Non-canonical WNT5a regulates Epithelial-to-Mesenchymal Transition in the mouse ovarian surface epithelium

Atefeh Abedini,Derek Boerboom,Barbara C Vanderhyden,Céline Sayed,Lauren E Carter

doi:10.1038/s41598-020-66559-9

Atefeh Abedini, Derek Boerboom + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-66559-9

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Abstract

The ovarian surface epithelium (OSE) is a monolayer that covers the ovarian surface and is involved in ovulation by rupturing and enabling release of a mature oocyte and by repairing the wound after ovulation. Epithelial-to-mesenchymal transition (EMT) is a mechanism that may promote wound healing after ovulation. While this process is poorly understood in the OSE, in other tissues wound repair is known to be under the control of the local microenvironment and different growth factors such as the WNT signaling pathway. Among WNT family members, WNT4 and WNT5a are expressed in the OSE and are critical for the ovulatory process. The objective of this study was to determine the potential roles of WNT4 and WNT5a in regulating the OSE layer. Using primary cultures of mouse OSE cells, we found WNT5a, but not WNT4, promotes EMT through a non-canonical Ca2+-dependent pathway, up-regulating the expression of Vimentin and CD44, enhancing cell migration, and inhibiting the CTNNB1 pathway and proliferation. We conclude that WNT5a is a stimulator of the EMT in OSE cells, and acts by suppressing canonical WNT signaling activity and inducing the non-canonical Ca2+ pathway.

Highlights

The ovarian surface epithelium (OSE) consists of a layer of epithelial cells that undergoes repetitive regeneration after ovulation at each reproductive cycle in order to heal the surface of the ovary[1,2]
Α-SMA and Vimentin staining of the OSE cells treated with WNT5a indicated cells are transitioning into a more mesenchymal cell phenotype characterized by a larger cell size, spreading morphology and less cell-cell contact (Fig. 1A–C)
Various studies have shown that the local microenvironment, including the extracellular matrix, inflammatory molecules and growth factors (TGFβ and EGF) can all contribute to epithelial-mesenchymal transition (EMT) in the OSE29–31

Summary

Introduction

The ovarian surface epithelium (OSE) consists of a layer of epithelial cells that undergoes repetitive regeneration after ovulation at each reproductive cycle in order to heal the surface of the ovary[1,2]. The WNT signaling pathway plays an essential role in the regulation of EMT, cell proliferation, as well as differentiation and migration in a wide range of tissues including the ovary[13]. The canonical WNT signaling pathway is involved in the activation of CTNNB1 (non-phosphorylated form) and its translocation to the nucleus where it is associated with transcription factors and stimulates target gene expression[15]. Deregulation of the WNT/Ca2+ signaling pathway has been shown to mediate cytoskeleton rearrangements, cellular proliferation, cellular motility and EMT in cancer progression[16]. In the WNT/JNK signaling pathway, activation of a number of small GTP proteins, including c-Jun N-terminal kinase (JNK) can regulate different cellular processes such as cell polarity and migration[17]. Farookhi’s group determined CTNNB1 is localized to the cell membranes of OSE cells and suggests a role in cell adhesion in this cell type[20,22]

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