Cdc20 Is Critical for Meiosis I and Fertility of Female Mice

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Chromosome missegregation in germ cells is an important cause of unexplained infertility, miscarriages, and congenital birth defects in humans. However, the molecular defects that lead to production of aneuploid gametes are largely unknown. Cdc20, the activating subunit of the anaphase-promoting complex/cyclosome (APC/C), initiates sister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphase to anaphase. The physiological significance and full repertoire of functions of mammalian Cdc20 are unclear at present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generated hypomorphic mice that express low amounts of Cdc20. These mice are healthy and have a normal lifespan, but females produce either no or very few offspring, despite normal folliculogenesis and fertilization rates. When mated with wild-type males, hypomorphic females yield nearly normal numbers of fertilized eggs, but as these embryos develop, they become malformed and rarely reach the blastocyst stage. In exploring the underlying mechanism, we uncover that the vast majority of these embryos have abnormal chromosome numbers, primarily due to chromosome lagging and chromosome misalignment during meiosis I in the oocyte. Furthermore, cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I; and anaphase I onset is markedly delayed. These results demonstrate that the physiologically effective threshold level of Cdc20 is high for female meiosis I and identify Cdc20 hypomorphism as a mechanism for chromosome missegregation and formation of aneuploid gametes.

Vyšlo v časopise: Cdc20 Is Critical for Meiosis I and Fertility of Female Mice. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001147
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001147

Souhrn

Zdroje

1. VogtE

Kirsch-VoldersM

ParryJ

Eichenlaub-RitterU

2008 Spindle formation, chromosome segregation and the spindle checkpoint in mammalian oocytes and susceptibility to meiotic error. Mutat Res 651 14 29

2. HollandAJ

ClevelandDW

2009 Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol 10 478 487

3. SantaguidaS

MusacchioA

2009 The life and miracles of kinetochores. EMBO J 28 2511 2531

4. KulukianA

HanJS

ClevelandDW

2009 Unattached kinetochores catalyze production of an anaphase inhibitor that requires a Mad2 template to prime Cdc20 for BubR1 binding. Dev Cell 16 105 117

5. MusacchioA

SalmonED

2007 The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8 379 393

6. YuH

2006 Structural activation of Mad2 in the mitotic spindle checkpoint: the two-state Mad2 model versus the Mad2 template model. J Cell Biol 173 153 157

7. NasmythK

HaeringCH

2005 The structure and function of SMC and kleisin complexes. Annu Rev Biochem 74 595 648

8. PetersJM

TedeschiA

SchmitzJ

2008 The cohesin complex and its roles in chromosome biology. Genes Dev 22 3089 3114

9. RickeRM

van ReeJH

van DeursenJM

2008 Whole chromosome instability and cancer: a complex relationship. Trends Genet 24 457 466

10. HomerH

GuiL

CarrollJ

2009 A spindle assembly checkpoint protein functions in prophase I arrest and prometaphase progression. Science 326 991 994

11. BakerDJ

JeganathanKB

CameronJD

ThompsonM

JunejaS

2004 BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet 36 744 749

12. ReisA

MadgwickS

ChangHY

NabtiI

LevasseurM

2007 Prometaphase APCcdh1 activity prevents non-disjunction in mammalian oocytes. Nat Cell Biol 9 1192 1198

13. PetersJM

2006 The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7 644 656

14. WassmannK

NiaultT

MaroB

2003 Metaphase I arrest upon activation of the Mad2-dependent spindle checkpoint in mouse oocytes. Curr Biol 13 1596 1608

15. HomerHA

McDougallA

LevasseurM

MurdochAP

HerbertM

2005 Mad2 is required for inhibiting securin and cyclin B degradation following spindle depolymerisation in meiosis I mouse oocytes. Reproduction 130 829 843

16. TsurumiC

HoffmannS

GeleyS

GraeserR

PolanskiZ

2004 The spindle assembly checkpoint is not essential for CSF arrest of mouse oocytes. J Cell Biol 167 1037 1050

17. McGuinnessBE

AngerM

KouznetsovaA

Gil-BernabeAM

HelmhartW

2009 Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint. Curr Biol 19 369 380

18. LiM

ShinYH

HouL

HuangX

WeiZ

2008 The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory. Nat Cell Biol

19. Garci-HigueraI

ManchadoE

DubusP

CanameroM

MendezJ

2008 Genomic stability and tumour suppression by the APC/C cofactor Cdh1. Nat Cell Biol

20. JacksT

ShihTS

SchmittEM

BronsonRT

BernardsA

1994 Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 7 353 361

21. MeyersEN

LewandoskiM

MartinGR

1998 An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nat Genet 18 136 141

22. DawlatyMM

van DeursenJM

2006 Gene targeting methods for studying nuclear transport factors in mice. Methods 39 370 378

23. LiM

YorkJP

ZhangP

2007 Loss of Cdc20 causes a securin-dependent metaphase arrest in two-cell mouse embryos. Mol Cell Biol 27 3481 3488

24. HagtingA

Den ElzenN

VodermaierHC

WaizeneggerIC

PetersJM

2002 Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1. J Cell Biol 157 1125 1137

25. LeeJ

IwaiT

YokotaT

YamashitaM

2003 Temporally and spatially selective loss of Rec8 protein from meiotic chromosomes during mammalian meiosis. J Cell Sci 116 2781 2790

26. LeeJ

OkadaK

OgushiS

MiyanoT

MiyakeM

2006 Loss of Rec8 from chromosome arm and centromere region is required for homologous chromosome separation and sister chromatid separation, respectively, in mammalian meiosis. Cell Cycle 5 1448 1455

27. TorresEM

WilliamsBR

AmonA

2008 Aneuploidy: cells losing their balance. Genetics 179 737 746

28. JeganathanK

MalureanuL

BakerDJ

AbrahamSC

van DeursenJM

2007 Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J Cell Biol 179 255 267

29. GuilleminY

LalleP

GilletG

GuerinJF

HamamahS

2009 Oocytes and early embryos selectively express the survival factor BCL2L10. J Mol Med 87 923 940

30. WolthuisR

Clay-FarraceL

van ZonW

YekezareM

KoopL

2008 Cdc20 and Cks direct the spindle checkpoint-independent destruction of cyclin A. Mol Cell 30 290 302

31. den ElzenN

PinesJ

2001 Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase. J Cell Biol 153 121 136

32. KudoNR

WassmannK

AngerM

SchuhM

WirthKG

2006 Resolution of chiasmata in oocytes requires separase-mediated proteolysis. Cell 126 135 146

33. PetronczkiM

SiomosMF

NasmythK

2003 Un menage a quatre: the molecular biology of chromosome segregation in meiosis. Cell 112 423 440

34. PidouxA

AllshireR

2003 Chromosome segregation: clamping down on deviant orientations. Curr Biol 13 R385 387

35. KallioMJ

BeardmoreVA

WeinsteinJ

GorbskyGJ

2002 Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells. J Cell Biol 158 841 847

36. PedersenT

PetersH

1968 Proposal for a classification of oocytes and follicles in the mouse ovary. J Reprod Fertil 17 555 557

37. KasperLH

BrindlePK

SchnabelCA

PritchardCE

ClearyML

1999 CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol Cell Biol 19 764 776

38. DawlatyMM

MalureanuL

JeganathanKB

KaoE

SustmannC

2008 Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIalpha. Cell 133 103 115

39. TaylorSS

HusseinD

WangY

ElderkinS

MorrowCJ

2001 Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells. J Cell Sci 114 4385 4395

40. WoodsLM

HodgesCA

BaartE

BakerSM

LiskayM

1999 Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlh1 mutant mice. J Cell Biol 145 1395 1406

41. HoganB

BeddingtonR

ConstantiniF

LacyE

1994 Manipulating the mouse embryo: Cold spring harbor press.

42. YeoCX

GilchristRB

ThompsonJG

LaneM

2008 Exogenous growth differentiation factor 9 in oocyte maturation media enhances subsequent embryo development and fetal viability in mice. Hum Reprod 23 67 73

43. TarkowskiA

1966 An air-drying method for chromosome preparations from mouse eggs. Cytogenetics 5 394 400

44. BrunetS

PolanskiZ

VerlhacMH

KubiakJZ

MaroB

1998 Bipolar meiotic spindle formation without chromatin. Curr Biol 8 1231 1234

45. MalureanuLA

JeganathanKB

HamadaM

WasilewskiL

DavenportJ

2009 BubR1 N terminus acts as a soluble inhibitor of cyclin B degradation by APC/C(Cdc20) in interphase. Dev Cell 16 118 131

46. LemaireP

GarrettN

GurdonJB

1995 Expression cloning of Siamois, a Xenopus homeobox gene expressed in dorsal-vegetal cells of blastulae and able to induce a complete secondary axis. Cell 81 85 94