OVO-like 1 regulates progenitor cell fate in human trophoblast development

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 45; pp. E6175 - E6184
• Main Authors: Renaud, Stephen J., Chakraborty, Damayanti, Mason, Clifford W., Rumi, M. A. Karim, Vivian, Jay L., Soares, Michael J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.11.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Analysis of Variance; Animals; Base Sequence; Biological Sciences; Blotting, Western; Cell Differentiation - physiology; Cells; Chromatin Immunoprecipitation; DNA-Binding Proteins - metabolism; Female; Fluorescent Antibody Technique; Gases; Gene Expression Regulation, Developmental - physiology; Genes; Humans; Immunohistochemistry; In Situ Hybridization; Mice; Mice, Inbred C57BL; Microarray Analysis; Molecular Sequence Data; Nutrients; Placenta; PNAS Plus; Pregnancy; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - genetics; Sequence Analysis, RNA; Stem Cells - physiology; Tissues; Transcription Factors - metabolism; Trophoblasts - cytology; Trophoblasts - physiology; placenta; differentiation; epithelial barrier; OVO-like 1; trophoblast
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1507397112

Epithelial barrier integrity is dependent on progenitor cells that either divide to replenish themselves or differentiate into a specialized epithelium. This paradigm exists in human placenta, where cytotrophoblast cells either propagate or undergo a unique differentiation program: fusion into an overlying syncytiotrophoblast. Syncytiotrophoblast is the primary barrier regulating the exchange of nutrients and gases between maternal and fetal blood and is the principal site for synthesizing hormones vital for human pregnancy. How trophoblast cells regulate their differentiation into a syncytium is not well understood. In this study, we show that the transcription factor OVO-like 1 (OVOL1), a homolog ofDrosophilaovo, regulates the transition from progenitor to differentiated trophoblast cells. OVOL1 is expressed in human placenta and was robustly induced following stimulation of trophoblast differentiation. Disruption of OVOL1 abrogated cytotrophoblast fusion and inhibited the expression of a broad set of genes required for trophoblast cell fusion and hormonogenesis. OVOL1 was required to suppress genes that maintain cytotrophoblast cells in a progenitor state, includingMYC, ID1, TP63,andASCL2,and bound specifically to regions upstream of each of these genes. Our results reveal an important function of OVOL1 as a regulator of trophoblast progenitor cell fate during human trophoblast development.