Mutation Disrupts Synaptonemal Complex Formation, Recombination, and Chromosome Segregation in Mammalian Meiosis

English version České info

Meiosis is unique to germ cells and essential for reproduction. During the first meiotic division, homologous chromosomes pair, recombine, and form chiasmata. The homologues connect via axial elements and numerous transverse filaments to form the synaptonemal complex. The synaptonemal complex is a critical component for chromosome pairing, segregation, and recombination. We previously identified a novel germ cell–specific HORMA domain encoding gene, Hormad1, a member of the synaptonemal complex and a mammalian counterpart to the yeast meiotic HORMA domain protein Hop1. Hormad1 is essential for mammalian gametogenesis as knockout male and female mice are infertile. Hormad1 deficient (Hormad1^−/⁻) testes exhibit meiotic arrest in the early pachytene stage, and synaptonemal complexes cannot be visualized by electron microscopy. Hormad1 deficiency does not affect localization of other synaptonemal complex proteins, SYCP2 and SYCP3, but disrupts homologous chromosome pairing. Double stranded break formation and early recombination events are disrupted in Hormad1^−/⁻ testes and ovaries as shown by the drastic decrease in the γH2AX, DMC1, RAD51, and RPA foci. HORMAD1 co-localizes with γH2AX to the sex body during pachytene. BRCA1, ATR, and γH2AX co-localize to the sex body and participate in meiotic sex chromosome inactivation and transcriptional silencing. Hormad1 deficiency abolishes γH2AX, ATR, and BRCA1 localization to the sex chromosomes and causes transcriptional de-repression on the X chromosome. Unlike testes, Hormad1^−/⁻ ovaries have seemingly normal ovarian folliculogenesis after puberty. However, embryos generated from Hormad1^−/⁻ oocytes are hyper- and hypodiploid at the 2 cell and 8 cell stage, and they arrest at the blastocyst stage. HORMAD1 is therefore a critical component of the synaptonemal complex that affects synapsis, recombination, and meiotic sex chromosome inactivation and transcriptional silencing.

Vyšlo v časopise: Mutation Disrupts Synaptonemal Complex Formation, Recombination, and Chromosome Segregation in Mammalian Meiosis. PLoS Genet 6(11): e32767. doi:10.1371/journal.pgen.1001190
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001190

Souhrn

Zdroje

1. PageSL

HawleyRS

2004 The genetics and molecular biology of the synaptonemal complex. Annu Rev Cell Dev Biol 20 525 558

2. BailisJM

RoederGS

1998 Synaptonemal complex morphogenesis and sister-chromatid cohesion require Mek1-dependent phosphorylation of a meiotic chromosomal protein. Genes Dev 12 3551 3563

3. KleinF

MahrP

GalovaM

BuonomoSB

MichaelisC

1999 A central role for cohesins in sister chromatid cohesion, formation of axial elements, and recombination during yeast meiosis. Cell 98 91 103

4. LoidlJ

KleinF

ScherthanH

1994 Homologous pairing is reduced but not abolished in asynaptic mutants of yeast. J Cell Biol 125 1191 1200

5. AravindL

KooninEV

1998 The HORMA domain: a common structural denominator in mitotic checkpoints, chromosome synapsis and DNA repair. Trends Biochem Sci 23 284 286

6. MichelLS

LiberalV

ChatterjeeA

KirchweggerR

PascheB

2001 MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409 355 359

7. DoblesM

LiberalV

ScottML

BenezraR

SorgerPK

2000 Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 101 635 645

8. HollingsworthNM

GoetschL

ByersB

1990 The HOP1 gene encodes a meiosis-specific component of yeast chromosomes. Cell 61 73 84

9. SmithAV

RoederGS

1997 The yeast Red1 protein localizes to the cores of meiotic chromosomes. J Cell Biol 136 957 967

10. ZetkaMC

KawasakiI

StromeS

MullerF

1999 Synapsis and chiasma formation in Caenorhabditis elegans require HIM-3, a meiotic chromosome core component that functions in chromosome segregation. Genes Dev 13 2258 2270

11. ArmstrongSJ

CarylAP

JonesGH

FranklinFC

2002 Asy1, a protein required for meiotic chromosome synapsis, localizes to axis-associated chromatin in Arabidopsis and Brassica. J Cell Sci 115 3645 3655

12. ColaiacovoMP

MacQueenAJ

Martinez-PerezE

McDonaldK

AdamoA

2003 Synaptonemal complex assembly in C. elegans is dispensable for loading strand-exchange proteins but critical for proper completion of recombination. Dev Cell 5 463 474

13. CouteauF

NabeshimaK

VilleneuveA

ZetkaM

2004 A component of C. elegans meiotic chromosome axes at the interface of homolog alignment, synapsis, nuclear reorganization, and recombination. Curr Biol 14 585 592

14. RossKJ

FranszP

ArmstrongSJ

VizirI

MulliganB

1997 Cytological characterization of four meiotic mutants of Arabidopsis isolated from T-DNA-transformed lines. Chromosome Res 5 551 559

15. CarylAP

ArmstrongSJ

JonesGH

FranklinFC

2000 A homologue of the yeast HOP1 gene is inactivated in the Arabidopsis meiotic mutant asy1. Chromosoma 109 62 71

16. PangasSA

YanW

MatzukMM

RajkovicA

2004 Restricted germ cell expression of a gene encoding a novel mammalian HORMA domain-containing protein. Gene Expr Patterns 5 257 263

17. WojtaszL

DanielK

RoigI

Bolcun-FilasE

XuH

2009 Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS Genet 5 e1000702 doi:10.1371/journal.pgen.1000702

18. FukudaT

DanielK

WojtaszL

TothA

HoogC

2010 A novel mammalian HORMA domain-containing protein, HORMAD1, preferentially associates with unsynapsed meiotic chromosomes. Exp Cell Res 316 158 171

19. KironmaiKM

MuniyappaK

FriedmanDB

HollingsworthNM

ByersB

1998 DNA-binding activities of Hop1 protein, a synaptonemal complex component from Saccharomyces cerevisiae. Mol Cell Biol 18 1424 1435

20. Mao-DraayerY

GalbraithAM

PittmanDL

CoolM

MaloneRE

1996 Analysis of meiotic recombination pathways in the yeast Saccharomyces cerevisiae. Genetics 144 71 86

21. CarballoJA

JohnsonAL

SedgwickSG

ChaRS

2008 Phosphorylation of the axial element protein Hop1 by Mec1/Tel1 ensures meiotic interhomolog recombination. Cell 132 758 770

22. BailisJM

SmithAV

RoederGS

2000 Bypass of a meiotic checkpoint by overproduction of meiotic chromosomal proteins. Mol Cell Biol 20 4838 4848

23. MeuwissenRL

OffenbergHH

DietrichAJ

RiesewijkA

van IerselM

1992 A coiled-coil related protein specific for synapsed regions of meiotic prophase chromosomes. EMBO J 11 5091 5100

24. DobsonMJ

PearlmanRE

KaraiskakisA

SpyropoulosB

MoensPB

1994 Synaptonemal complex proteins: occurrence, epitope mapping and chromosome disjunction. J Cell Sci 107 Pt 10 2749 2760

25. LammersJH

OffenbergHH

van AalderenM

VinkAC

DietrichAJ

1994 The gene encoding a major component of the lateral elements of synaptonemal complexes of the rat is related to X-linked lymphocyte-regulated genes. Mol Cell Biol 14 1137 1146

26. OffenbergHH

SchalkJA

MeuwissenRL

van AalderenM

KesterHA

1998 SCP2: a major protein component of the axial elements of synaptonemal complexes of the rat. Nucleic Acids Res 26 2572 2579

27. YuanL

LiuJG

ZhaoJ

BrundellE

DaneholtB

2000 The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol Cell 5 73 83

28. del MazoJ

KremerL

AvilaJ

1987 Centromeric proteins recognized by CREST sera and meiotic chromosome segregation. Chromosoma 96 55 59

29. YuanL

LiuJG

HojaMR

WilbertzJ

NordqvistK

2002 Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296 1115 1118

30. PittmanDL

CobbJ

SchimentiKJ

WilsonLA

CooperDM

1998 Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol Cell 1 697 705

31. de VriesFA

de BoerE

van den BoschM

BaarendsWM

OomsM

2005 Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation. Genes Dev 19 1376 1389

32. GasiorSL

WongAK

KoraY

ShinoharaA

BishopDK

1998 Rad52 associates with RPA and functions with rad55 and rad57 to assemble meiotic recombination complexes. Genes Dev 12 2208 2221

33. EdelmannW

CohenPE

KaneM

LauK

MorrowB

1996 Meiotic pachytene arrest in MLH1-deficient mice. Cell 85 1125 1134

34. KolasNK

MarconE

CrackowerMA

HoogC

PenningerJM

2005 Mutant meiotic chromosome core components in mice can cause apparent sexual dimorphic endpoints at prophase or X-Y defective male-specific sterility. Chromosoma 114 92 102

35. WolteringD

BaumgartnerB

BagchiS

LarkinB

LoidlJ

2000 Meiotic segregation, synapsis, and recombination checkpoint functions require physical interaction between the chromosomal proteins Red1p and Hop1p. Mol Cell Biol 20 6646 6658

36. WardIM

ChenJ

2001 Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J Biol Chem 276 47759 47762

37. PrielerS

PenknerA

BordeV

KleinF

2005 The control of Spo11's interaction with meiotic recombination hotspots. Genes Dev 19 255 269

38. NakamuraTM

DuLL

RedonC

RussellP

2004 Histone H2A phosphorylation controls Crb2 recruitment at DNA breaks, maintains checkpoint arrest, and influences DNA repair in fission yeast. Mol Cell Biol 24 6215 6230

39. Fernandez-CapetilloO

MahadevaiahSK

CelesteA

RomanienkoPJ

Camerini-OteroRD

2003 H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell 4 497 508

40. TurnerJM

AprelikovaO

XuX

WangR

KimS

2004 BRCA1, histone H2AX phosphorylation, and male meiotic sex chromosome inactivation. Curr Biol 14 2135 2142

41. KozlovSV

GrahamME

PengC

ChenP

RobinsonPJ

2006 Involvement of novel autophosphorylation sites in ATM activation. EMBO J 25 3504 3514

42. YoshidaK

KondohG

MatsudaY

HabuT

NishimuneY

1998 The mouse RecA-like gene Dmc1 is required for homologous chromosome synapsis during meiosis. Mol Cell 1 707 718

43. EdelmannW

CohenPE

KneitzB

WinandN

LiaM

1999 Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet 21 123 127

44. BarlowC

LiyanageM

MoensPB

TarsounasM

NagashimaK

1998 Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125 4007 4017

45. PangasSA

ChoiY

BallowDJ

ZhaoY

WestphalH

2006 Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proc Natl Acad Sci U S A 103 8090 8095

46. DebK

ReeseJ

PariaBC

2006 Methodologies to study implantation in mice. Methods Mol Med 121 9 34

47. RevenkovaE

EijpeM

HeytingC

HodgesCA

HuntPA

2004 Cohesin SMC1 beta is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination. Nat Cell Biol 6 555 562

48. YangF

De La FuenteR

LeuNA

BaumannC

McLaughlinKJ

2006 Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis. J Cell Biol 173 497 507

49. XuY

AshleyT

BrainerdEE

BronsonRT

MeynMS

1996 Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10 2411 2422

50. RomanienkoPJ

Camerini-OteroRD

2000 The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell 6 975 987

51. de los SantosT

HollingsworthNM

1999 Red1p, a MEK1-dependent phosphoprotein that physically interacts with Hop1p during meiosis in yeast. J Biol Chem 274 1783 1790

52. WangH

HoogC

2006 Structural damage to meiotic chromosomes impairs DNA recombination and checkpoint control in mammalian oocytes. J Cell Biol 173 485 495

53. Di GiacomoM

BarchiM

BaudatF

EdelmannW

KeeneyS

2005 Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc Natl Acad Sci U S A 102 737 742

54. HollingsworthNM

PonteL

1997 Genetic interactions between HOP1, RED1 and MEK1 suggest that MEK1 regulates assembly of axial element components during meiosis in the yeast Saccharomyces cerevisiae. Genetics 147 33 42

55. HassoldT

HuntP

2001 To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2 280 291

56. HodgesCA

RevenkovaE

JessbergerR

HassoldTJ

HuntPA

2005 SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat Genet 37 1351 1355

57. HandelMA

SchimentiJC

2010 Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet 11 124 136

58. RevenkovaE

EijpeM

HeytingC

GrossB

JessbergerR

2001 Novel meiosis-specific isoform of mammalian SMC1. Mol Cell Biol 21 6984 6998

59. GoateA

Chartier-HarlinMC

MullanM

BrownJ

CrawfordF

1991 Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349 704 706

60. WarmingS

CostantinoN

CourtDL

JenkinsNA

CopelandNG

2005 Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res 33 e36

61. RajkovicA

PangasSA

BallowD

SuzumoriN

MatzukMM

2004 NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science 305 1157 1159

62. BaltusAE

MenkeDB

HuYC

GoodheartML

CarpenterAE

2006 In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. Nat Genet 38 1430 1434

63. ChoiY

BallowDJ

XinY

RajkovicA

2008 Lim homeobox gene, lhx8, is essential for mouse oocyte differentiation and survival. Biol Reprod 79 442 449

64. 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

65. RajkovicA

YanMSC

KlysikM

MatzukM

2001 Discovery of germ cell-specific transcripts by expressed sequence tag database analysis. Fertil Steril 76 550 554

66. WangPJ

McCarreyJR

YangF

PageDC

2001 An abundance of X-linked genes expressed in spermatogonia. Nat Genet 27 422 426

67. MouilletJF

ChuT

NelsonDM

MishimaT

SadovskyY

2010 MiR-205 silences MED1 in hypoxic primary human trophoblasts. FASEB J

68. SmythGK

2004 Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3 Article3

69. SeliE

LaliotiMD

FlahertySM

SakkasD

TerziN

2005 An embryonic poly(A)-binding protein (ePAB) is expressed in mouse oocytes and early preimplantation embryos. Proc Natl Acad Sci U S A 102 367 372