Role of sex steroids in fish sex determination and differentiation as revealed by gene editing.

The involvement of sex steroids in sex determination and differentiation is relatively conserved among non-mammalian vertebrates, especially in fish. Thanks to the advances in genome sequencing and genome editing, significant progresses have been made in the understanding of steroidogenic pathway and hormonal regulation of sex determination and differentiation in fish. It seems that loss of function study of single gene challenges the traditional views that estrogen is required for ovarian differentiation and androgen is needed for testicular development, but it is not so in essence. Steroidogenic enzymes can be classified into two categories based on expression and enzyme activities in fish. One type, encoded by star2, cyp17a1 and cyp19a1a, is involved in estrogen production and exclusively expressed in the gonads. Mutation of these genes results in the up-regulation of male pathway genes and sex reversal from genetic female to male. The other type, encoded by the duplicated paralogs of the above genes, including star1, cyp11a1, cyp17a2 and cyp19a1b, as well as cyp11c1 gene, is dominantly expressed both in gonads and extra-gonadal tissues. Mutation of these genes alters the steroids (androgen, DHP and cortisol) production and spermatogenesis, fertility, secondary sexual characteristics and sexual behavior, but usually does not affect the sex differentiation. For the estrogen receptors (esr1, esr2a and esr2b), single mutation failed to, but double and triple mutation leads to sex reversal from female to male, indicating that at least Esr2a and Esr2b are required to mediate the role of estrogen in sex determination proved by gene editing experiments. Taken together, results from gene editing enrich our understanding of steroid synthesis pathways and further confirm the critical role of estrogen in female sex determination by antagonizing the male pathway in fish.

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