TY - JOUR T1 - Sex Reversal in Zebrafish fancl Mutants Is Caused by Tp53-Mediated Germ Cell Apoptosis A1 - Rodríguez-Marí, Adriana A1 - Cañestro, Cristian A1 - BreMiller, Ruth A. A1 - Nguyen-Johnson, Alexandria A1 - Asakawa, Kazuhide A1 - Kawakami, Koichi A1 - Postlethwait, John H. Y1 - 2010/07/22 N2 - Author Summary Zebrafish has become an important model for understanding vertebrate development and human disease, yet the genetic mechanisms that regulate gonad fate to determine zebrafish sex remain elusive. In this work, we describe a mutation in the fancl gene that causes zebrafish to develop exclusively as male due to 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 zebrafish 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 fancl mutants by compromising oocyte survival, possibly by eliminating a hypothesized oocyte-derived signal, which alters sex determination in zebrafish. JF - PLOS Genetics JA - PLOS Genetics VL - 6 IS - 7 UR - https://doi.org/10.1371/journal.pgen.1001034 SP - e1001034 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pgen.1001034 ER -