<i>DMRT1</i> is a testis-determining gene in rabbits and is also essential for female fertility.

Abstract

DMRT1 is the testis-determining factor in several species of vertebrates, but its involvement in mammalian testes differentiation, where <i>SRY</i> is the testis-determining gene, remains ambiguous. So far, DMRT1 loss-of-function has been described in two mammalian species and induces different phenotypes: Disorders of Sex Development (46, XY DSD) in men and male infertility in mice. We thus abolished DMRT1 expression by CRISPR/Cas9 in a third species of mammal, the rabbit. First, we observed that gonads from XY <i>DMRT1^-/-</i> rabbit fetuses differentiated like ovaries, highlighting that DMRT1 is involved in testis determination. In addition to SRY, DMRT1 is required in the supporting cells to increase the expression of the <i>SOX9</i> gene, which heads the testicular genetic cascade. Second, we highlighted another function of DMRT1 in the germline since XX and XY <i>DMRT1^-/-</i> ovaries did not undergo meiosis and folliculogenesis. XX <i>DMRT1^-/-</i> adult females were sterile, showing that DMRT1 is also crucial for female fertility. To conclude, these phenotypes indicate an evolutionary continuum between non-mammalian vertebrates such as birds and non-rodent mammals. Furthermore, our data support the potential involvement of <i>DMRT1</i> mutations in different human pathologies, such as 46, XY DSD as well as male and female infertility.