Revisiting old vaginal topics: conversion of the Mllerian vagina and origin of the "sinus" vagina

Abstract

Vaginal development has been a longstanding controversy, which hampers studies on vaginal diseases as well as cervical and uterine diseases. Most concerns center on: why is the vaginal epithelium different from the uterine epithelium; and where does the vagina originate from? It is commonly held that the rodent vagina has a dual origin: the cranial part is derived from the Mullerian duct (Mullerian vagina) and the caudal part derived from the urogenital sinus (sinus vagina). This concept was deduced from morphological observations. However, it cannot explain the difference between the Mullerian vagina and the uterus. Moreover, accumulating new data from genetic and molecular studies contradicts the urogenital sinus origin of the sinus vagina. The present review summarizes previous morphological observations and new findings from genetic and molecular studies, and addresses molecular mechanisms underlying the origin and organogenesis of the vagina in rodents. It provides evidence to show that the whole vagina is derived the Mullerian duct. BMP4 reshapes the intermediate mesoderm-derived Mullerian duct into the vaginal primordium. The latter thus exhibits different features from the uterus, including the stratified squamous epithelium and insensitivity to anti-Mullerian hormone. The sinus vagina is formed by extrinsic BMP4-mediated caudal extension of the Mullerian duct. The present review thus shows how a century of controversy over the origin and organogenesis of the vagina has been resolved. This new understanding will provide additional insight into genetic diseases and tumors of the female reproductive tract.

Genetic Syndromes and Genes Involved in the Development of the Female Reproductive Tract: A Possible Role for Gene Therapy

“…It has been a commonly held belief (based on murine studies) that the vagina is of dual origin. The Müllerian ducts form the cranial portion, the so-called "Müllerian vagina", while the urogenital sinus is the origin of the caudal portion, the so-called "sinus vagina" as reviewed by Cai [38] and Kurita [39]. However, based on murine studies Cai [38] concluded that the recent evidence supports a Müllerian duct origin for the entire vagina.…”

“…The Müllerian ducts form the cranial portion, the so-called "Müllerian vagina", while the urogenital sinus is the origin of the caudal portion, the so-called "sinus vagina" as reviewed by Cai [38] and Kurita [39]. However, based on murine studies Cai [38] concluded that the recent evidence supports a Müllerian duct origin for the entire vagina. More recent cell lineage tracing studies in humans have demonstrated that the Wolffian ducts, Müllerian ducts, and the urogenital sinus all play integral roles during the formation of the human vagina in a caudal to cranial manner [40].…”

“…In murine models, Hoxa13 and bone morphogenetic protein 4 (BMP4) appear to be strongly expressed in the Müllerian vagina but not in the uterus [26,38,41]. In these murine models, Hoxa13 has been shown to up regulate BMP4 [42].…”

“…It has also been noted that Wnt7a subsequently disappears in the vagina when BMP4 appears [46]. It is believed that BMP4 is responsible for desensitizing the mesoderm to anti-Müllerian hormone and inducing a stratified squamous cell in the vagina [38]. Importantly, Wnt7a drives the expression of anti-Müllerian hormone receptor type II, which is responsible for Müllerian regression [47].…”

“…This influence occurs before Hoxa13 is present. At this point in development, Sonic Hedgehog (SHH) has been shown to be the activator of BMP4 guiding the Müllerian ducts caudally and playing a key role in the partitioning the cloaca [38]. Knockout animal models of SHH have shown improper partitioning of the cloaca [53].…”