β-catenin/Tcf-signaling appears to establish the murine ovarian surface epithelium (OSE) and remains active in selected postnatal OSE cells

Abstract

BackgroundWnts are a family of secreted signaling molecules involved in a number of developmental processes including the establishment of cell fate, polarity and proliferation. Recent studies also implicate wnts in epithelial adult stem cell maintenance, renewal and differentiation. Wnts transduce their signal through one of three signaling pathways. The best studied, the wnt/β-catenin pathway, leads to an increase in intracellular β-catenin which acts as a co-transcription factor with members of the Tcf/Lef family. A number of wnts are expressed in the ovary, specifically in the membrana granulosa and ovarian surface epithelium (OSE). We investigated the spatio-temporal pattern of β-catenin/Tcf expression in the OSE using responsive transgenic (TopGal) mice.ResultsThe generated β-galactosidase response (lacZ+) identified the cell population that overlies the medio-lateral surface of the indifferent gonad at embryonic day (E) 11.5. From E12.5 onwards, lacZ expression disappeared in cells covering the testis but remained with ovary development. LacZ+ OSE cells were present throughout embryonic and postnatal ovarian development but demonstrated an age-dependent decrease to a small proportion when animals were weaned and remained at this proportion with aging. Flow cytometric (FACS) and ovarian section analyses showed lacZ+ cells constitute approximately 20% of OSE in postnatal (day 1) mice which fell to 8% in 5 day-old animals while in prepubertal and adult mice this accounted for only 0.2% of OSE. Apoptosis was undetected in OSE of neonates and β-catenin/Tcf-signaling cells were proliferative in neonatal mice indicating that neither cell death nor proliferation failure was responsible for the proportion alteration. It appeared that lacZ+ cells give rise to lacZ- cells and this was confirmed in cell cultures. The DNA-binding dye DyeCycle Violet was used to set up the side population (SP) assay aimed at identifying subpopulations of OSE cells with chemoresistance phenotype associated with ABCG2 transporter activity. FACS analysis revealed lacZ+ cells exhibit cytoprotective mechanisms as indicated by enrichment within the SP.ConclusionsThe study raises the possibility that wnt/β-catenin-signaling cells constitute a progenitor cell population and could underlie the pronounced histopathology observed for human ovarian cancer.

Activation of the Canonical WNT Signaling Pathway Promotes Ovarian Surface Epithelial Proliferation Without Inducing β‐Catenin/Tcf‐Mediated Reporter Expression

“…In the embryonic mouse gonad, β‐catenin is localized to OSE cell membrane by E12.5 (Bernard et al, ). This developmental stage corresponds to the stage when the female gonad is overlaid by lacZ + cells (Usongo and Farookhi, ). To reconcile this observation, we speculate that the high membranous staining of β‐catenin may mask any nuclear detection.…”

“…It is also possible that nuclear accumulation of β‐catenin may be a dynamic process and as such difficult to localize. The expression of non‐canonical Wnts within the OSE (Usongo and Farookhi, ) may rapidly redirect any nuclear β‐catenin to the cell membrane, as has been the case with Wnt 4 expression (Bernard et al, ).…”

“…In a previous study, we demonstrated that β‐catenin/Tcf‐signaling (lacZ + ) OSE cells overlie the differentiating ovary but decreased to a small proportion when mice were weaned (Usongo and Farookhi, ). Here, we show that β‐catenin is localized to the membrane of the ovarian epithelium during postnatal development.…”

Tissue transglutaminase regulates β‐catenin signaling through a c‐Src‐dependent mechanism

“…Other reports link Wnt‐β‐catenin signaling to recurrent chemoresistant OC (23, 24) and Wnt‐7A overexpression correlates with poor clinical outcome of serous OC (25). Active β‐catenin/TCF signaling has been identified in progenitor ovarian surface epithelial cells and in OC‐initiating (stem) cells (23, 26), supporting a role for this pathway in ovarian tumor initiation and persistence.…”

ABCG2 is not able to catalyze glutathione efflux and does not contribute to GSH-dependent collateral sensitivity

“…Some signaling pathways, such as notch (Battacharya et al, 2007), CXCL12-CXCR4 (Katoh and Katoh, 2010), Oct4-TCL1-AKT (Wang et al, 2010), PTEN/P13K/Akt (Li et al, 2011), β-catenin/Tcf (Usongo and Farookhi, 2012), AhR (Dubrovska et al, 2012), and HIF-2α with TGF-β/Smad2 (Cui et al, 2013) are related to the ABCG2 status as a marker of stem cells or stem-like cancer cells. Nrf2, a critical transcription factor that regulates antioxidants, detoxification enzymes, and drug efflux proteins in response to oxidative stress (Hong et al, 2010; Singh et al, 2010; Chen et al, 2012; Zhang et al, 2012; Ishikawa et al, 2013; Shelton and Jaiswal, 2013), may provide a link between cellular GSH homeostasis and ABCG2 expression.…”