Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success.
Successful pregnancy depends on well coordinated developmental events involving both maternal and embryonic components. Although a host of signaling pathways participate in implantation, decidualization, and placentation, whether there is a common molecular link that coordinates these processes remains unknown. By exploiting genetic, molecular, pharmacological, and physiological approaches, we show here that the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) delta plays a central role at various stages of pregnancy, whereas maternal PPARdelta is critical to implantation and decidualization, and embryonic PPARdelta is vital for placentation. Using trophoblast stem cells, we further elucidate that a reciprocal relationship between PPARdelta-AKT and leukemia inhibitory factor-STAT3 signaling pathways serves as a cell lineage sensor to direct trophoblast cell fates during placentation. This novel finding of stage-specific integration of maternal and embryonic PPARdelta signaling provides evidence that PPARdelta is a molecular link that coordinates implantation, decidualization, and placentation crucial to pregnancy success. This study is clinically relevant because deferral of on time implantation leads to spontaneous pregnancy loss, and defective trophoblast invasion is one cause of preeclampsia in humans.
Wang
Haibin
H
Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Xie
Huirong
H
Sun
Xiaofei
X
Tranguch
Susanne
S
Zhang
Hao
H
Jia
Xiangxu
X
Wang
Dingzhi
D
Das
Sanjoy K
SK
Desvergne
Béatrice
B
Wahli
Walter
W
DuBois
Raymond N
RN
Dey
Sudhansu K
SK
D000818:Animals; D003656:Decidua / Q000378:metabolism; D010064:Embryo Implantation; D005260:Female; D005306:Fertilization; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010060:Ovulation; D047494:PPAR delta / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D014327:Trophoblasts / Q000378:metabolism
D047494:PPAR delta; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse