Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract

Abstract

The murine female reproductive tract differentiates along the anteroposterior axis during postnatal development. This process is marked by the emergence of distinct cell types in the oviduct, uterus, cervix and vagina and is dependent upon specific mesenchymal-epithelial interactions as demonstrated by earlier heterografting experiments. Members of the Wnt family of signaling molecules have been recently identified in this system and an early functional role in reproductive tract development has been demonstrated. Mice were generated using ES-mediated homologous recombination for the Wnt-7a gene (Parr, B. A. and McMahon, A. P. (1995) Nature 374, 350–353). Since Wnt-7a is expressed in the female reproductive tract, we examined the developmental consequences of lack of Wnt-7a in the female reproductive tract. We observe that the oviduct lacks a clear demarcation from the anterior uterus, and acquires several cellular and molecular characteristics of the uterine horn. The uterus acquires cellular and molecular characteristics that represent an intermediate state between normal uterus and vagina. Normal vaginas have stratified epithelium and normal uteri have simple columnar epithelium, however, mutant uteri have stratified epithelium. Additionally, Wnt-7a mutant uteri do not form glands. The changes observed in the oviduct and uterus are accompanied by a postnatal loss of hoxa-10 and hoxa-11 expression, revealing that Wnt-7a is not required for early hoxa gene expression, but is required for maintenance of expression. These clustered hox genes have been shown to play a role in anteroposterior patterning in the female reproductive tract. In addition to this global posterior shift in the female reproductive tract, we note that the uterine smooth muscle is disorganized, indicating development along the radial axis is affected. Changes in the boundaries and levels of other Wnt genes are detectable at birth, prior to changes in morphologies. These results suggest that a mechanism whereby Wnt-7a signaling from the epithelium maintains the molecular and morphological boundaries of distinct cellular populations along the anteroposterior and radial axes of the female reproductive tract.

DSCAM-AS1 Long Non-Coding RNA Exerts Oncogenic Functions in Endometrial Adenocarcinoma via Activation of a Tumor-Promoting Transcriptome Profile

“…The fact that we did not observe any sign of TRAIL-triggered apoptosis might be explained by the missing expression of death receptor 4 (DR4) in HEC-1B cells, since loss or down-regulation of DR4 is known to desensitize cells to TRAIL-triggered cell death. WNT7a gene (7.15-fold up-regulated) codes for a secreted ligand of the wingless (WNT) family, which not only guides the development of the anterior-posterior axis in the female reproductive tract but also plays a critical role in uterine smooth muscle pattering and maintenance of adult uterine function [ 61 ]. With regard to cancer, WNT7a seems to have pleiotropic functions.…”

Modeling Endometrium Biology and Disease

“…WNT secreted protein Reduction in endometrial glands [29] Wnt5a WNT secreted protein Absence of endometrial glands [30] Wnt7a WNT secreted protein Absence of endometrial glands [18] Ctnnb1 Signaling protein adhesion Absence of endometrial glands [31,32] Lef1 TF Absence of endometrial glands [33] Timp1 ECM modulator Accelerated gland formation [34,35]…”

“…Hoxa9 is found in the oviduct, Hoxa10 in the uterus, Hoxa11 in the uterus and cervix, and Hoxa13 in the cervix and upper vagina [ 42 ]. Maintenance of Hoxa10 and Hoxa11 expression during FRT development is regulated through WNT7A, of which the expression occurs throughout the entire MD [ 18 ]. Only after birth, Wnt7a expression is restricted to the epithelium of the oviduct and uterus.…”

“…Only after birth, Wnt7a expression is restricted to the epithelium of the oviduct and uterus. Loss of Wnt7a in the differentiating MD results in partial homeotic transformation of oviduct to uterus and of uterus to vagina [ 18 , 19 ] ( Table 1 ). During morphogenesis, HOXA10 is not only required for proper patterning of the FRT as mutants show homeotic transformation of part (1/4th) of the proximal uterus into oviduct with fallopian tube morphology, but also later in the mature uterus for successful embryo implantation.…”

“…When fetal Wnt5a null FRT was xenografted into adult mice, postnatal development was normal, except for the absence of endometrial glands. WNT7A is also essential for gland formation, as Wnt7a mutant mice do not have endometrial glands [ 18 ]. Defective uterine gland development is also observed in mutants affecting the WNT downstream pathway, in particular the canonical WNT signal transmitter ß-catenin (cadherin-associated protein ß1, Ctnnb1 ) and the mediating transcription factor lymphoid enhancer binding factor-1 (LEF1).…”