Abstract
Although the zebrafish is a major model organism, how they determine sex is not well understood. In domesticated zebrafish, sex determination appears to be polygenic, being influenced by multiple genetic factors that may vary from strain to strain, and additionally can be influenced by environmental factors. However, the requirement of germ cells for female sex determination is well documented: animals that lack germ cells, or oocytes in particular, develop exclusively as males. Recently, it has been determined that oocytes are also required throughout the adult life of the animal to maintain the differentiated female state. How oocytes control sex differentiation and maintenance of the sexual phenotype is unknown. We therefore generated targeted mutations in genes for two oocyte produced signaling molecules, Bmp15 and Gdf9 and here report a novel role for Bmp15 in maintaining adult female sex differentiation in zebrafish. Females deficient in Bmp15 begin development normally but switch sex during the mid- to late- juvenile stage, and become fertile males. Additionally, by generating mutations in the aromatase cyp19a1a, we show that estrogen production is necessary for female development and that the function of Bmp15 in female sex maintenance is likely linked to the regulation of estrogen biosynthesis via promoting the development of estrogen-producing granulosa cells in the oocyte follicle.
Highlights
Sex determination is the process by which an animal determines whether it will develop as a male or a female
We find that bmp15 mutant females initially have normal development, but during the juvenile stage, oocytes are degraded after they arrest at early stages, and the premeiotic germ cells switch to a spermatogenic program as the gonad transforms to a fully functional testis
If there is a direct correlation between germ cell numbers and the eventual number of oocytes an animal can produce by the end of the sex determination stage, animals with increased total germ cells will have a higher probability of producing the threshold number of oocytes and oocyte signal(s) required to stabilize female-specific gene expression in the gonad
Summary
Sex determination is the process by which an animal determines whether it will develop as a male or a female. Though in most animals the primary and secondary sex determination mechanisms are considered to lead to a stably differentiated sexual fate, in some animals, sex can be reversed. Even in species that do not normally switch sex during their adult life cycles, such as mammals, there is evidence that sex differentiation of the gonad is not irreversible once established, but instead it requires constant maintenance via sex-specific transcription factors that function to maintain sex-appropriate gene expression. It is important to understand the mechanism that allows animals to maintain a stable sexual fate, but at the same time retain enough flexibility in sex determination and differentiation as to allow for functional sex reversal mechanisms to evolve when this trait is advantageous
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