Female-to-male sex reversal in mice caused by transgenic overexpression of Dmrt1

Abstract

Genes related to Dmrt1, which encodes a DNA-binding DM domain transcription factor, act as triggers for primary sex determination in a broad range of metazoan species. However, this role is fulfilled in mammals by Sry, a newly evolved gene on the Y chromosome, such that Dmrt1 has become dispensable for primary sex determination and instead maintains Sertoli cell phenotype in postnatal testes. Here, we report that enforced expression of Dmrt1 in XX mouse fetal gonads using a Wt1-BAC transgene system is sufficient to drive testicular differentiation and male secondary sex development. XX transgenic fetal gonads showed typical testicular size and vasculature. Key ovarian markers, including Wnt4 and Foxl2, were repressed. Sertoli cells expressing the hallmark testis-determining gene Sox9 were formed, although they did not assemble into normal testis cords. Other bipotential lineages differentiated into testicular cell types, including steroidogenic fetal Leydig cells and non-meiotic germ cells. As a consequence, male internal and external reproductive organs developed postnatally, with an absence of female reproductive tissues. These results reveal that Dmrt1 has retained its ability to act as the primary testis-determining trigger in mammals, even though this function is no longer normally required. Thus, Dmrt1 provides a common thread in the evolution of sex determination mechanisms in metazoans.

Chinmo is sufficient to induce male fate in somatic cells of the adult Drosophila ovary

“…In female mice, transgenic overexpression of Dmrt1 in somatic gonadal cells causes transdifferentiation of adult granulosa cells to Sertoli cells, which indicates that DMRT1 is sufficient to convert fully differentiated female somatic cells into functional male somatic cells. Interestingly, this somatic sex conversion does not depend on the male sex determinant SOX9 (Lindeman et al, 2015;Zhao et al, 2015). Similarly, in adult Drosophila females, we have found that ectopic expression of chinmo masculinizes the ovary independently of the male sex determinant Dsx M .…”

Disorders of Sex Development with Testicular Differentiation in SRY-Negative 46,XX Individuals: Clinical and Genetic Aspects

“…Although no SRY -negative 46,XX DSD patients with testicular tissue and DMRT1 overexpression have as yet been identified, increased expression of Dmrt1 in the foetal gonads of transgenic XX mice is sufficient to drive testicular differentiation and male sex development [Zhao et al, 2015].…”

The Gonadal Supporting Cell Lineage and Mammalian Sex Determination: The Differentiation of Sertoli and Granulosa Cells

“…Studies of compound mutant mice, lacking both Dmrt1 and pro-ovary genes such as Foxl2, suggest that DMRT1 acts to prevent retinoic acid (RA)-dependent reprogramming of Sertoli cells in the postnatal testis, allowing Sertoli cells to utilize RA signaling to support germ cell development (Minkina et al 2014). However, notwithstanding its role in Sertoli cell fate maintenance, recent experiments in which Dmrt1 is overexpressed in the mouse XX embryonic gonad, resulting in Sertoli cell development, indicate that the potential to respond to DMRT1 at the primary sex-determining stage still exists in the mouse genome (Lindeman et al 2015;Zhao et al 2015). The situation in humans is just as unclear.…”