Mechanistic Drivers of Müllerian Duct Development and Differentiation Into the Oviduct

Abstract

The conduits of life; the animal oviducts and human fallopian tubes are of paramount importance for reproduction in amniotes. They connect the ovary with the uterus and are essential for fertility. They provide the appropriate environment for gamete maintenance, fertilization and preimplantation embryonic development. However, serious pathologies, such as ectopic pregnancy, malignancy and severe infections, occur in the oviducts. They can have drastic effects on fertility, and some are life-threatening. Despite the crucial importance of the oviducts in life, relatively little is known about the molecular drivers underpinning the embryonic development of their precursor structures, the Müllerian ducts, and their successive differentiation and maturation. The Müllerian ducts are simple rudimentary tubes comprised of an epithelial lumen surrounded by a mesenchymal layer. They differentiate into most of the adult female reproductive tract (FRT). The earliest sign of Müllerian duct formation is the thickening of the anterior mesonephric coelomic epithelium to form a placode of two distinct progenitor cells. It is proposed that one subset of progenitor cells undergoes partial epithelial-mesenchymal transition (pEMT), differentiating into immature Müllerian luminal cells, and another subset undergoes complete EMT to become Müllerian mesenchymal cells. These cells invaginate and proliferate forming the Müllerian ducts. Subsequently, pEMT would be reversed to generate differentiated epithelial cells lining the fully formed Müllerian lumen. The anterior Müllerian epithelial cells further specialize into the oviduct epithelial subtypes. This review highlights the key established molecular and genetic determinants of the processes involved in Müllerian duct development and the differentiation of its upper segment into oviducts. Furthermore, an extensive genome-wide survey of mouse knockout lines displaying Müllerian or oviduct phenotypes was undertaken. In addition to widely established genetic determinants of Müllerian duct development, our search has identified surprising associations between loss-of-function of several genes and high-penetrance abnormalities in the Müllerian duct and/or oviducts. Remarkably, these associations have not been investigated in any detail. Finally, we discuss future directions for research on Müllerian duct development and oviducts.

The Role of BMP Signaling in Female Reproductive System Development and Function

“…During embryogenesis, the development of the vertebrate urogenital system, which consists of the kidneys, gonads, and urinary and reproductive tracts, begins after gastrulation through the differentiation of the intermediate mesoderm (IM) [ 10 ]. The IM gives rise to two urogenital mesonephroi that compose the female (Müllerian) and male (Wolffian) primitive genital tracts [ 11 ]. The Wolffian ducts (WDs, also known as mesonephric ducts) differentiate into structures of the male reproductive tract, such as the epididymides, vas deferentia, and seminal vesicles [ 10 ].…”

Patient-derived endometrial organoids from MRKH patients: Insight in disease causing pathways

“…Müllerian duct development (Santana Gonzalez et al, 2021) is, as all developmental processes, a highly complex sequence of events that involves activation and silencing of signaling pathways, expression of transcription factors (e.g., homeobox proteins), production of cascades of growth factors which all must be precisely coordinated in space and time to arrive at the desired outcome (Mammoto and Ingber, 2010).…”

“…The uterus, both fallopian tubes, cervix and the upper third of the vagina develop from the Müllerian ducts (MD) whose development can be divided into three phases (Santana Gonzalez et al, 2021). The first phase is the specification phase when Müllerian precursor cells are specified in the surface epithelium at the cranial pole of the mesonephros (embryonic kidney).…”

“…Under the influence of several signaling cascades and factors (e.g., Anti-Müller-Hormone; AMH) the MDs regress in males, whereas lack of these hormones in females leads to regression of the WDs (Kobayashi and Behringer, 2003). After female sex determination, expression of Hox genes and retinoic acid (RA) signaling drive segmentation of the proximal and distal Müllerian duct (Santana Gonzalez et al, 2021). Each specified Müllerian segment will give rise to a different part of the female reproductive tract with the most anterior differentiating into the oviducts and the most posterior into the upper vagina.…”

Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

“…The complete process is executed in three chronological stages between developmental weeks 7 and 8 (Carnegie stage 18-23) ( Hashimoto, 2003 ). Although, this has been reviewed in detail elsewhere ( Mullen and Behringer, 2014 ; Cunha et al, 2018 ; Roly et al, 2018 ; Santana González et al, 2021 ), we provide a brief summary here. First, specific progenitors on the mesonephric coelomic epithelium ( Box 1 ) commit to a Müllerian fate (stage I) and subsequently invaginate into the mesonephric mesenchyme (stage II).…”