Roles of brca2 (fancd1) 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 n...

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Autores: Rodríguez Marí, Adriana, Wilson, Catherine, Titus, T. A., Cañestro García, Cristian, BreMiller, Ruth A., Yan, Yi-Lin, Nanda, I., Johnston, A., Kanki, J. P., Grayl, E. M., He, Xinjun, Spitsbergen, J., Schindeler, D., Postlethwait, John H.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2011
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/43406
Acesso em linha:https://hdl.handle.net/2445/43406
Access Level:acceso abierto
Palavra-chave:Peix zebra
Fisiologia animal
Tumors
Genòmica
Zebra danio
Animal physiology
Genomics
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spelling Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in ZebrafishRodríguez Marí, AdrianaWilson, CatherineTitus, T. A.Cañestro García, CristianBreMiller, Ruth A.Yan, Yi-LinNanda, I.Johnston, A.Kanki, J. P.Grayl, E. M.He, XinjunSpitsbergen, J.Schindeler, D.Postlethwait, John H.Peix zebraFisiologia animalTumorsGenòmicaZebra danioAnimal physiologyTumorsGenomicsMild 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.Public Library of Science (PLoS)2011info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/43406Articles publicats en revistes (Genètica, Microbiologia i Estadística)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1001357PLoS Genetics, 2011, vol. 7, num. 3, p. e1001357http://dx.doi.org/10.1371/journal.pgen.1001357cc-by (c) Rodríguez Marí, Adriana et al., 2011http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/434062026-05-27T06:46:51Z
dc.title.none.fl_str_mv Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
title Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
spellingShingle Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
Rodríguez Marí, Adriana
Peix zebra
Fisiologia animal
Tumors
Genòmica
Zebra danio
Animal physiology
Tumors
Genomics
title_short Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
title_full Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
title_fullStr Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
title_full_unstemmed Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
title_sort Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish
dc.creator.none.fl_str_mv Rodríguez Marí, Adriana
Wilson, Catherine
Titus, T. A.
Cañestro García, Cristian
BreMiller, Ruth A.
Yan, Yi-Lin
Nanda, I.
Johnston, A.
Kanki, J. P.
Grayl, E. M.
He, Xinjun
Spitsbergen, J.
Schindeler, D.
Postlethwait, John H.
author Rodríguez Marí, Adriana
author_facet Rodríguez Marí, Adriana
Wilson, Catherine
Titus, T. A.
Cañestro García, Cristian
BreMiller, Ruth A.
Yan, Yi-Lin
Nanda, I.
Johnston, A.
Kanki, J. P.
Grayl, E. M.
He, Xinjun
Spitsbergen, J.
Schindeler, D.
Postlethwait, John H.
author_role author
author2 Wilson, Catherine
Titus, T. A.
Cañestro García, Cristian
BreMiller, Ruth A.
Yan, Yi-Lin
Nanda, I.
Johnston, A.
Kanki, J. P.
Grayl, E. M.
He, Xinjun
Spitsbergen, J.
Schindeler, D.
Postlethwait, John H.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Peix zebra
Fisiologia animal
Tumors
Genòmica
Zebra danio
Animal physiology
Tumors
Genomics
topic Peix zebra
Fisiologia animal
Tumors
Genòmica
Zebra danio
Animal physiology
Tumors
Genomics
description 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.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/43406
url https://hdl.handle.net/2445/43406
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1001357
PLoS Genetics, 2011, vol. 7, num. 3, p. e1001357
http://dx.doi.org/10.1371/journal.pgen.1001357
dc.rights.none.fl_str_mv cc-by (c) Rodríguez Marí, Adriana et al., 2011
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Rodríguez Marí, Adriana et al., 2011
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Genètica, Microbiologia i Estadística)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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