Wt1 Is Required for the Regression of Müllerian Ducts in Male Mice by Inducing Wif1 and Osx Expression

In mammals, Müllerian ducts (MDs) are the precursors of the female reproductive tract which regress in males during embryonic development. Failure of MD regression results in persistent Müllerian duct syndrome (PMDS) in humans. Although several factors essential for MD regression have been identified, the underlying regulatory network remains incompletely understood. In this study, we found that the Wilms tumour gene (Wt1) was highly expressed in the MD mesenchyme of male mice. Mesenchyme-specific inactivation of Wt1 resulted in MD retention and male infertility. The expression of Amh in the testes and its receptor Amhr2 in the MD mesenchyme remained unchanged in Wt1^-/flox; Amhr2-cre male mice. Instead, the expression of Wnt inhibitory factor 1 (Wif1) and Osterix (Osx) was significantly reduced, accompanied by nuclear accumulation of β-catenin in the MD mesenchyme of Wt1-deficient mice. Further studies revealed that Wif1 and Osx were direct transcriptional targets of WT1. These findings identify Wt1 as a previously unrecognized mesenchymal regulator of MD regression by inducing Wif1 and Osx expression and provide new insights into the regulatory mechanisms underlying MD regression as well as the aetiology of reproductive tract disorders associated with WT1 mutations.