Down-regulation of transcription factor OVOL2 contributes to epithelial-mesenchymal transition in a noninvasive type of trophoblast implantation to the maternal endometrium

Embryo implantation into the uterine endometrium is required for pregnancy establishment in most mammals. By using global expression analysis, we investigated the molecules that are related to epithelial- mesenchymal transition (EMT) in noninvasive bovine trophoblasts and found that the transcription factor, ovo-like zinc finger 2 (OVOL2), which is essential for mesenchymal-epithelial transition in various cancers, was downregulated after trophoblast attachment to the endometrial epitheliumin utero. In cultured bovine trophoblast cells, OVOL2 down-regulation occurred onlywhen cells were allowed to attach to bovine endometrial epithelial cells via the TEAD3/YAP signaling pathway. This resulted in the up-regulation of the EMT-associated transcription factors, ZEB1 and SNAI2, and the mesenchymal cell markers, N-cadherin (CDH2) and vimentin (VIM), whereas epithelial cellmarker, E-cadherin (CDH1), was down-regulated. In contrast, OVOL2 overexpression in bovine trophoblast cells exhibited a decrease in ZEB1 transcripts and an increase in E-cadherin. These observations revealed that ovo-like protein (OVOL)2 down-regulation occurred concurrently with conceptus implantation into the uterine endometriumvia theYAP/TEAD3 signaling pathway, and suggest that the down-regulation ofOVOL2 expression contributes to the up-regulation of EMT-related transcription factor expression,which enablesEMTprogression in the noninvasive bovine trophectoderm postimplantation.