Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Rodríguez-Marí, Adriana, Cañestro, Cristian, BreMiller, Ruth A., Nguyen-Johnson, Alexandria, Asakawa, Kazuhide, Kawakami, Koichi, Postlethwait, John H.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908690/
https://www.ncbi.nlm.nih.gov/pubmed/20661450
http://dx.doi.org/10.1371/journal.pgen.1001034
_version_ 1782184222815944704
author Rodríguez-Marí, Adriana
Cañestro, Cristian
BreMiller, Ruth A.
Nguyen-Johnson, Alexandria
Asakawa, Kazuhide
Kawakami, Koichi
Postlethwait, John H.
author_facet Rodríguez-Marí, Adriana
Cañestro, Cristian
BreMiller, Ruth A.
Nguyen-Johnson, Alexandria
Asakawa, Kazuhide
Kawakami, Koichi
Postlethwait, John H.
author_sort Rodríguez-Marí, Adriana
collection PubMed
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.
format Text
id pubmed-2908690
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-29086902010-07-26 Sex Reversal in Zebrafish fancl Mutants Is Caused by Tp53-Mediated Germ Cell Apoptosis Rodríguez-Marí, Adriana Cañestro, Cristian BreMiller, Ruth A. Nguyen-Johnson, Alexandria Asakawa, Kazuhide Kawakami, Koichi Postlethwait, John H. PLoS Genet Research Article 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. Public Library of Science 2010-07-22 /pmc/articles/PMC2908690/ /pubmed/20661450 http://dx.doi.org/10.1371/journal.pgen.1001034 Text en Rodríguez-Marí et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Rodríguez-Marí, Adriana
Cañestro, Cristian
BreMiller, Ruth A.
Nguyen-Johnson, Alexandria
Asakawa, Kazuhide
Kawakami, Koichi
Postlethwait, John H.
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
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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908690/
https://www.ncbi.nlm.nih.gov/pubmed/20661450
http://dx.doi.org/10.1371/journal.pgen.1001034
work_keys_str_mv AT rodriguezmariadriana sexreversalinzebrafishfanclmutantsiscausedbytp53mediatedgermcellapoptosis
AT canestrocristian sexreversalinzebrafishfanclmutantsiscausedbytp53mediatedgermcellapoptosis
AT bremillerrutha sexreversalinzebrafishfanclmutantsiscausedbytp53mediatedgermcellapoptosis
AT nguyenjohnsonalexandria sexreversalinzebrafishfanclmutantsiscausedbytp53mediatedgermcellapoptosis
AT asakawakazuhide sexreversalinzebrafishfanclmutantsiscausedbytp53mediatedgermcellapoptosis
AT kawakamikoichi sexreversalinzebrafishfanclmutantsiscausedbytp53mediatedgermcellapoptosis
AT postlethwaitjohnh sexreversalinzebrafishfanclmutantsiscausedbytp53mediatedgermcellapoptosis