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Requirement of Bmpr1a for Müllerian duct regression during male sexual development

Abstract

Elimination of the developing female reproductive tract in male fetuses is an essential step in mammalian sexual differentiation1. In males, the fetal testis produces the transforming growth factor β (TGF-β) 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 vagina2. Amh induces regression by binding to a specific type II receptor (Amhr2) expressed in the mesenchyme surrounding the ductal epithelium3,4,5,6,7. Mutations in AMH or AMHR2 in humans and mice disrupt signaling, producing male pseudohermaphrodites that possess oviducts and uteri8,9,10. The type I receptor and Smad proteins that are required in vivo for Müllerian duct regression have not yet been identified11,12,13,14. 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 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.

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Figure 1: Amhr2cre knock-in mice.
Figure 2: Gross morphology and histological analysis of Bmpr1a conditional mutant males.
Figure 3: Expression analysis of Amh and Amhr2.

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Acknowledgements

We thank S. Pfaff for the IRES–cre plasmid, L. Li for help in the construction of the cre targeting vector, A. Bradley for embryonic stem and STO feeder cells, J.M. Deng for assistance with tissue culture, P. Soriano for R26R mice and Y. Wang for help with histology. This work was supported by grants from the US National Institutes of Health and the Barnts Family to R.R.B. S.P.J. is supported by a fellowship from the Lalor Foundation. DNA sequencing and veterinary resources were supported by the US National Institutes of Health Cancer Center Support (Core) Grant.

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Correspondence to Richard R. Behringer.

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Jamin, S., Arango, N., Mishina, Y. et al. Requirement of Bmpr1a for Müllerian duct regression during male sexual development. Nat Genet 32, 408–410 (2002). https://doi.org/10.1038/ng1003

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