Mechanistic Drivers of Müllerian Duct Development and Differentiation Into the Oviduct.

Laura Santana Gonzalez,Mara Artibani,Abdulkhaliq Alsaadi,Ioanna A Rota,Matteo Morotti,Nina Wietek,Ahmed A Ahmed,Ashwag Albukhari,Tatjana Sauka-Spengler,Zhiyuan Hu

doi:10.3389/fcell.2021.605301

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.

Highlights

The paramesonephric or Müllerian ducts are the embryonic anlagen of most of the female reproductive tract
The scope of this review focuses on the cellular mechanisms and genetic/molecular entities involved in Müllerian development and successive differentiation into oviducts
This deletion is the cause of a case of uterine fusion anomaly (Ledig et al, 2018). These are typical examples of mutations with incomplete penetrance and variable expressivity, which suggests that additional genetic and non-genetic factors control full penetrance in the human phenotypes. This deletion includes the gene HNF1β, a POU homeodomain transcription factor expressed in the mesoepithelial progenitors during mouse Müllerian duct development as well as in the adult oviducts and uterine horns

Summary

Introduction

The paramesonephric or Müllerian ducts are the embryonic anlagen of most of the female reproductive tract. Mesoepithelial progenitors sequentially upregulate the embryonic transcription factors Pax2, Emx2, and Lim1 ( Pax8, Pbx1, Hnf1b, and Wnt7a in mouse), while mesenchymal precursors express markers such as Wnt4 (and Dmrt1 in chicken) (Jacob et al, 1999; Vainio et al, 1999; Schnabel et al, 2003; Kobayashi et al, 2004; Guioli et al, 2007; Orvis and Behringer, 2007; Lokmane et al, 2010; Ayers et al, 2015; Atsuta and Takahashi, 2016; Prunskaite-Hyyryläinen et al, 2016).

Results

Conclusion