Author:

Keywords:

amh, amhr2, female reproductive tract, male reproductive tract, mullerian ducts, signal transduction, wolffian duct, sexual development, conditional knockout, signaling pathway, ii receptor, mice, expression, gene, cell, mechanisms, Science & Technology, Life Sciences & Biomedicine, Reproductive Biology, AMH, AMHR2, Mullerian ducts, Wolffian duct, WOLFFIAN DUCT, CONDITIONAL KNOCKOUT, SIGNALING PATHWAY, MICE, CELL, MECHANISMS, EXPRESSION, MEMBRANE, GENE, ALK2, Activin Receptors, Type I, Animals, Anti-Mullerian Hormone, Bone Morphogenetic Protein Receptors, Type I, Female, Infertility, Male, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Models, Biological, Mullerian Ducts, Pregnancy, Signal Transduction, Smad1 Protein, Smad5 Protein, Smad8 Protein, 06 Biological Sciences, 11 Medical and Health Sciences, Obstetrics & Reproductive Medicine, 3003 Animal production, 3109 Zoology, 3215 Reproductive medicine

Abstract:

Amniotes, regardless of genetic sex, develop two sets of genital ducts: the Wolffian and Mulerian 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 Mullerian 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-Mullerian hormone, which activates the regression of the Mullerian duct. Anti-Mullerian 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-Mullerian hormone receptor 2 (AMHR2), in the Mullerian duct mesenchyme and through an unknown mechanism(s); the mesenchyme induces the regression of the Mullerian duct mesoepithelium. Using tissue-specific gene inactivation with an Amhr2-Cre allele, we have determined that two TGF-beta type 1 receptors (Acvr1 and Bmpr1a) and all three BMP receptor-Smads (Smad1, Smad5, and Smad8) function redundantly in transducing the anti-Mullerian hormone signal required for Mullerian duct regression. Loss of these genes in the Mullerian duct mesenchyme results in male infertility due to retention of Mullerian duct derivatives in an otherwise virilized male.