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Requirement of Bmpr1a for Müllerian duct regression during male sexual development
Soazik P Jamin1, Nelson A Arango, Yuji Mishina
1Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
Elimination of the developing female reproductive tract in male fetuses is an essential step in mammalian sexual differentiation. In males, the fetal testis produces the transforming growth factor beta (TGF-beta) family member anti-Müllerian hormone (Amh, also known as Müllerian-inhibiting substance (Mis)), which causes regression of the Müllerian ducts, the primordia of the oviducts, uterus and upper vagina. Amh induces regression by binding to a specific type II receptor (Amhr2) expressed in the mesenchyme surrounding the ductal epithelium. Mutations in AMH or AMHR2 in humans and mice disrupt signaling, producing male pseudohermaphrodites that possess oviducts and uteri. The type I receptor and Smad proteins that are required in vivo for Müllerian duct regression have not yet been identified. 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 Müllerian ducts leads to retention of oviducts and uteri in males. These results identify Bmpr1a as a type I receptor for Amh-induced regression of Müllerian 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.
Insights
In male mammals, the bone morphogenetic protein receptor type 1A (Bmpr1a) is crucial for Müllerian duct regression, ensuring proper sexual differentiation. Its disruption results in the retention of female reproductive organs in males.
Area of Science:
- Developmental Biology
- Genetics
- Endocrinology
Background:
- Mammalian sexual differentiation requires the regression of female reproductive structures in males.
- Anti-Müllerian hormone (Amh) from fetal testes induces Müllerian duct regression via its type II receptor (Amhr2).
- The specific type I receptor mediating Amh signaling for Müllerian duct regression remained unidentified.
Purpose of the Study:
- To identify the type I receptor essential for Amh-mediated Müllerian duct regression in male fetuses.
- To elucidate the role of Bone Morphogenetic Protein (BMP) signaling in male sexual development.
Main Methods:
- Targeted genetic disruption of the Bmpr1a gene in mesenchymal cells of the developing Müllerian ducts in a mouse model.
- Analysis of reproductive tract development in genetically modified male fetuses.
Main Results:
- Disruption of Bmpr1a in Müllerian duct mesenchyme led to the retention of oviducts and uteri in male fetuses.
- This identifies Bmpr1a as the critical type I receptor for Amh signaling.
- Bmpr1a is essential for male sexual differentiation by mediating Müllerian duct regression.
Conclusions:
- Bone morphogenetic protein receptor type 1A (Bmpr1a) is the indispensable type I receptor for anti-Müllerian hormone (Amh)-induced Müllerian duct regression.
- The BMP signaling pathway has been evolutionarily adapted for male sexual development in amniotes.
- Findings identify a key molecular mechanism in mammalian sexual differentiation.