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Functional Redundancy of TGF-beta Family Type I Receptors and Receptor-Smads in Mediating Anti-Müllerian Hormone-Induced Müllerian Duct Regression in the Mouse¹

Program in Genes and Development,⁴ Graduate School of Biomedical Sciences at Houston, The University of Texas, Houston, Texas 77030 Department of Molecular Genetics,⁵ The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 INSERM U782,⁶ University of Paris 11, 92140 Clamart, France Department of Biology,⁷ The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region, People's Republic of China Laboratory of Reproductive and Developmental Toxicology,⁸ National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709 The Sabin Research Institute,⁹ University of Southern California, Los Angeles, California 90027 Dan L. Duncan Cancer Center and the Department of Molecular and Cellular Biology,¹⁰ Baylor College of Medicine, Houston, Texas 77030 Laboratory of Cell Regulation and Carcinogenesis,¹¹ National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 VIB Department of Molecular and Developmental Genetics, and the Department of Human Genetics,¹² Katholieke Universiteit Leuven, 3000 Leuven, Belgium Institute of Biosciences and Technology,¹³ Texas A&M University, Houston, Texas 77030

ABSTRACT

Amniotes, regardless of genetic sex, develop two sets of genital ducts: the Wolffian and Müllerian ducts. For normal sexual development to occur, one duct must differentiate into its corresponding organs, and the other must regress. In mammals, the Wolffian duct differentiates into the male reproductive tract, mainly the vasa deferentia, epididymides, and seminal vesicles, whereas the Müllerian duct develops into the four components of the female reproductive tract, the oviducts, uterus, cervix, and upper third of the vagina. In males, the fetal Leydig cells produce testosterone, which stimulates the differentiation of the Wolffian duct, whereas the Sertoli cells of the fetal testes express anti-Müllerian hormone, which activates the regression of the Müllerian duct. Anti-Müllerian hormone is a member of the transforming growth factor-beta (TGF-beta) family of secreted signaling molecules and has been shown to signal through the BMP pathway. It binds to its type II receptor, anti-Müllerian hormone receptor 2 (AMHR2), in the Müllerian duct mesenchyme and through an unknown mechanism(s); the mesenchyme induces the regression of the Müllerian duct mesoepithelium. Using tissue-specific gene inactivation with an Amhr2-Cre allele, we have determined that two TGF-beta type I receptors (Acvr1 and Bmpr1a) and all three BMP receptor-Smads (Smad1, Smad5, and Smad8) function redundantly in transducing the anti-Müllerian hormone signal required for Müllerian duct regression. Loss of these genes in the Müllerian duct mesenchyme results in male infertility due to retention of Müllerian duct derivatives in an otherwise virilized male.

AMH, AMHR2, female reproductive tract, male reproductive tract, Müllerian ducts, signal transduction, Wolffian duct

³These authors contributed equally to this work.

¹Supported by National Institutes of Health (NIH) grant HD30284 and the Ben F. Love Endowment to R.R.B., NIH DE/HD12324 to J.F.M., and NIH DEO13085 to V.M.K. G.D.O. was supported by the National Cancer Institute CA09299 Training Program in the Molecular Genetics of Cancer. S.P.J. was supported in part by a Lalor Foundation Postdoctoral Fellowship.

Correspondence: ²FAX: 713 834 6339; e-mail: rrb{at}mdanderson.org