Molecular mechanisms of hormone-mediated Mullerian duct regression: involvement of beta-catenin

Regression of the Mullerian duct in the male embryo is one unequivocal effe ct of anti-Mullerian hormone, a glycoprotein secreted by the Sertoli cells of the testis, This hormone induces ductal epithelial regression through a paracrine mechanism originating in periductal mesenchyme, To probe the mech anisms of action of anti-Mullerian hormone, we have studied the sequence of cellular and molecular events involved in duct regression. Studies were pe rformed in male rat embryos and in transgenic mice overexpressing or lackin g anti-Mullerian hormone, both in vivo and in vitro. Anti-Mullerian hormone causes regression of the cranial part of the Mulleri an duct whereas it continues to grow caudally. Our work shows that this pat tern of regression is correlated with a cranial to caudal gradient of anti- Mullerian hormone receptor protein, followed by a wave of apoptosis spreadi ng along the Mullerian duct as its progresses caudally, Apoptosis is also i nduced by AMH in female Mullerian duct in vitro. Furthermore, apoptotic ind exes are increased in Mullerian epithelium of transgenic mice of both sexes overexpressing the human anti-Mullerian hormone gene, exhibiting a positiv e correlation with serum hormone concentration. Inversely, apoptosis is red uced in male anti-Mullerian hormone-deficient mice. We also show that apopt osis is a decisive but not sufficient process, and that epitheliomesenchyma l transformation is an important event of Mullerian regression. The most striking result of this study is that anti-Mullerian hormone actio n in peri-Mullerian mesenchyme leads in vivo and in vitro to an accumulatio n of cytoplasmic beta-catenin, The co-localization of beta-catenin with lym phoid enhancer factor 1 in the nucleus of peri-Mullerian mesenchymal cells, demonstrated in primary culture, suggests that overexpressed beta-catenin in association with lymphoid enhancer factor 1 may alter transcription of t arget genes and may lead to changes in mesenchymal gene expression and cell fate during Mullerian duct regression. To our knowledge, this is the first report that beta-catenin, known for its role in Wnt signaling, may mediate anti-Mullerian hormone action.