Lhx1 is required in Müllerian duct epithelium for uterine development

Abstract

The female reproductive tract organs of mammals, including the oviducts, uterus, cervix and upper vagina, are derived from the Müllerian ducts, a pair of epithelial tubes that form within the mesonephroi. The Müllerian ducts form in a rostral to caudal manner, guided by and dependent on the Wolffian ducts that have already formed. Experimental embryological studies indicate that caudal elongation of the Müllerian duct towards the urogenital sinus occurs in part by proliferation at the ductal tip. The molecular mechanisms that regulate the elongation of the Müllerian duct are currently unclear. Lhx1 encodes a LIM-homeodomain transcription factor that is essential for male and female reproductive tract development. Lhx1 is expressed in both the Wolffian and Müllerian ducts. Wolffian duct-specific knockout of Lhx1 results in degeneration of the Wolffian duct and consequently the non cell-autonomous loss of the Müllerian duct. To determine the role of Lhx1 specifically in the Müllerian duct epithelium, we performed a Müllerian duct-specific knockout study using Wnt7a-Cre mice. Loss of Lhx1 in the Müllerian duct epithelium led to a block in Müllerian duct elongation and uterine hypoplasia characterized by loss of the entire endometrium (luminal and glandular epithelium and stroma) and inner circular but not the outer longitudinal muscle layer. Time-lapse imaging and molecular analyses indicate that Lhx1 acts cell autonomously to maintain ductal progenitor cells for Müllerian duct elongation. These studies identify LHX1 as the first transcription factor that is essential in the Müllerian duct epithelial progenitor cells for female reproductive tract development. Furthermore, these genetic studies demonstrate the requirement of epithelial-mesenchymal interactions for uterine tissue compartment differentiation.

Preformed Wolffian duct regulates Müllerian duct elongation independently of canonical Wnt signaling or Lhx1 expression

“…3D). This observation is reminiscent of Müllerian duct-specific Lhx1 mutant mice, which show impaired migratory activity in the tip regions (Huang et al, 2014). However, our mutant mice retained Lhx1 expression, which was confirmed by section immunostaining (Fig.…”

“…Thus, Müllerian duct elongation was dependent on the preformed Wolffian duct. Although Lhx1 in the Wolffian and Mül-lerian ducts is essential for Müllerian duct elongation (Huang et al, 2014;Kobayashi et al, 2005), the unaltered Lhx1 expression observed in both ducts of the mutant mice indicates that loss of Lhx1 expression is not the major cause of the Müllerian duct defects.…”

“…This tip region contains proliferating progenitors that, at least partly, contribute to duct elongation (Orvis Chiga et al and Behringer, 2007). It is also reported that the tip cells exhibit dynamic morphological changes, forming and retracting multiple cytoplasmic extensions, which suggests a migratory activity of the tip cells (Huang et al, 2014). Thus, we performed histological examinations using sections of the tip region of the elongating Müllerian duct at E12.5.…”

“…Since these genes are expressed in both ducts, it is difficult to discriminate whether the absence of the Müllerian duct is caused by cell-autonomous requirements of these genes in the Müllerian duct or by non-cell-autonomous effects caused by loss of the Wolffian duct. Indeed, Müllerian duct-specific Lhx1 deletion revealed that this gene is required cell-autonomously in the Müllerian duct (Huang et al, 2014). The Müllerian duct tip is considered to contain progenitor-like cells with migratory capacity, which may be responsible for the Müllerian duct elongation.…”

Genetic association between PAX2 and mullerian duct anomalies in Han Chinese females

“…Research proves that the JNK can regulate downstream of the WNT signaling pathway, which is essential for the development of female reproductive ducts [30]. Other MDA candidate genes, such as LHX1, which also encodes for a transcription factor, participate in the period of mullerian duct formation [31]. And it is possible that PAX2 can adjust upstream of or in parallel with LHX1 and cooperatively regulate other factors in the development of the mullerian duct [22].…”