TEAD4 Transcriptional Activity Regulates Proliferation of Trophoblast Progenitors During Mammalian Placental Development
Biswarup Saha, Pratik Home, Arindam Paul, Soma Ray and Soumen Paul
Department of Pathology & Laboratory Medicine, Institute of Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
In placental mammals, trophoblast cells are essential for embryo implantation and successful progression of the pregnancy. During placental development, distinct trophoblast cell types are specified from trophoblast stem cells (TSCs) or TSC-like trophoblast progenitors. However, molecular mechanisms, which regulate proliferation and differentiation of trophoblast stem/progenitor cells, are poorly understood. In this study, we show that transcriptional activity of TEAD4, a TEA domain containing transcription factor, plays a crucial role in promoting cell proliferation in trophoblast progenitors of both rodent and human placenta. In the early stage of mouse and human placentas, TEAD4 is present within the nuclei of TSC-like progenitors and directly regulates expression of TSC-specific genes. Our genetic analysis with mouse TSC lines and primary cytotrophoblasts from first-trimester human placenta also confirmed that TEAD4 promotes proliferation of trophoblast stem/progenitors cells by regulating expression of several Cyclins/CDKs. In contrast to trophoblast progenitors of a developing placenta, differentiated trophoblast cells within matured rodent and human placentas generally lack TEAD4 transcriptional activity due to its absence in their nuclei. However, intriguingly, both matured mouse and human placentas harbor a small number of trophoblast population, characterized by the presence of TEAD4 in their nuclei and higher transcription of TEAD4-regulated genes. Thus, TEAD4 transcriptional activity marks a population of trophoblast cells that are actively proliferating or poised for proliferation in matured mammalian placenta. Our study indicates that transcriptional activity of TEAD4 balances progenitor vs. differentiated state of trophoblast population during mammalian placental development.