Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis

The molecular genetic mechanisms of sex determination are not known for most vertebrates, including zebrafish. We identified a mutation in the zebrafish fancl gene that causes homozygous mutants to develop as fertile males due to female-to-male sex reversal. Fancl is a member of the Fanconi Anemia/B...

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Autores: Rodríguez Marí, Adriana, Cañestro García, Cristian, BreMiller, Ruth A., Nguyen-Johnson, Alexandria, Asakawa, Kazuhide, Kawakami, Koichi, Postlethwait, John H.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2010
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/43423
Acceso en línea:https://hdl.handle.net/2445/43423
Access Level:acceso abierto
Palabra clave:Peix zebra
Fisiologia animal
Determinació del sexe
Genètica molecular
Zebra danio
Animal physiology
Sex determination
Molecular genetics
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spelling Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell ApoptosisRodríguez Marí, AdrianaCañestro García, CristianBreMiller, Ruth A.Nguyen-Johnson, AlexandriaAsakawa, KazuhideKawakami, KoichiPostlethwait, John H.Peix zebraFisiologia animalDeterminació del sexeGenètica molecularZebra danioAnimal physiologySex determinationMolecular geneticsThe molecular genetic mechanisms of sex determination are not known for most vertebrates, including zebrafish. We identified a mutation in the zebrafish fancl gene that causes homozygous mutants to develop as fertile males due to female-to-male sex reversal. Fancl is a member of the Fanconi Anemia/BRCA DNA repair pathway. Experiments showed that zebrafish fancl was expressed in developing germ cells in bipotential gonads at the critical time of sexual fate determination. Caspase-3 immunoassays revealed increased germ cell apoptosis in fancl mutants that compromised oocyte survival. In the absence of oocytes surviving through meiosis, somatic cells of mutant gonads did not maintain expression of the ovary gene cyp19a1a and did not down-regulate expression of the early testis gene amh; consequently, gonads masculinized and became testes. Remarkably, results showed that the introduction of a tp53 (p53) mutation into fancl mutants rescued the sex-reversal phenotype by reducing germ cell apoptosis and, thus, allowed fancl mutants to become fertile females. Our results show that Fancl function is not essential for spermatogonia and oogonia to become sperm or mature oocytes, but instead suggest that Fancl function is involved in the survival of developing oocytes through meiosis. This work reveals that Tp53-mediated germ cell apoptosis induces sex reversal after the mutation of a DNA-repair pathway gene by compromising the survival of oocytes and suggests the existence of an oocyte-derived signal that biases gonad fate towards the female developmental pathway and thereby controls zebrafish sex determination.Public Library of Science (PLoS)2010info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/43423Articles 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.1001034PLoS Genetics, 2010, vol. 6, num. 7, p. e1001034http://dx.doi.org/10.1371/journal.pgen.1001034cc-by (c) Rodríguez Marí, Adriana et al., 2010http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/434232026-05-27T06:46:51Z
dc.title.none.fl_str_mv Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis
title Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis
spellingShingle Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis
Rodríguez Marí, Adriana
Peix zebra
Fisiologia animal
Determinació del sexe
Genètica molecular
Zebra danio
Animal physiology
Sex determination
Molecular genetics
title_short Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis
title_full Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis
title_fullStr Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis
title_full_unstemmed Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis
title_sort Sex Reversal in Zebrafish fancl Mutants is Caused by Tp53-Mediated Germ Cell Apoptosis
dc.creator.none.fl_str_mv Rodríguez Marí, Adriana
Cañestro García, Cristian
BreMiller, Ruth A.
Nguyen-Johnson, Alexandria
Asakawa, Kazuhide
Kawakami, Koichi
Postlethwait, John H.
author Rodríguez Marí, Adriana
author_facet Rodríguez Marí, Adriana
Cañestro García, Cristian
BreMiller, Ruth A.
Nguyen-Johnson, Alexandria
Asakawa, Kazuhide
Kawakami, Koichi
Postlethwait, John H.
author_role author
author2 Cañestro García, Cristian
BreMiller, Ruth A.
Nguyen-Johnson, Alexandria
Asakawa, Kazuhide
Kawakami, Koichi
Postlethwait, John H.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Peix zebra
Fisiologia animal
Determinació del sexe
Genètica molecular
Zebra danio
Animal physiology
Sex determination
Molecular genetics
topic Peix zebra
Fisiologia animal
Determinació del sexe
Genètica molecular
Zebra danio
Animal physiology
Sex determination
Molecular genetics
description The molecular genetic mechanisms of sex determination are not known for most vertebrates, including zebrafish. We identified a mutation in the zebrafish fancl gene that causes homozygous mutants to develop as fertile males due to female-to-male sex reversal. Fancl is a member of the Fanconi Anemia/BRCA DNA repair pathway. Experiments showed that zebrafish fancl was expressed in developing germ cells in bipotential gonads at the critical time of sexual fate determination. Caspase-3 immunoassays revealed increased germ cell apoptosis in fancl mutants that compromised oocyte survival. In the absence of oocytes surviving through meiosis, somatic cells of mutant gonads did not maintain expression of the ovary gene cyp19a1a and did not down-regulate expression of the early testis gene amh; consequently, gonads masculinized and became testes. Remarkably, results showed that the introduction of a tp53 (p53) mutation into fancl mutants rescued the sex-reversal phenotype by reducing germ cell apoptosis and, thus, allowed fancl mutants to become fertile females. Our results show that Fancl function is not essential for spermatogonia and oogonia to become sperm or mature oocytes, but instead suggest that Fancl function is involved in the survival of developing oocytes through meiosis. This work reveals that Tp53-mediated germ cell apoptosis induces sex reversal after the mutation of a DNA-repair pathway gene by compromising the survival of oocytes and suggests the existence of an oocyte-derived signal that biases gonad fate towards the female developmental pathway and thereby controls zebrafish sex determination.
publishDate 2010
dc.date.none.fl_str_mv 2010
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/2445/43423
url https://hdl.handle.net/2445/43423
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.1001034
PLoS Genetics, 2010, vol. 6, num. 7, p. e1001034
http://dx.doi.org/10.1371/journal.pgen.1001034
dc.rights.none.fl_str_mv cc-by (c) Rodríguez Marí, Adriana et al., 2010
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., 2010
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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