Requirement of Bmpr1a for Mullerian duct regression during male sexual development

Elimination of the developing female reproductive tract in male fetuses is an essential step in mammalian sexual differentiation(1). In males, the fetal testis produces the transforming growth factor beta (TGF-beta) family member anti-Mullerian hormone (Amh, also known as Mullerian-inhibiting substance (Mis)), which causes regression of the Mullerian ducts, the primordia of the oviducts, uterus and upper vagina(2). Amh induces regression by binding to a specific type II receptor (Amhr2) expressed in the mesenchyme surrounding the ductal epithelium(3-7). Mutations in AMH or AMHR2 in humans and mice disrupt signaling, producing male pseudohermaphrodites that possess oviducts and uteri(8-10). The type I receptor and Smad proteins that are required in vivo for Mullerian duct regression have not yet been identified(11-14). Here we show that targeted disruption of the widely expressed type I bone morphogenetic protein (BMP) receptor Bmpr1a (also known as Alk3) in the mesenchymal cells of the Mullerian ducts leads to retention of oviducts and uteri in males. These results identify Bmpr1a as a type I receptor for Amh-induced regression of Mullerian ducts. Because Bmpr1a is evolutionarily conserved, these findings indicate that a component of the BMP signaling pathway has been co-opted during evolution for male sexual development in amniotes.