Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice

Abstract

The sexual differentiation paradigm contends that the female pattern of the reproductive system is established by default, as the male reproductive tracts (Wolffian ducts) in the female degenerate due to a lack of androgen. Here, we discovered that female mouse embryos lacking Coup-tfII in the Wolffian duct mesenchyme became intersex that contained both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced p-ERK signaling in Wolffian duct epithelium was responsible for the retention in an androgen-independent manner. These results support our hypothesis that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium crosstalk responsible for Wolffian duct maintenance.

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

“…However, at the initiation of ovarian development, FOXL2 and COUP-TF2 appear to be mutually exclusive at the cellular level, with distinct location in the somatic and stromal cells of the fetal ovary, respectively [81]. COUP-TF2 is expressed at the same time as WT1 in early gonadal embryogenesis [83] and it regulates negatively the expression of the pro-testis Sox9 gene in the osteogenic mesenchyme. Hence, it is hypothesized that testis development in these individuals with NR2F2 mutations is driven by SOX9 activation via WT1 [82].…”

“…In addition, COUP-TF2 is responsible for eliminating the male reproductive tract in female embryos through its activation in the Wolffian duct mesenchyme, independently of the absence of androgens [83]. In 46,XY individuals, COUP-TF2 is expressed in Leydig cells from the adult population and is known to bind to DNA sequences similar to NR5A1 elements.…”

Osterixfunctions downstream of anti-Müllerian hormone signaling to regulate Müllerian duct regression

“…Reproductive tract differentiation in amniotes is unique because initially both WD and MD are generated in the embryo independent of genetic sex. Sex-specific signaling results in loss of the WD in females and regression of the MD in males (1,2). MD regression requires transforming growth factor-β family member anti-Müllerian hormone (AMH) secreted from the Sertoli cells of the fetal testis and its type 1 and 2 receptors present in MD mesenchyme (3)(4)(5)(6)(7).…”

Osterixfunctions downstream of anti-Müllerian hormone signaling to regulate Müllerian duct regression

“…Reproductive tract differentiation in amniotes is unique because initially both WD and MD are generated in the embryo independent of genetic sex. Sex-specific signaling results in loss of the WD in females and regression of the MD in males (1,2). MD regression requires transforming growth factor-β family member AMH secreted from the Sertoli cells of the fetal testis and its type 1 and 2 receptors present in MD mesenchyme (3)(4)(5)(6)(7).…”