DMRT1 prevents female reprogramming in the postnatal mammalian testis

Abstract

Sex in mammals is determined in the foetal 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 foetal gonad between a male regulatory gene network in which Sry activates Sox9 and a female network involving Wnt/β-catenin signaling (Supplemental Fig. 1)2. In females the primary sex-determining decision is not final: loss of the FOXL2 transcription factor in adult granulosa cells can reprogramme 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 reprogrammes 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 foetal 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 etiology of human syndromes linked to DMRT1, including disorders of sexual differentiation6 and testicular cancer7.

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

“…1,5 Animal studies have revealed multiple and long-lasting interactions between these male and female pathways; for instance, the loss of Foxl2 or Dmrt1 in murine adult granulosa and Sertoli cells, respectively, results in trans-differentiation to an opposite cell fate. 6,7 Subtle imbalances of this strictly regulated sex-specific gene network can lead to disorders or differences of sex development (DSD). 1 Currently, mutations in genes known to be involved in sex development explain the molecular pathogenesis in only a minority of 46,XY DSD cases.…”

Expression characterization of testicular DMRT1 in both Sertoli cells and spermatogenic cells of polyploid gibel carp

“…In mammals, DMRT1 was found to be expressed both in Sertoli cells and in germ cells (Lei et al, 2007). Moreover, it was indicated that DMRT1 in Sertoli cells was essential to maintain testis determination (Matson et al, 2011) and regulate tubule morphology, spermatogenesis, and sperm function in mammals (Agbor et al, 2013). Additionally, DMRT1 in spermatogonia was demonstrated to determine whether spermatogonia undergo mitosis and spermatogonial differentiation or meiosis (Matson et al, 2010).…”

La différenciation du sexe

“…Une publication très récente [38] rapportant l'invalidation spécifique de Dmrt1 dans les cellules de Sertoli renforce la constatation d'une non-conservation de rôles importants de Foxl2 dans l'ovaire et de Dmrt1 dans le testicule chez la souris. Ce travail de l'équipe de David Zarkower publié en Juillet 2011 peut être considéré comme le pendant mâle de l'invalidation à l'âge adulte de Foxl2 dans l'ovaire [6,7].…”