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Roles of brca2 (fancd1) in oocyte nuclear architecture,gametogenesis,gonad tumors,and genome stability in zebrafish
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نویسنده
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rodríguez-marí a. ,wilson c. ,titus t.a. ,cañestro c. ,bremiller r.a. ,yan y.-l. ,nanda i. ,johnston a. ,kanki j.p. ,gray e.m. ,he x. ,spitsbergen j. ,schindler d. ,postlethwait j.h.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 3
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چکیده
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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. © 2011 rodríguez-marí et al.
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آدرس
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institute of neuroscience,university of oregon,eugene,or, United States, institute of neuroscience,university of oregon,eugene,or, United States, institute of neuroscience,university of oregon,eugene,or, United States, institute of neuroscience,university of oregon,eugene,or,united states,departament de genética,universitat de barcelona,barcelona, Spain, institute of neuroscience,university of oregon,eugene,or, United States, institute of neuroscience,university of oregon,eugene,or, United States, institute of human genetics,biocenter,university of würzburg,würzburg, Germany, dana farber cancer institute,boston,ma, United States, dana farber cancer institute,boston,ma, United States, institute of neuroscience,university of oregon,eugene,or, United States, institute of neuroscience,university of oregon,eugene,or, United States, marine and freshwater biomedical sciences center,oregon state university,corvallis,or, United States, institute of human genetics,biocenter,university of würzburg,würzburg, Germany, institute of neuroscience,university of oregon,eugene,or, United States
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Authors
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