynshaw-Boris A, Hirotsune S. NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3 recruitment. Mol Cell Biol 2007;27:352 367 PubMed PMC

Cazales M, Schmitt E, Montembault E, Dozier C, Prigent C, Ducommun B. CDC25B phosphorylation by Aurora-A occurs at the G2/M transition and is inhibited by DNA damage. Cell Cycle 2005;4:1233 1238 PubMed

Dutertre S, Cazales M, Quaranta M, Froment C, Trabut V, Dozier C, Mirey G, Bouche JP, Theis-Febvre N, Schmitt E, Monsarrat B, Prigent Cet al. Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2-M transition. J Cell Sci 2004;117:2523 2531 PubMed

Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 2008;455:119 123 PubMed

Seki A, Coppinger JA, Jang CY, Yates JR, Fang G. Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science 2008;320:1655 1658 PubMed PMC

Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W, Galvin KM, Hoar KM, Huck JJ, LeRoy PJ, Ray ET, Sells TBet al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci U S A 2007;104:4106 4111 PubMed PMC

Van Horn RD, Chu S, Fan L, Yin T, Du J, Beckmann R, Mader M, Zhu G, Toth J, Blanchard K, Ye XS. Cdk1 activity is required for mitotic activation of aurora A during G2/M transition of human cells. J Biol Chem 2010;285:21849 21857 PubMed PMC

Barr AR, Gergely F. Aurora-A: the maker and breaker of spindle poles. J Cell Sci 2007;120:2987 2996 PubMed

Lens SM, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer 2010;10:825 841 PubMed

Saskova A, Solc P, Baran V, Kubelka M, Schultz RM, Motlik J. Aurora kinase A controls meiosis I progression in mouse oocytes. Cell Cycle 2008;7:2368 2376 PubMed PMC

Shuda K, Schindler K, Ma J, Schultz RM, Donovan PJ. Aurora kinase B modulates chromosome alignment in mouse oocytes. Mol Reprod Dev 2009;76:1094 1105 PubMed PMC

Solc P, Schultz RM, Motlik J. Prophase I arrest and progression to metaphase I in mouse oocytes: comparison of resumption of meiosis and recovery from G2-arrest in somatic cells. Mol Hum Reprod 2010;16:654 664 PubMed PMC

Bayliss R, Sardon T, Vernos I, Conti E. Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol Cell 2003;12:851 862 PubMed

Tsai MY, Wiese C, Cao K, Martin O, Donovan P, Ruderman J, Prigent C, Zheng YA. Ran signalling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nat Cell Biol 2003;5:242 248 PubMed

Brunet S, Dumont J, Lee KW, Kinoshita K, Hikal P, Gruss OJ, Maro B, Verlhac MH. Meiotic regulation of TPX2 protein levels governs cell cycle progression in mouse oocytes. PLoS ONE 2008;3:e3338. PubMed PMC

Ma C, Cummings C, Liu XJ. Biphasic activation of Aurora-A kinase during the meiosis I- meiosis II transition in Xenopus oocytes. Mol Cell Biol 2003;23:1703 1716 PubMed PMC

Nishimura Y, Endo T, Kano K, Naito K. Porcine Aurora A accelerates Cyclin B and Mos synthesis and promotes meiotic resumption of porcine oocytes. Anim Reprod Sci 2009;113:114 124 PubMed

Hu HM, Chuang CK, Lee MJ, Tseng TC, Tang TK. Genomic organization, expression, and chromosome localization of a third aurora-related kinase gene, Aie1. DNA Cell Biol 2000;19:679 688 PubMed

Kimmins S, Crosio C, Kotaja N, Hirayama J, Monaco L, Hoog C, van Duin M, Gossen JA, Sassone-Corsi P. Differential functions of the Aurora-B and Aurora-C kinases in mammalian spermatogenesis. Mol Endocrinol 2007;21:726 739 PubMed

Kimura M, Matsuda Y, Yoshioka T, Okano Y. Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem 1999;274:7334 7340 PubMed

Chen HL, Tang CJ, Chen CY, Tang TK. Overexpression of an Aurora-C kinase-deficient mutant disrupts the Aurora-B/INCENP complex and induces polyploidy. J Biomed Sci 2005;12:297 310 PubMed

Sharif B, Na J, Lykke-Hartmann K, McLaughlin SH, Laue E, Glover DM, Zernicka-Goetz M. The chromosome passenger complex is required for fidelity of chromosome transmission and cytokinesis in meiosis of mouse oocytes. J Cell Sci 2010;123:4292 4300 PubMed PMC

Schindler K, Davydenko O, Fram G, Lampson MA, Schultz RM. Maternally recruited Aurora C kinase is more stable than Aurora B to support mouse oocyte maturation and early development. Proc Natl Acad Sci U S A 2012;109:E2215 E2222 PubMed PMC

Bornslaeger EA, Mattei P, Schultz RM. Involvement of cAMP-dependent protein kinase and protein phosphorylation in regulation of mouse oocyte maturation. Dev Biol 1986;114:453 462 PubMed

Downs SM, Daniel SA, Bornslaeger EA, Hoppe PC, Eppig JJ. Maintenance of meiotic arrest in mouse oocytes by purines: modulation of cAMP levels and cAMP phosphodiesterase activity. Gamete Res 1989;23:323 334 PubMed

Masciarelli S, Horner K, Liu C, Park SH, Hinckley M, Hockman S, Nedachi T, Jin C, Conti M, Manganiello V. Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility. J Clin Invest 2004;114:196 205 PubMed PMC

Conti M, Hsieh M, Zamah AM, Oh JS. Novel signaling mechanisms in the ovary during oocyte maturation and ovulation. Mol Cell Endocrinol 2012;356:65 73 PubMed PMC

Han SJ, Chen R, Paronetto MP, Conti M. Wee1B is an oocyte-specific kinase involved in the control of meiotic arrest in the mouse. Curr Biol 2005;15:1670 1676 PubMed

Lincoln AJ, Wickramasinghe D, Stein P, Schultz RM, Palko ME, De Miguel MP, Tessarollo L, Donovan PJ. Cdc25b phosphatase is required for resumption of meiosis during oocyte maturation. Nat Genet 2002;30:446 449 PubMed

Oh JS, Han SJ, Conti M. Wee1B, Myt1, and Cdc25 function in distinct compartments of the mouse oocyte to control meiotic resumption. J Cell Biol 2010;188:199 207 PubMed PMC

Nakajima H, Toyoshima-Morimoto F, Taniguchi E, Nishida E. Identification of a consensus motif for Plk (Polo-like kinase) phosphorylation reveals Myt1 as a Plk1 substrate. J Biol Chem 2003;278:25277 25280 PubMed

Watanabe N, Arai H, Iwasaki J, Shiina M, Ogata K, Hunter T, Osada H. Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways. Proc Natl Acad Sci U S A 2005;102:11663 11668 PubMed PMC

Zhang D, Hirota T, Marumoto T, Shimizu M, Kunitoku N, Sasayama T, Arima Y, Feng L, Suzuki M, Takeya M, Saya H. Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models. Oncogene 2004;23:8720 8730 PubMed

Lewandoski M, Wassarman KM, Martin GR. Zp3-cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line. Curr Biol 1997;7:148 151 PubMed

Iannuccelli E, Mompart F, Gellin J, Lahbib-Mansais Y, Yerle M, Boudier T. NEMO: a tool for analyzing gene and chromosome territory distributions from 3D-FISH experiments. Bioinformatics 2010;26:696 697 PubMed

Sanfins A, Lee GY, Plancha CE, Overstrom EW, Albertini DF. Distinctions in meiotic spindle structure and assembly during in vitro and in vivo maturation of mouse oocytes. Biol Reprod 2003;69:2059 2067 PubMed

Littlepage LE, Wu H, Andresson T, Deanehan JK, Amundadottir LT, Ruderman JV. Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A. Proc Natl Acad Sci U S A 2002;99:15440 15445 PubMed PMC

Satinover DL, Leach CA, Stukenberg PT, Brautigan DL. Activation of Aurora-A kinase by protein phosphatase inhibitor-2, a bifunctional signaling protein. Proc Natl Acad Sci U S A 2004;101:8625 8630 PubMed PMC

Norris RP, Freudzon M, Nikolaev VO, Jaffe LA. Epidermal growth factor receptor kinase activity is required for gap junction closure and for part of the decrease in ovarian follicle cGMP in response to LH. Reproduction 2010;140:655 662 PubMed PMC

Norris RP, Ratzan WJ, Freudzon M, Mehlmann LM, Krall J, Movsesian MA, Wang H, Ke H, Nikolaev VO, Jaffe LA. Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte. Development 2009;136:1869 1878 PubMed PMC

Calarco-Gillam PD, Siebert MC, Hubble R, Mitchison T, Kirschner M. Centrosome development in early mouse embryos as defined by an autoantibody against pericentriolar material. Cell 1983;35:621 629 PubMed

Szollosi D, Calarco P, Donahue RP. Absence of centrioles in the first and second meiotic spindles of mouse oocytes. J Cell Sci 1972;11:521 541 PubMed

Carabatsos MJ, Combelles CM, Messinger SM, Albertini DF. Sorting and reorganization of centrosomes during oocyte maturation in the mouse. Microsc Res Tech 2000;49:435 444 PubMed

Gueth-Hallonet C, Antony C, Aghion J, Santa-Maria A, Lajoie-Mazenc I, Wright M. Maro B. gamma-Tubulin is present in acentriolar MTOCs during early mouse development. J Cell Sci 1993;105(Pt 1):157 166 PubMed

Schatten H, Sun QY. Centrosome dynamics during mammalian oocyte maturation with a focus on meiotic spindle formation. Mol Reprod Dev 2011;78:757 768 PubMed

Nigg EA, Stearns T. The centrosome cycle: centriole biogenesis, duplication and inherent asymmetries. Nat Cell Biol 2011;13:1154 1160 PubMed PMC

Can A, Semiz O, Cinar O. Centrosome and microtubule dynamics during early stages of meiosis in mouse oocytes. Mol Hum Reprod 2003;9:749 756 PubMed

Schuh M, Ellenberg J. Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes. Cell 2007;130:484 498 PubMed

Mahen R, Venkitaraman AR. Pattern formation in centrosome assembly. Curr Opin Cell Biol 2012;24:14 23 PubMed

Breuer M, Kolano A, Kwon M, Li CC, Tsai TF, Pellman D, Brunet S, Verlhac MH. HURP permits MTOC sorting for robust meiotic spindle bipolarity, similar to extra centrosome clustering in cancer cells. J Cell Biol 2010;191:1251 1260 PubMed PMC

Panigone S, Hsieh M, Fu M, Persani L, Conti M. Luteinizing hormone signaling in preovulatory follicles involves early activation of the epidermal growth factor receptor pathway. Mol Endocrinol 2008;22:924 936 PubMed PMC

Park JY, Su YQ, Ariga M, Law E, Jin SL, Conti M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 2004;303:682 684 PubMed

Jullien D, Bugler B, Dozier C, Cazales M, Ducommun B. Identification of N-terminally truncated stable nuclear isoforms of CDC25B that are specifically involved in G2/M checkpoint recovery. Cancer Res 2011;71:1968 1977 PubMed

van Vugt MA, Bras A, Medema RH. Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells. Mol Cell 2004;15:799 811 PubMed

Pirino G, Wescott MP, Donovan PJ. Protein kinase A regulates resumption of meiosis by phosphorylation of Cdc25B in mammalian oocytes. Cell Cycle 2009;8:665 670 PubMed

Zhang Y, Zhang Z, Xu XY, Li XS, Yu M, Yu AM, Zong ZH, Yu BZ. Protein kinase A modulates Cdc25B activity during meiotic resumption of mouse oocytes. Dev Dyn 2008;237:3777 3786 PubMed

Kramer A, Maier B, Bartek J. Centrosome clustering and chromosomal (in)stability: a matter of life and death. Mol Oncol 2011;5:324 335 PubMed PMC

Toya M, Terasawa M, Nagata K, Iida Y, Sugimoto A. A kinase-independent role for Aurora A in the assembly of mitotic spindle microtubules in Caenorhabditis elegans embryos. Nat Cell Biol 2011;13:708 714 PubMed

Peset I, Seiler J, Sardon T, Bejarano LA, Rybina S, Vernos I. Function and regulation of Maskin, a TACC family protein, in microtubule growth during mitosis. J Cell Biol 2005;170:1057 1066 PubMed PMC

Ibanez E, Sanfins A, Combelles CM, Overstrom EW, Albertini DF. Genetic strain variations in the metaphase-II phenotype of mouse oocytes matured in vivo or in vitro. Reproduction 2005;130:845 855 PubMed

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