A Novel Mouse Synaptonemal Complex Protein Is Essential for Loading of Central Element Proteins, Recombination, and Fertility
The synaptonemal complex (SC) is a proteinaceous, meiosis-specific structure that is highly conserved in evolution. During meiosis, the SC mediates synapsis of homologous chromosomes. It is essential for proper recombination and segregation of homologous chromosomes, and therefore for genome haploidization. Mutations in human SC genes can cause infertility. In order to gain a better understanding of the process of SC assembly in a model system that would be relevant for humans, we are investigating meiosis in mice. Here, we report on a newly identified component of the murine SC, which we named SYCE3. SYCE3 is strongly conserved among mammals and localizes to the central element (CE) of the SC. By generating a Syce3 knockout mouse, we found that SYCE3 is required for fertility in both sexes. Loss of SYCE3 blocks synapsis initiation and results in meiotic arrest. In the absence of SYCE3, initiation of meiotic recombination appears to be normal, but its progression is severely impaired resulting in complete absence of MLH1 foci, which are presumed markers of crossovers in wild-type meiocytes. In the process of SC assembly, SYCE3 is required downstream of transverse filament protein SYCP1, but upstream of the other previously described CE–specific proteins. We conclude that SYCE3 enables chromosome loading of the other CE–specific proteins, which in turn would promote synapsis between homologous chromosomes.
Vyšlo v časopise:
A Novel Mouse Synaptonemal Complex Protein Is Essential for Loading of Central Element Proteins, Recombination, and Fertility. PLoS Genet 7(5): e32767. doi:10.1371/journal.pgen.1002088
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002088
Souhrn
The synaptonemal complex (SC) is a proteinaceous, meiosis-specific structure that is highly conserved in evolution. During meiosis, the SC mediates synapsis of homologous chromosomes. It is essential for proper recombination and segregation of homologous chromosomes, and therefore for genome haploidization. Mutations in human SC genes can cause infertility. In order to gain a better understanding of the process of SC assembly in a model system that would be relevant for humans, we are investigating meiosis in mice. Here, we report on a newly identified component of the murine SC, which we named SYCE3. SYCE3 is strongly conserved among mammals and localizes to the central element (CE) of the SC. By generating a Syce3 knockout mouse, we found that SYCE3 is required for fertility in both sexes. Loss of SYCE3 blocks synapsis initiation and results in meiotic arrest. In the absence of SYCE3, initiation of meiotic recombination appears to be normal, but its progression is severely impaired resulting in complete absence of MLH1 foci, which are presumed markers of crossovers in wild-type meiocytes. In the process of SC assembly, SYCE3 is required downstream of transverse filament protein SYCP1, but upstream of the other previously described CE–specific proteins. We conclude that SYCE3 enables chromosome loading of the other CE–specific proteins, which in turn would promote synapsis between homologous chromosomes.
Zdroje
1. ZicklerDKlecknerN 1999 Meiotic chromosomes: integrating structure and function. Annu Rev Genet 33 603 754
2. PageSLHawleyRS 2004 The genetics and molecular biology of the synaptonemal complex. Annu Rev Cell Dev Biol 20 525 558
3. YangFWangPJ 2009 The mammalian synaptonemal complex: a scaffold and beyond. Genome Dyn 5 69 80
4. RoederGS 1995 Sex and the single cell: meiosis in yeast. Proc Natl Acad Sci U S A 92 10450 10456
5. ColaiácovoMP 2006 The many facets of SC function during C. elegans meiosis. Chromosoma 115 195 211
6. KlecknerN 2006 Chiasma formation: chromatin/axis interplay and the role(s) of the synaptonemal complex. Chromosoma 115 175 194
7. ZicklerD 2006 From early homologue recognition to synaptonemal complex formation. Chromosoma 115 158 174
8. BhallaNDernburgAF 2008 Prelude to a division. Annu Rev Cell Dev Biol 24 397 424
9. McKeeBD 2009 Homolog pairing and segregation in Drosophila meiosis. Genome Dyn 5 56 68
10. ZetkaM 2009 Homologue pairing, recombination and segregation in Caenorhabditis elegans. Genome Dyn 5 43 55
11. CostaYCookeH 2007 Dissecting the mammalian synaptonemal complex using targeted mutations. Chromosome Res 15 579 589
12. HandelMASchimentiJC 2010 Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet doi:10.1038/nrg2723
13. MiyamotoTHasuikeSYogevLMaduroMRIshikawaM 2003 Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet 362 1714 1719
14. BaierAAlsheimerMBenaventeR 2007 Synaptonemal complex protein SYCP3: conserved polymerization properties among vertebrates. Biochim Biophys Acta 1774 595 602
15. BolorHMoriTNishiyamaSItoYHosobaE 2009 Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am J Hum Genet 84 14 20
16. ZicklerDKlecknerN 1998 The leptotene–zygotene transition of meiosis. Annu Rev Genet 32 619 697
17. PelttariJHojaMRYuanLLiuJGBrundellE 2001 A meiotic chromosomal core consisting of cohesin complex proteins recruits DNA recombination proteins and promotes synapsis in the absence of an axial element in mammalian meiotic cells. Mol Cell Biol 21 5667 5677
18. PrietoISujaJAPezziNKremerLMartínez-AC 2001 Mammalian STAG3 is a cohesin specific to sister chromatid arms in meiosis I. Nat Cell Biol 3 761 6
19. EijpeMOffenbergHJessbergerRRevenkovaEHeytingC 2003 Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1β and SMC3. J Cell Biol 160 657 670
20. YuanLLiuJZhaoJBrundellEDaneholtB 2000 The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol Cell 5 73 83
21. YuanLLiuJHojaMWilbertzJNordqvistK 2002 Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296 1115 1118
22. LiebeBAlsheimerMHöögCBenaventeRScherthanH 2004 Telomere attachment, meiotic chromosome condensation, pairing, and bouquet stage duration are modified in spermatocytes lacking axial elements. Mol Biol Cell 15 827 837
23. MeuwissenRLJOffenbergHHDietrichAJJRiesewijkAvan IerselM 1992 A coiled-coil related protein specific for synapsed regions of meiotic prophase chromosomes. EMBO J 11 5091 5100
24. LiuJGYuanLBrundellEBjörkrothBDaneholtB 1996 Localization of the N-terminus of SCP1 to the central element of the synaptonemal complex and evidence for direct interactions between the N-termini of SCP1 molecules organized head-to-head. Exp Cell Res 226 11 19
25. SchmekelKMeuwissenRLDietrichAJJVinkACGvan MarleJ 1996 Organization of SCP1 protein molecules within synaptonemal complexes of the rat. Exp Cell Res 226 20 30
26. OllingerRAlsheimerMBenaventeR 2005 Mammalian protein SCP1 forms synaptonemal complex-like structures in the absence of meiotic chromosomes. Mol Biol Cell 16 212 217
27. de VriesFAde BoerEvan den BoschMBaarendsWMOomsM 2005 Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation. Genes Dev 19 1376 1389
28. CostaYSpeedROllingerRAlsheimerMSempleCA 2005 Two novel proteins recruited by synaptonemal complex protein 1 (SYCP1) are at the centre of meiosis. J Cell Sci 118 2755 2762
29. HamerGGellKKouznetsovaANovakIBenaventeR 2006 Characterization of a novel meiosis-specific protein within the central element of the synaptonemal complex. J Cell Sci 119 4025 4032
30. Bolcun-FilasEHallESpeedRTaggartMGreyC 2009 Mutation of the mouse Syce1 gene disrupts synapsis and suggests a link between synaptonemal complex structural components and DNA repair. PLoS Genet 5 e1000393 doi:10.1371/journal.pgen.1000393
31. Bolcun-FilasECostaYSpeedRTaggartMBenaventeR 2007 SYCE2 is required for synaptonemal complex assembly, double strand break repair, and homologous recombination. J Cell Biol 176 741 747
32. HamerGWangHBolcun-FilasECookeHJBenaventeR 2008 Progression of meiotic recombination requires structural maturation of the central element of the synaptonemal complex. J Cell Sci 121 2445 2451
33. RomanienkoPJCamerini-OteroRD 2000 The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell 6 975 987
34. BaudatFManovaKYuenJPJasinMKeeneyS 2000 Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking SPO11. Mol Cell 6 989 998
35. MaratouKForsterTCostaYTaggartMSpeedR 2004 Expression profiling of the developing testis in wild-type and Dazl knockout mice. Mol Reprod Dev 67 26 54
36. MoensPBHeytingCDietrichAJJvan RaamsdonkWChenQ 1987 Synaptonemal complex antigen location and conservation. J Cell Biol 105 93 103
37. KranzAFuJDuerschkeKWeidlichSNaumannR 2010 An improved Flp deleter mouse in C57Bl/6 based on Flpo recombinase. Genesis doi:10.1002/dvg.20641
38. MahadevaiahSKTurnerJMBaudatFRogakouEPde BoerP 2001 Recombinational DNA double-strand breaks in mice precede synapsis. Nat Genet 27 271 276
39. AlbiniSMJonesGH 1987 Synaptonemal complex spreading in Allium cepa and A. fistulosum. Chromosoma 95 324 338
40. BarlowALBensonFEWestSCHulténMA 1997 Distribution of the Rad51 recombinase in human and mouse spermatocytes. EMBO J 16 5207 15
41. MoensPBKolasNKTarsounasMMarconECohenPE 2002 The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination. J Cell Sci 115 1611 1622
42. CarpenterAT 1975 Electron microscopy of meiosis in Drosophila melanogaster females: II. The recombination nodule–a recombination-associated structure at pachytene? Proc Natl Acad Sci USA 72 3186 9
43. MoensPBMarconEShoreJSKochakpourNSpyropoulosB 2007 Initiation and resolution of interhomolog connections: crossover and non-crossover sites along mouse synaptonemal complexes. J Cell Sci 120 1017 1027
44. MarconEMoensP 2003 MLH1p and MLH3p localize to precociously induced chiasmata of okadaic-acid-treated mouse spermatocytes. Genetics 165 2283 7
45. BakerSMPlugAWProllaTABronnerCEHarrisAC 1996 Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat Genet 13 336 342
46. BorumK 1961 Oogenesis in the mouse. A study of the meiotic prophase. Exp Cell Res 24 495 507
47. SpeedRM 1982 Meiosis in the foetal mouse ovary. I. An analysis at the light microscope level using surface-spreading. Chromosoma 85 427 37
48. Stewart-HutchinsonPJHaleCMWirtzDHodzicD 2008 Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness. Exp Cell Res 314 1892 1905
49. RasmussenSWHolmPB 1978 Human meiosis II. Chromosome pairing and recombination nodules in human spermatocytes. Carlsberg Res Commun 43 275 327
50. SchmekelKDaneholtB 1998 Evidence for close contact between recombination nodules and the central element of the synaptonemal complex. Chromosome Res 6 155 159
51. TarsounasMMoritaTPearlmanREMoensPB 1999 RAD51 and DMC1 form mixed complexes associated with mouse meiotic chromosome cores and synaptonemal complexes. J Cell Biol 147 207 220
52. YangFGellKvan der HeijdenGWEckardtSLeuNA 2008 Meiotic failure in male mice lacking an X-linked factor. Genes Dev 22 682 691
53. SchultzJCopleyRRDoerksTPontingCPBorkP 2000 SMART: A Web-based tool for the study of genetically mobile domains. Nucleic Acids Res 28 231 4
54. BlomNGammeltoftSBrunakS 1999 Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 294 1351 1362
55. LarkinMABlackshieldsGBrownNPChennaRMcGettiganPA 2007 Clustal W and Clustal X version 2.0. Bioinformatics 23 2947 2948
56. LaemmliUK 1970 Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227 680 685
57. SchaggerH 2006 Tricine-SDS-PAGE. Nat Protoc 1 16 22
58. MatsudairaP 1987 Sequence from picomole quantities of proteins electroblotted onto polyvinylidene difluoride membranes. J Biol Chem 262 10035 10038
59. de BoerELhuissierFGPHeytingC 2009 Cytological analysis of interference in mouse meiosis. Meiosis 2 355 382
60. WinkelKAlsheimerMÖllingerRBenaventeR 2009 Protein SYCP2 provides a link between transverse filaments and lateral elements of mammalian synaptonemal complexes. Chromosoma 118 259 267
61. AlsheimerMBenaventeR 1996 Change of karyoskeleton during mammalian spermatogenesis: expression pattern of nuclear lamin C2 and its regulation. Exp Cell Res 228 181 188
62. AhmedAEde RooijDG 2009 Staging of mouse seminiferous tubule cross-sections. Meiosis 2 263 277
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 5
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