Roles of () in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
Mild mutations in BRCA2 (FANCD1) cause Fanconi anemia (FA) when homozygous, while severe mutations cause common cancers including breast, ovarian, and prostate cancers when heterozygous. Here we report a zebrafish brca2 insertional mutant that shares phenotypes with human patients and identifies a novel brca2 function in oogenesis. Experiments showed that mutant embryos and mutant cells in culture experienced genome instability, as do cells in FA patients. In wild-type zebrafish, meiotic cells expressed brca2; and, unexpectedly, transcripts in oocytes localized asymmetrically to the animal pole. In juvenile brca2 mutants, oocytes failed to progress through meiosis, leading to female-to-male sex reversal. Adult mutants became sterile males due to the meiotic arrest of spermatocytes, which then died by apoptosis, followed by neoplastic proliferation of gonad somatic cells that was similar to neoplasia observed in ageing dead end (dnd)-knockdown males, which lack germ cells. The construction of animals doubly mutant for brca2 and the apoptotic gene tp53 (p53) rescued brca2-dependent sex reversal. Double mutants developed oocytes and became sterile females that produced only aberrant embryos and showed elevated risk for invasive ovarian tumors. Oocytes in double-mutant females showed normal localization of brca2 and pou5f1 transcripts to the animal pole and vasa transcripts to the vegetal pole, but had a polarized rather than symmetrical nucleus with the distribution of nucleoli and chromosomes to opposite nuclear poles; this result revealed a novel role for Brca2 in establishing or maintaining oocyte nuclear architecture. Mutating tp53 did not rescue the infertility phenotype in brca2 mutant males, suggesting that brca2 plays an essential role in zebrafish spermatogenesis. Overall, this work verified zebrafish as a model for the role of Brca2 in human disease and uncovered a novel function of Brca2 in vertebrate oocyte nuclear architecture.
Vyšlo v časopise:
Roles of () in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish. PLoS Genet 7(3): e32767. doi:10.1371/journal.pgen.1001357
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001357
Souhrn
Mild mutations in BRCA2 (FANCD1) cause Fanconi anemia (FA) when homozygous, while severe mutations cause common cancers including breast, ovarian, and prostate cancers when heterozygous. Here we report a zebrafish brca2 insertional mutant that shares phenotypes with human patients and identifies a novel brca2 function in oogenesis. Experiments showed that mutant embryos and mutant cells in culture experienced genome instability, as do cells in FA patients. In wild-type zebrafish, meiotic cells expressed brca2; and, unexpectedly, transcripts in oocytes localized asymmetrically to the animal pole. In juvenile brca2 mutants, oocytes failed to progress through meiosis, leading to female-to-male sex reversal. Adult mutants became sterile males due to the meiotic arrest of spermatocytes, which then died by apoptosis, followed by neoplastic proliferation of gonad somatic cells that was similar to neoplasia observed in ageing dead end (dnd)-knockdown males, which lack germ cells. The construction of animals doubly mutant for brca2 and the apoptotic gene tp53 (p53) rescued brca2-dependent sex reversal. Double mutants developed oocytes and became sterile females that produced only aberrant embryos and showed elevated risk for invasive ovarian tumors. Oocytes in double-mutant females showed normal localization of brca2 and pou5f1 transcripts to the animal pole and vasa transcripts to the vegetal pole, but had a polarized rather than symmetrical nucleus with the distribution of nucleoli and chromosomes to opposite nuclear poles; this result revealed a novel role for Brca2 in establishing or maintaining oocyte nuclear architecture. Mutating tp53 did not rescue the infertility phenotype in brca2 mutant males, suggesting that brca2 plays an essential role in zebrafish spermatogenesis. Overall, this work verified zebrafish as a model for the role of Brca2 in human disease and uncovered a novel function of Brca2 in vertebrate oocyte nuclear architecture.
Zdroje
1. WoosterR
WeberBL
2003 Breast and ovarian cancer. N Engl J Med 348 2339 2347
2. EdwardsSM
Kote-JaraiZ
MeitzJ
HamoudiR
HopeQ
2003 Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 1 12
3. GaytherSA
de FoyKA
HarringtonP
PharoahP
DunsmuirWD
2000 The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 60 4513 4518
4. EastonD
1997 Breast cancer genes--what are the real risks? Nat Genet 16 210 211
5. AntoniouA
PharoahPD
NarodS
RischHA
EyfjordJE
2003 Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72 1117 1130
6. TavtigianSV
SimardJ
RommensJ
CouchF
Shattuck-EidensD
1996 The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12 333 337
7. ConnorF
SmithA
WoosterR
StrattonM
DixonA
1997 Cloning, chromosomal mapping and expression pattern of the mouse Brca2 gene. Hum Mol Genet 6 291 300
8. MoynahanME
2002 The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans. Oncogene 21 8994 9007
9. FrappartPO
McKinnonPJ
2007 BRCA2 function and the central nervous system. Cell Cycle 6 2453 2457
10. CotroneoMS
HaagJD
ZanY
LopezCC
ThuwajitP
2007 Characterizing a rat Brca2 knockout model. Oncogene 26 1626 1635
11. NevelingK
EndtD
HoehnH
SchindlerD
2009 Genotype-phenotype correlations in Fanconi anemia. Mutat Res 668 73 91
12. D'AndreaA
2003 Fanconi anemia. Curr Biol 13 R546
13. BagbyGC
AlterBP
2006 Fanconi anemia. Semin Hematol 43 147 156
14. RosenbergPS
AlterBP
EbellW
2008 Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. Haematologica 93 511 517
15. HowlettNG
TaniguchiT
OlsonS
CoxB
WaisfiszQ
2002 Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297 606 609
16. HirschB
ShimamuraA
MoreauL
BaldingerS
Hag-alshiekhM
2004 Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood 103 2554 2559
17. AlterBP
RosenbergPS
BrodyLC
2007 Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 44 1 9
18. MoynahanME
CuiTY
JasinM
2001 Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 61 4842 4850
19. WongJC
AlonN
McKerlieC
HuangJR
MeynMS
2003 Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia. Hum Mol Genet 12 2063 2076
20. Rodríguez-MaríA
CañestroC
BreMillerRA
Nguyen-JohnsonA
AsakawaK
2010 Sex Reversal in Zebrafish fancl Mutants Results from Tp53-Mediated Germ Cell Apoptosis. PLoS Genet 6 e1001034
21. LiX
Le BeauMM
CicconeS
YangFC
FreieB
2005 Ex vivo culture of Fancc−/− stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy. Blood 105 3465 3471
22. ChenPL
ChenCF
ChenY
XiaoJ
SharpZD
1998 The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci U S A 95 5287 5292
23. HakemR
de la PompaJL
MakTW
1998 Developmental studies of Brca1 and Brca2 knock-out mice. J Mammary Gland Biol Neoplasia 3 431 445
24. SharanSK
PyleA
CoppolaV
BabusJ
SwaminathanS
2004 BRCA2 deficiency in mice leads to meiotic impairment and infertility. Development 131 131 142
25. TitusTA
YanYL
WilsonC
StarksAM
FrohnmayerJD
2009 The Fanconi anemia/BRCA gene network in zebrafish: embryonic expression and comparative genomics. Mutat Res 668 117 132
26. CatchenJM
ConeryJS
PostlethwaitJH
2009 Automated identification of conserved synteny after whole-genome duplication. Genome Res 19 1497 1505
27. PostlethwaitJH
WoodsIG
Ngo-HazelettP
YanY-L
KellyPD
2000 Zebrafish comparative genomics and the origins of vertebrate chromosomes. Genome Res 10 1890 1902
28. TitusTA
SelvigDR
QinB
WilsonC
StarksAM
2006 The Fanconi anemia gene network is conserved from zebrafish to human. Gene 371 211 223
29. AmoresA
ForceA
YanY-L
JolyL
AmemiyaC
1998 Zebrafish hox clusters and vertebrate genome evolution. Science 282 1711 1714
30. TaylorJ
BraaschI
FrickeyT
MeyerA
Van De PeerY
2003 Genome duplication, a trait shared by 22,000 species of ray-finned fish. Genome Res 13 382 390
31. JaillonO
AuryJM
BrunetF
PetitJL
Stange-ThomannN
2004 Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype. Nature 431 946 957
32. TengDH
BogdenR
MitchellJ
BaumgardM
BellR
1996 Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet 13 241 244
33. TakataM
TachiiriS
FujimoriA
ThompsonLH
MikiY
2002 Conserved domains in the chicken homologue of BRCA2. Oncogene 21 1130 1134
34. WarrenM
SmithA
PartridgeN
MasabandaJ
GriffinD
2002 Structural analysis of the chicken BRCA2 gene facilitates identification of functional domains and disease causing mutations. Hum Mol Genet 11 841 851
35. MilnerJ
1997 Structures and functions of the tumor suppressor p53. Pathol Biol (Paris) 45 797 803
36. BignellG
MicklemG
StrattonMR
AshworthA
WoosterR
1997 The BRC repeats are conserved in mammalian BRCA2 proteins. Hum Mol Genet 6 53 58
37. YangH
JeffreyPD
MillerJ
KinnucanE
SunY
2002 BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297 1837 1848
38. DeutschM
LongM
1999 Intron-exon structures of eukaryotic model organisms. Nucleic Acids Res 27 3219 3228
39. CheesmanSE
NealJT
MittgeE
SeredickBM
GuilleminK
2010 Microbes and Health Sackler Colloquium: Epithelial cell proliferation in the developing zebrafish intestine is regulated by the Wnt pathway and microbial signaling via Myd88. Proc Natl Acad Sci U S A
40. ZabludoffSD
WrightWW
HarshmanK
WoldBJ
1996 BRCA1 mRNA is expressed highly during meiosis and spermiogenesis but not during mitosis of male germ cells. Oncogene 13 649 653
41. HowleyC
HoRK
2000 mRNA localization patterns in zebrafish oocytes. Mech Dev 92 305 309
42. AbramsEW
MullinsMC
2009 Early zebrafish development: it's in the maternal genes. Curr Opin Genet Dev 19 396 403
43. SchroederTM
AnschutzF
KnoppA
1964 Spontane Chromosomenaberrationen bei familiärer Panmyelopathie. Humangenetik 1 194 196
44. AuerbachAD
1993 Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp Hematol 21 731 733
45. DarzynkiewiczZ
1990 Differential staining of DNA and RNA in intact cells and isolated cell nuclei with acridine orange. Methods Cell Biol 33 285 298
46. KlovstadM
AbduU
SchupbachT
2008 Drosophila brca2 is required for mitotic and meiotic DNA repair and efficient activation of the meiotic recombination checkpoint. PLoS Genet 4 e31
47. TakahashiH
1977 Juvenile hermaphroditism in the zebrafish, Brachydanio rerio. Bull Fac Fish Hokkaido Univ 28 57 65
48. UchidaD
YamashitaM
KitanoT
IguchiT
2002 Oocyte apoptosis during the transition from ovary-like tissue to testes during sex differentiation of juvenile zebrafish. J Exp Biol 205 711 718
49. SelmanK
WallaceRA
SarkaA
Q.X
1993 Stages of oocyte development in the zebrafish Brachydanio rerio. J Morphol 218 203 224
50. DaiC
KrantzSB
1999 Interferon gamma induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. Blood 93 3309 3316
51. YoonC
KawakamiK
HopkinsN
1997 Zebrafish vasa homologue RNA is localized to the cleavage planes of 2- and 4-cell-stage embryos and is expressed in the primordial germ cells. Development 124 3157 3165
52. Rodriguez-MariA
YanYL
BremillerRA
WilsonC
CanestroC
2005 Characterization and expression pattern of zebrafish Anti-Mullerian hormone (Amh) relative to sox9a, sox9b, and cyp19a1a, during gonad development. Gene Expr Patterns 5 655 667
53. von HofstenJ
LarssonA
OlssonPE
2005 Novel steroidogenic factor-1 homolog (ff1d) is coexpressed with anti-Mullerian hormone (AMH) in zebrafish. Dev Dyn 233 595 604
54. ChiangEF
YanYL
GuiguenY
PostlethwaitJ
ChungB
2001 Two Cyp19 (P450 aromatase) genes on duplicated zebrafish chromosomes are expressed in ovary or brain. Mol Biol Evol 18 542 550
55. MoensPB
2006 Zebrafish: chiasmata and interference. Genome 49 205 208
56. ZicklerD
KlecknerN
1998 The leptotene-zygotene transition of meiosis. Annu Rev Genet 32 619 697
57. ScherthanH
2001 A bouquet makes ends meet. Nat Rev Mol Cell Biol 2 621 627
58. BerghmansS
MurpheyRD
WienholdsE
NeubergD
KutokJL
2005 tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A 102 407 412
59. ParantJM
GeorgeSA
HoldenJA
YostHJ
2010 Genetic modeling of Li-Fraumeni syndrome in zebrafish. Dis Model Mech 3 45 56
60. KosakaK
KawakamiK
SakamotoH
InoueK
2007 Spatiotemporal localization of germ plasm RNAs during zebrafish oogenesis. Mech Dev 124 279 289
61. MarlowFL
MullinsMC
2008 Bucky ball functions in Balbiani body assembly and animal-vegetal polarity in the oocyte and follicle cell layer in zebrafish. Dev Biol 321 40 50
62. LindemanRE
PelegriF
2010 Vertebrate maternal-effect genes: Insights into fertilization, early cleavage divisions, and germ cell determinant localization from studies in the zebrafish. Mol Reprod Dev 77 299 313
63. LealMC
CardosoER
NobregaRH
BatlouniSR
BogerdJ
2009 Histological and stereological evaluation of zebrafish (Danio rerio) spermatogenesis with an emphasis on spermatogonial generations. Biol Reprod 81 177 187
64. SlanchevK
SteblerJ
de la Cueva-MendezG
RazE
2005 Development without germ cells: the role of the germ line in zebrafish sex differentiation. Proc Natl Acad Sci U S A 102 4074 4079
65. YoungrenKK
CoveneyD
PengX
BhattacharyaC
SchmidtLS
2005 The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 435 360 364
66. SharanSK
MorimatsuM
AlbrechtU
LimDS
RegelE
1997 Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386 804 810
67. ForceA
LynchM
PickettFB
AmoresA
YanY-L
1999 Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151 1531 1545
68. HussainS
WilsonJB
MedhurstAL
HejnaJ
WittE
2004 Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hum Mol Genet 13 1241 1248
69. KaneDA
KimmelCB
1993 The zebrafish midblastula transition. Development 119 447 456
70. AuerbachAD
WolmanSR
1976 Susceptibility of Fanconi's anaemia fibroblasts to chromosome damage by carcinogens. Nature 261 494 496
71. HoughtalingS
NewellA
AkkariY
TaniguchiT
OlsonS
2005 Fancd2 functions in a double strand break repair pathway that is distinct from non-homologous end joining. Hum Mol Genet 14 3027 3033
72. DomchekSM
MerillatSL
TiggesJ
TweedAJ
WeinarM
2005 Sex ratio skewing of offspring in families with hereditary susceptibility to breast cancer. J Med Genet 42 511 513
73. MoldovanGL
D'AndreaAD
2009 How the fanconi anemia pathway guards the genome. Annu Rev Genet 43 223 249
74. GodthelpBC
WiegantWW
WaisfiszQ
MedhurstAL
ArwertF
2006 Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/BRCA2. Mutat Res 594 39 48
75. TarsounasM
DaviesD
WestSC
2003 BRCA2-dependent and independent formation of RAD51 nuclear foci. Oncogene 22 1115 1123
76. MaackG
SegnerH
2003 Morphological development of the gonads in zebrafish. J Fish Biol 62 895 906
77. WangX
BartfaiR
Sleptsova-FreidrichI
OrbanL
2007 The timing and extent of ‘juvenile ovary’ phase are highly variable during zebrafish testis differentiation. Journal of Fish Biology 70 33 44
78. SiegfriedKR
Nusslein-VolhardC
2008 Germ line control of female sex determination in zebrafish. Dev Biol
79. DraperBW
McCallumCM
MoensCB
2007 nanos1 is required to maintain oocyte production in adult zebrafish. Dev Biol 305 589 598
80. HouwingS
KammingaLM
BerezikovE
CronemboldD
GirardA
2007 A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish. Cell 129 69 82
81. PaigenKea
2008 The recombinational anatomy of a mouse chromosome. PLoS Genet 4 e1000119
82. MooreJL
RushLM
BrenemanC
MohideenMA
ChengKC
2006 Zebrafish genomic instability mutants and cancer susceptibility. Genetics 174 585 600
83. AuerbachAD
2009 Fanconi anemia and its diagnosis. Mutat Res 668 4 10
84. HirshAE
FraserHB
2001 Protein dispensability and rate of evolution. Nature 411 1046 1049
85. AmsterdamA
HopkinsN
2006 Mutagenesis strategies in zebrafish for identifying genes involved in development and disease. Trends Genet 22 473 478
86. WesterfieldM
1995 The zebrafish book: a guide for the laboratory use of zebrafish (Danio rerio). Eugene, , OR University of Oregon Press
87. YanYL
MillerCT
NissenR
SingerA
LiuD
2002 A zebrafish sox9 gene required for cartilage morphogenesis. Development 129 5065 5079
88. WeidingerG
SteblerJ
SlanchevK
DumstreiK
WiseC
2003 dead end, a novel vertebrate germ plasm component, is required for zebrafish primordial germ cell migration and survival. Curr Biol 13 1429 1434
89. ReimersMJ
La DuJK
PerieraCB
GiovaniniJ
TanguayRL
2006 Ethanol-dependent toxicity in zebrafish is partially attenuated by antioxidants. Neurotoxicol Teratol 28 497 508
90. HigginsDG
SharpPM
1988 CLUSTAL: a package for performing multiple sequence alignment on a microcomputer. Gene 73 237 244
91. PerriereG
GouyM
1996 WWW-query: an on-line retrieval system for biological sequence banks. Biochimie 78 364 369
92. KyteJ
DoolittleRF
1982 A simple method for displaying the hydropathic character of a protein. J Mol Biol 157 105 132
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 3
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Whole-Exome Re-Sequencing in a Family Quartet Identifies Mutations As the Cause of a Novel Skeletal Dysplasia
- Origin-Dependent Inverted-Repeat Amplification: A Replication-Based Model for Generating Palindromic Amplicons
- FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
- Limited dCTP Availability Accounts for Mitochondrial DNA Depletion in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)