OVO-like 1 regulates progenitor cell fate in human trophoblast development.
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 of Drosophila ovo, 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, including MYC, ID1, TP63, and ASCL2, 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.
Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160; srenaud4@uwo.ca msoares@kumc.edu.
Stephen J
SJ
Renaud
Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160;
Damayanti
D
Chakraborty
Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160.
Clifford W
CW
Mason
Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160;
M A Karim
MA
Rumi
Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160;
Jay L
JL
Vivian
Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160; Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160 srenaud4@uwo.ca msoares@kumc.edu.
Michael J
MJ
Soares
D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology*
D004268:DNA-Binding Proteins; C490319:OVOL1 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors
OVO-like 1; differentiation; epithelial barrier; placenta; trophoblast