| Sex Reversal in Zebrafish fancl Mutants Is Caused by Tp53-Mediated Germ Cell Apoptosis | ||
| PLoS Genetics Vol 6 | ||
| Kawakami Laboratory, Division of Molecular and Developmental Biology | ||
| Sex Reversal in Zebrafish fancl Mutants Is Caused by
Tp53-Mediated Germ Cell Apoptosis. Adriana Rodriguez-Mari, Cristian Canestro, Ruth A. BreMiller, Alexandria Nguyen-Johnson,Kazuhide Asakawa, Koichi Kawakami, and John H. Postlethwait PLoS Genetics, Vol 6, e1001034. (2010) In zebrafish, the genetic mechanisms that regulate gonad fate to determine sex are not known. In this work, we describe a mutation in the fancl gene that causes female-to-male sex reversal. Fancl is a member of the Fanconi Anemia/BRCA pathway involved in the repair of damaged DNA. We find that the sex-reversal phenotype is caused by an abnormal increase of programmed germ cell death during the critical period for sex determination in which oocytes progress through meiosis. This abnormal increase in germ cell death compromises oocyte survival, gonadal somatic cells do not maintain the female gene expression profile, gonads become masculinized to testes, and mutants develop into fertile males. Remarkably, we show that the introduction of a mutated allele of the tp53 (p53) tumor suppressor gene into fancl mutants rescues the sex-reversal phenotype by reducing germ cell death. We conclude that Tp53-mediated germ cell death alters gonad fate selection in the fancl mutants by compromising oocyte survival, possibly by eliminating a hypothesized oocyte-derived signal, which alters sex determination in zebrafish. (This work is carried out in collaboration with Postlethwait lab at University of Oregon, USA)
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