Fanconi anemia (FA) is a human disease of bone marrow failure, leukemia, 
squamous cell carcinoma, and developmental anomalies, including hypogonadism and 
infertility. Bone marrow transplants improve hematopoietic phenotypes but do not 
prevent other cancers. FA arises from mutation in any of the 15 FANC genes that 
cooperate to repair double stranded DNA breaks by homologous recombination. 
Zebrafish has a single ortholog of each human FANC gene and unexpectedly, 
mutations in at least two of them (fancl and fancd1(brca2)) lead to 
female-to-male sex reversal. Investigations show that, as in human, zebrafish 
fanc genes are required for genome stability and for suppressing apoptosis in 
tissue culture cells, in embryos treated with DNA damaging agents, and in 
meiotic germ cells. The sex reversal phenotype requires the action of Tp53 
(p53), an activator of apoptosis. These results suggest that in normal sex 
determination, zebrafish oocytes passing through meiosis signal the gonadal soma 
to maintain expression of aromatase, an enzyme that converts androgen to 
estrogen, thereby feminizing the gonad and the individual. According to this 
model, normal male and female zebrafish differ in genetic factors that control 
the strength of the late meiotic oocyte-derived signal, probably by regulating 
the number of meiotic oocytes, which environmental factors can also alter. 
Transcripts from fancd1(brca2) localize at the animal pole of the zebrafish 
oocyte cytoplasm and are required for normal oocyte nuclear architecture, for 
normal embryonic development, and for preventing ovarian tumors. Embryonic DNA 
repair and sex reversal phenotypes provide assays for the screening of small 
molecule libraries for therapeutic substances for FA.