DMRT1 prevents female reprogramming in the postnatal mammalian testis

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Abstract
The presence or absence of the Y-chromosome gene Sry determines whether precursor cells differentiate into testicular Sertoli cells or ovarian granulosa cells in the mammalian fetus. Loss of the transcription factor FOXL2 in the adult ovary can lead to transdifferentiation of granulosa cells into Sertoli cells, but in males the sex-determining decision was thought to be stable. This study shows that this is not the case: adult mouse testicular cells become ovarian cells if the Dmrt1 gene is lost. In the absence of transcription factor DMRT1, FOXL2 is activated and Sertoli cells are reprogrammed as granulosa cells. Sex in mammals is determined in the fetal gonad by the presence or absence of the Y chromosome gene Sry, which controls whether bipotential precursor cells differentiate into testicular Sertoli cells or ovarian granulosa cells1. This pivotal decision in a single gonadal cell type ultimately controls sexual differentiation throughout the body. Sex determination can be viewed as a battle for primacy in the fetal gonad between a male regulatory gene network in which Sry activates Sox9 and a female network involving WNT/β-catenin signalling2. In females the primary sex-determining decision is not final: loss of the FOXL2 transcription factor in adult granulosa cells can reprogram granulosa cells into Sertoli cells2. Here we show that sexual fate is also surprisingly labile in the testis: loss of the DMRT1 transcription factor3 in mouse Sertoli cells, even in adults, activates Foxl2 and reprograms Sertoli cells into granulosa cells. In this environment, theca cells form, oestrogen is produced and germ cells appear feminized. Thus Dmrt1 is essential to maintain mammalian testis determination, and competing regulatory networks maintain gonadal sex long after the fetal choice between male and female. Dmrt1 and Foxl2 are conserved throughout vertebrates4,5 and Dmrt1-related sexual regulators are conserved throughout metazoans3. Antagonism between Dmrt1 and Foxl2 for control of gonadal sex may therefore extend beyond mammals. Reprogramming due to loss of Dmrt1 also may help explain the aetiology of human syndromes linked to DMRT1, including disorders of sexual differentiation6 and testicular cancer7.

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