Cellular and Molecular Life Sciences

, Volume 76, Issue 11, pp 2217–2229 | Cite as

Fbxo30 regulates chromosome segregation of oocyte meiosis

  • Yimei Jin
  • Mo Yang
  • Chang Gao
  • Wei Yue
  • Xiaoling Liang
  • Bingteng Xie
  • Xiaohui Zhu
  • Shangrong Fan
  • Rong LiEmail author
  • Mo LiEmail author
Original Article


As the female gamete, meiotic oocytes provide not only half of the genome but also almost all stores for fertilization and early embryonic development. Because de novo mRNA transcription is absent in oocyte meiosis, protein-level regulations, especially the ubiquitin proteasome system, are more crucial. As the largest family of ubiquitin E3 ligases, Skp1–Cullin–F-box complexes recognize their substrates via F-box proteins with substrate-selected specificity. However, the variety of F-box proteins and their unknown substrates hinder our understanding of their functions. In this report, we find that Fbxo30, a new member of F-box proteins, is enriched in mouse oocytes, and its expression level declines substantially after the metaphase of the first meiosis (MI). Notably, depletion of Fbxo30 causes significant chromosome compaction accompanied by chromosome segregation failure and arrest at the MI stage, and this arrest is not caused by over-activation of spindle assembly checkpoint. Using immunoprecipitation and mass spectrometric analysis, we identify stem-loop-binding protein (SLBP) as a novel substrate of Fbxo30. SLBP overexpression caused by Fbxo30 depletion results in a remarkable overload of histone H3 on chromosomes that excessively condenses chromosomes and inhibits chromosome segregation. Our finding uncovers an unidentified pathway-controlling chromosome segregation and cell progress.


Cell cycle Ubiquitination F-box family Chromosome condensation SLBP 



We are grateful to Dr. Hengyu Fan for the insightful comments and suggestions on the manuscript. Mass spectrometry experiments were carried out by Junchen Company (Beijing, China) and Zhengdakangjian Company (Beijing, China). This work was supported by the National Natural Science Foundation of China (NSFC) (81622035, 81871160), Key Special Fund of Ministry of Science and Technology of China (2017YFC1001501, 2016YFC1000604, 2018YFC1003800), and the Foundation for Innovative Research Groups of NSFC (81521002). ML is a member of the Thousand Young Talents Plan of China.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

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  1. 1.
    Stitzel ML, Seydoux G (2007) Regulation of the oocyte-to-zygote transition. Science 316(5823):407–408. CrossRefGoogle Scholar
  2. 2.
    Matzuk MM, Burns KH, Viveiros MM, Eppig JJ (2002) Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science 296(5576):2178–2180. CrossRefGoogle Scholar
  3. 3.
    Tripathi A, Kumar KV, Chaube SK (2010) Meiotic cell cycle arrest in mammalian oocytes. J Cell Physiol 223(3):592–600. Google Scholar
  4. 4.
    Dumont J, Desai A (2012) Acentrosomal spindle assembly and chromosome segregation during oocyte meiosis. Trends Cell Biol 22(5):241–249. CrossRefGoogle Scholar
  5. 5.
    Schuh M, Ellenberg J (2007) Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes. Cell 130(3):484–498 (S0092-8674(07)00792-1) CrossRefGoogle Scholar
  6. 6.
    Fan HY, Sun QY (2004) Involvement of mitogen-activated protein kinase cascade during oocyte maturation and fertilization in mammals. Biol Reprod 70(3):535–547. CrossRefGoogle Scholar
  7. 7.
    Nebreda AR, Ferby I (2000) Regulation of the meiotic cell cycle in oocytes. Curr Opin Cell Biol 12(6):666–675CrossRefGoogle Scholar
  8. 8.
    Handel MA, Schimenti JC (2010) Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet 11(2):124–136. CrossRefGoogle Scholar
  9. 9.
    De La Fuente R (2006) Chromatin modifications in the germinal vesicle (GV) of mammalian oocytes. Dev Biol 292(1):1–12. CrossRefGoogle Scholar
  10. 10.
    Chen J, Melton C, Suh N, Oh JS, Horner K, Xie F, Sette C, Blelloch R, Conti M (2011) Genome-wide analysis of translation reveals a critical role for deleted in azoospermia-like (Dazl) at the oocyte-to-zygote transition. Genes Dev 25(7):755–766. CrossRefGoogle Scholar
  11. 11.
    Wang S, Kou Z, Jing Z, Zhang Y, Guo X, Dong M, Wilmut I, Gao S (2010) Proteome of mouse oocytes at different developmental stages. Proc Natl Acad Sci USA 107(41):17639–17644. CrossRefGoogle Scholar
  12. 12.
    Suzumori N, Burns KH, Yan W, Matzuk MM (2003) RFPL4 interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway. Proc Natl Acad Sci USA 100(2):550–555. CrossRefGoogle Scholar
  13. 13.
    Yu C, Ji SY, Sha QQ, Sun QY, Fan HY (2015) CRL4-DCAF1 ubiquitin E3 ligase directs protein phosphatase 2A degradation to control oocyte meiotic maturation. Nat Commun 6:8017. CrossRefGoogle Scholar
  14. 14.
    Nabti I, Grimes R, Sarna H, Marangos P, Carroll J (2017) Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II. Nat Commun 8:15346. CrossRefGoogle Scholar
  15. 15.
    McGuinness BE, Anger M, Kouznetsova A, Gil-Bernabe AM, Helmhart W, Kudo NR, Wuensche A, Taylor S, Hoog C, Novak B, Nasmyth K (2009) Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint. Curr Biol 19(5):369–380. CrossRefGoogle Scholar
  16. 16.
    Lane SI, Yun Y, Jones KT (2012) Timing of anaphase-promoting complex activation in mouse oocytes is predicted by microtubule-kinetochore attachment but not by bivalent alignment or tension. Development 139(11):1947–1955. CrossRefGoogle Scholar
  17. 17.
    Peters JM (2006) The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7(9):644–656. CrossRefGoogle Scholar
  18. 18.
    Cardozo T, Pagano M (2004) The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol 5(9):739–751. CrossRefGoogle Scholar
  19. 19.
    Yen HC, Elledge SJ (2008) Identification of SCF ubiquitin ligase substrates by global protein stability profiling. Science 322(5903):923–929. CrossRefGoogle Scholar
  20. 20.
    Frescas D, Pagano M (2008) Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 8(6):438–449. CrossRefGoogle Scholar
  21. 21.
    Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, Conaway RC, Conaway JW, Harper JW, Pavletich NP (2002) Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex. Nature 416(6882):703–709. CrossRefGoogle Scholar
  22. 22.
    Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW (1997) F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91(2):209–219 (S0092-8674(00)80403-1) CrossRefGoogle Scholar
  23. 23.
    Kipreos ET, Pagano M (2000) The F-box protein family. Genome Biol 1(5):REVIEWS3002. CrossRefGoogle Scholar
  24. 24.
    Yin S, Ai J-S, Shi L-H, Wei L, Yuan J, Ouyang Y-C, Hou Y, Chen D-Y, Schatten H, Sun Q-Y (2008) Shugoshin1 may play important roles in separation of homologous chromosomes and sister chromatids during mouse oocyte meiosis. PLoS One 3(10):e3516. CrossRefGoogle Scholar
  25. 25.
    Hodges CA, Hunt PA (2002) Simultaneous analysis of chromosomes and chromosome-associated proteins in mammalian oocytes and embryos. Chromosoma 111(3):165–169. CrossRefGoogle Scholar
  26. 26.
    Li H, Guo F, Rubinstein B, Li R (2008) Actin-driven chromosomal motility leads to symmetry breaking in mammalian meiotic oocytes. Nat Cell Biol 10(11):1301–1308. CrossRefGoogle Scholar
  27. 27.
    Xie B, Zhang L, Zhao H, Bai Q, Fan Y, Zhu X, Yu Y, Li R, Liang X, Sun QY, Li M, Qiao J (2018) Poly(ADP-ribose) mediates asymmetric division of mouse oocyte. Cell Res 28(4):462–475. CrossRefGoogle Scholar
  28. 28.
    Schneider I, Lenart P (2017) Chromosome segregation: is the spindle all about microtubules? Curr Biol 27(21):R1168–R1170. CrossRefGoogle Scholar
  29. 29.
    Heald R, Tournebize R, Blank T, Sandaltzopoulos R, Becker P, Hyman A, Karsenti E (1996) Self-organization of microtubules into bipolar spindles around artificial chromosomes in Xenopus egg extracts. Nature 382(6590):420–425. CrossRefGoogle Scholar
  30. 30.
    Koshland D, Strunnikov A (1996) Mitotic chromosome condensation. Annu Rev Cell Dev Biol 12:305–333. CrossRefGoogle Scholar
  31. 31.
    Belmont AS (2006) Mitotic chromosome structure and condensation. Curr Opin Cell Biol 18(6):632–638 (S0955-0674(06)00152-9) CrossRefGoogle Scholar
  32. 32.
    Wilkins BJ, Rall NA, Ostwal Y, Kruitwagen T, Hiragami-Hamada K, Winkler M, Barral Y, Fischle W, Neumann H (2014) A cascade of histone modifications induces chromatin condensation in mitosis. Science 343(6166):77–80. CrossRefGoogle Scholar
  33. 33.
    Swain JE, Ding J, Brautigan DL, Villa-Moruzzi E, Smith GD (2007) Proper chromatin condensation and maintenance of histone H3 phosphorylation during mouse oocyte meiosis requires protein phosphatase activity. Biol Reprod 76(4):628–638. CrossRefGoogle Scholar
  34. 34.
    Tada K, Susumu H, Sakuno T, Watanabe Y (2011) Condensin association with histone H2A shapes mitotic chromosomes. Nature 474(7352):477–483. CrossRefGoogle Scholar
  35. 35.
    Marzluff WF, Wagner EJ, Duronio RJ (2008) Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat Rev Genet 9(11):843–854. CrossRefGoogle Scholar
  36. 36.
    Marzluff WF, Duronio RJ (2002) Histone mRNA expression: multiple levels of cell cycle regulation and important developmental consequences. Curr Opin Cell Biol 14(6):692–699 (S0955067402003873) CrossRefGoogle Scholar
  37. 37.
    Krapivinsky G, Krapivinsky L, Manasian Y, Clapham DE (2014) The TRPM7 chanzyme is cleaved to release a chromatin-modifying kinase. Cell 157(5):1061–1072. CrossRefGoogle Scholar
  38. 38.
    Tadros W, Lipshitz HD (2009) The maternal-to-zygotic transition: a play in two acts. Development 136(18):3033–3042. CrossRefGoogle Scholar
  39. 39.
    Wassmann K, Niault T, Maro B (2003) Metaphase I arrest upon activation of the Mad2-dependent spindle checkpoint in mouse oocytes. Curr Biol 13(18):1596–1608 (S0960-9822(03)00654-7) CrossRefGoogle Scholar
  40. 40.
    Zhang P, Ni X, Guo Y, Guo X, Wang Y, Zhou Z, Huo R, Sha J (2009) Proteomic-based identification of maternal proteins in mature mouse oocytes. BMC Genom 10:348. CrossRefGoogle Scholar
  41. 41.
    Weissman AM (2001) Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2(3):169–178. CrossRefGoogle Scholar
  42. 42.
    Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M (1999) Identification of a family of human F-box proteins. Curr Biol 9(20):1177–1179. CrossRefGoogle Scholar
  43. 43.
    Henikoff S, Ahmad K (2005) Assembly of variant histones into chromatin. Annu Rev Cell Dev Biol 21:133–153. CrossRefGoogle Scholar
  44. 44.
    Allard P, Champigny MJ, Skoggard S, Erkmann JA, Whitfield ML, Marzluff WF, Clarke HJ (2002) Stem-loop binding protein accumulates during oocyte maturation and is not cell-cycle-regulated in the early mouse embryo. J Cell Sci 115(23):4577–4586. CrossRefGoogle Scholar
  45. 45.
    Clarke HJ, Bustin M, Oblin C (1997) Chromatin modifications during oogenesis in the mouse: removal of somatic subtypes of histone H1 from oocyte chromatin occurs post-natally through a post-transcriptional mechanism. J Cell Sci 110(Pt 4):477–487Google Scholar
  46. 46.
    Allard P, Champigny MJ, Skoggard S, Erkmann JA, Whitfield ML, Marzluff WF, Clarke HJ (2002) Stem-loop binding protein accumulates during oocyte maturation and is not cell-cycle-regulated in the early mouse embryo. J Cell Sci 115:4577–4586CrossRefGoogle Scholar
  47. 47.
    Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA (2012) National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med 9(12):e1001356. CrossRefGoogle Scholar
  48. 48.
    Inhorn MC, Patrizio P (2015) Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Hum Reprod Update 21(4):411–426. CrossRefGoogle Scholar
  49. 49.
    Hunt PA, Hassold TJ (2008) Human female meiosis: what makes a good egg go bad? Trends Genet 24(2):86–93. CrossRefGoogle Scholar
  50. 50.
    Nagaoka SI, Hodges CA, Albertini DF, Hunt PA (2011) Oocyte-specific differences in cell-cycle control create an innate susceptibility to meiotic errors. Curr Biol 21(8):651–657. CrossRefGoogle Scholar
  51. 51.
    Kitajima TS, Ohsugi M, Ellenberg J (2011) Complete kinetochore tracking reveals error-prone homologous chromosome biorientation in mammalian oocytes. Cell 146(4):568–581. CrossRefGoogle Scholar
  52. 52.
    Qiao J, Wang ZB, Feng HL, Miao YL, Wang Q, Yu Y, Wei YC, Yan J, Wang WH, Shen W, Sun SC, Schatten H, Sun QY (2014) The root of reduced fertility in aged women and possible therapentic options: current status and future perspects. Mol Asp Med 38:54–85. CrossRefGoogle Scholar
  53. 53.
    Wang ZB, Schatten H, Sun QY (2011) Why is chromosome segregation error in oocytes increased with maternal aging? Physiology (Bethesda) 26(5):314–325. Google Scholar
  54. 54.
    Lu Y, Dai X, Zhang M, Miao Y, Zhou C, Cui Z, Xiong B (2017) Cohesin acetyltransferase Esco2 regulates SAC and kinetochore functions via maintaining H4K16 acetylation during mouse oocyte meiosis. Nucleic Acids Res 45(16):9388–9397. CrossRefGoogle Scholar
  55. 55.
    Touati SA, Buffin E, Cladiere D, Hached K, Rachez C, van Deursen JM, Wassmann K (2015) Mouse oocytes depend on BubR1 for proper chromosome segregation but not for prophase I arrest. Nat Commun 6:6946. CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Yimei Jin
    • 1
    • 2
  • Mo Yang
    • 1
    • 2
  • Chang Gao
    • 3
  • Wei Yue
    • 1
  • Xiaoling Liang
    • 1
    • 4
  • Bingteng Xie
    • 1
    • 2
  • Xiaohui Zhu
    • 1
    • 2
  • Shangrong Fan
    • 1
    • 4
  • Rong Li
    • 1
    • 2
    Email author
  • Mo Li
    • 1
    • 2
    Email author
  1. 1.Center for Reproductive MedicinePeking University Third HospitalBeijingChina
  2. 2.Key Laboratory of Assisted ReproductionMinistry of EducationBeijingChina
  3. 3.Department of Obstetrics and GynecologyPeking University Third HospitalBeijingChina
  4. 4.Department of Obstetrics and GynecologyPeking University Shenzhen HospitalShenzhenChina

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