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The cell biology and molecular genetics of Müllerian duct development

Advanced Review

Zahida Yesmin Roly, Brendan Backhouse, Andrew Cutting, Tiong Yang Tan, Andrew H. Sinclair, Katie L. Ayers, Andrew T. Major, Craig A. Smith

Published Online: Jan 19 2018

DOI: 10.1002/wdev.310

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The Müllerian ducts are part of the embryonic urogenital system. They give rise to mature structures that serve a critical function in the transport and development of the oocyte and/or embryo. In most vertebrates, both sexes initially develop Müllerian ducts during embryogenesis, but they regress in males under the influence of testis‐derived Anti‐Müllerian Hormone (AMH). A number of regulatory factors have been shown to be essential for proper duct development, including Bmp and Wnt signaling molecules, together with homeodomain transcription factors such as PAX2 and LIM1. Later in development, the fate of the ducts diverges between males and females and is regulated by AMH and Wnt signaling molecules (duct regression in males) and Hox genes (duct patterning in females). Most of the genes and molecular pathways known to be involved in Müllerian duct development have been elucidated through animal models, namely, the mouse and chicken. In addition, genetic analysis of humans with reproductive tract disorders has further defined molecular mechanisms of duct formation and differentiation. However, despite our current understanding of Müllerian duct development, some questions remain to be answered at the molecular genetic level. This article is categorized under: Early Embryonic Development > Development to the Basic Body Plan

Schematic view of urogenital system development in humans. (a) At the undifferentiated phase, the gonads develop on the ventromedial surface of the mesonephric kidneys. Two pairs of ducts form, the Wolffian (mesonephric) ducts and the Müllerian (paramesonephric) ducts. (b) Later in development, the action of AMH in males leads to Müllerian duct regression, while testosterone stimulates differentiation of the Wolffian ducts into male structures (vas deferens, epididymis and seminal vesicles). In the female, lack of these hormones leads to Müllerian duct differentiation into female structures (fallopian tubes) and regression of the Wolffian ducts. The mesonephros regresses in both sexes. (c) By birth, the paired testes and associated male ducts descend into the scrotum. In females, the fallopian tubes fuse caudally, giving rise to the uterus and upper portion of the vagina. (Bladder omitted in the female for clarity)

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HOX gene expression domains and patterning of the mammalian female reproductive tract. A subset of the HOXA cluster is expressed in a linear series along the length of the embryonic Müllerian duct (mouse studies). These expression domains correlate with subsequent regional differentiation of the ducts into fallopian tubes, fused uterus, cervix and vagina. (Reprinted with permission from Lynch et al. (). Copyright 2004 The Royal Society) Additional data from Du and Taylor ()

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Fate of the Müllerian duct in males and females. In both sexes, PAX2 and LIM1 are expressed during duct specification and elongation. These genes directly or indirectly regulate the expression of WNT7A in the Müllerian duct epithelium (MDE). WNT7A can activate expression of AMHR2 (AMH type II receptor) in the Müllerian duct mesenchyme (MDM). WNT4 is also expressed in the MDM. The AMH type I receptors (ALK2/3/6) also play a role in AMH signaling. Only in males, AMH secreted by the developing testis binds to AMHR2 to recruit type I receptors, and initiate intracellular Smad signaling, leading to activation of metalloproteases, apoptosis and duct regression. In females, lack of foetal AMH allows further duct development rather than regression. WNT7A can activate Hox genes involved in duct differentiation

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Genetic regulation of Müllerian duct (MD) specification, invagination and elongation, based on data from chicken and mouse embryos. (Reprinted with permission from Atsuta and Takahashi (). Copyright 2016 The Company of Biologists Ltd) Bmp signaling induces PAX2 expression in the cranial coelomic epithelium (orange) adjacent to the Wolffian duct (WD). BMP/PAX2 then activate Fgf signaling (blue) in the Müllerian surface epithelium (MSE). This then triggers LIM1 expression in the MSE (purple). Cells from the MSE (and possibly the mesonephros) give rise to the underlying Müllerian duct mesenchyme (MDM) which requires WNT4 expression (green). PAX2/LIM1‐positive MSE cells undergo invagination to from the Müllerian duct epithelium (MDE). WNT9B derived from the WD is required for duct elongation (red)

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The widely accepted three phase model of Müllerian duct development in vertebrate embryos, based on data from mouse and chicken. Only one side of the urogenital system is shown (dorsal view). (a) The Müllerian duct forms in a craniocaudal direction. During phase 1 (specification), Müllerian precursor cells are specified in the surface epithelium (Müllerian surface epithelium, MSE) at the cranial pole of the mesonephros (embryonic kidney). During phase 2 (invagination), these cells become “mesoepithelial” and invaginate in a caudal direction, moving between mesenchyme (the Müllerian duct mesenchyme, MDM). During phase 3, invaginating cells form the Müllerian Duct Epithelium (MDE) make contract with the Wolffian duct and the duct elongates caudally, eventually fusing with the urogenital sinus. (b) Müllerian invagination and elongation in the chicken embryo, stained for expression of the duct marker, Lim1. (c) Schematic cross‐section shows Wolffian and Müllerian ducts in the transverse plane. The Müllerian duct has three components, from the outer to inner surface: the MSE, the MDM and the MDE. (d) Cross section of Lim1‐expressing chicken stage 28 Müllerian duct

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