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PMID:20661450

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Citation

Rodríguez-Marí, A, Cañestro, C, Bremiller, RA, Nguyen-Johnson, A, Asakawa, K, Kawakami, K and Postlethwait, JH (2010) Sex reversal in zebrafish fancl mutants is caused by Tp53-mediated germ cell apoptosis. PLoS Genet. 6:e1001034

Abstract

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.

Links

PubMed PMC2908690 Online version:10.1371/journal.pgen.1001034

Keywords

Animals; Apoptosis; Cell Survival; Fanconi Anemia Complementation Group L Protein/genetics; Fanconi Anemia Complementation Group L Protein/physiology; Female; Germ Cells/pathology; Male; Mutation; Oocytes; Sex Differentiation; Tumor Suppressor Protein p53/physiology; Zebrafish

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:B8JHS6

involved_in

GO:0048599: oocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-100810-2

P

Seeded From UniProt

complete

DANRE:Q1X868

involved_in

GO:0048599: oocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-100810-2

P

Seeded From UniProt

complete

DANRE:Q6NY39

involved_in

GO:0048599: oocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-100810-2

P

Seeded From UniProt

complete

DANRE:Q7SXP5

involved_in

GO:0048599: oocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-100810-2

P

Seeded From UniProt

complete


See also

References

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