The -KTS splice variant of WT1 is essential for ovarian determination in mice

Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pre-granulosa cells that govern testis and ovary development, respectively. While the Y-linked testis-determining gene Sry has been identified, the ovarian-determining factor remains unknown. Here we identify -KTS, a major alternatively spliced isoform of the Wilms’ tumor suppressor WT1, as a key determinant of female sex determination. Loss of -KTS variants blocks gonadal differentiation in mice, whilst increased expression, as found in Frasier syndrome, induces precocious differentiation of ovaries independently of their genetic sex. In XY embryos, this antagonizes Sry expression, resulting in male-to-female sex reversal. Our results identify - KTS as an ovarian-determining factor and demonstrate that its time of activation is critical in gonadal sex differentiation.