Stage-specific Integration of Maternal and Embryonic Peroxisome Proliferator-activated Receptor δ Signaling Is Critical to Pregnancy Success

Haibin Wang,Huirong Xie,Xiaofei Sun,Susanne Tranguch,Hao Zhang,Xiangxu Jia,Dingzhi Wang,Sanjoy K Das,Béatrice Desvergne,Walter Wahli,Raymond N Dubois,Sudhansu K Dey

doi:10.1074/jbc.m706577200

Abstract

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.

Highlights

Implantation is normal only if it occurs within a limited time period termed window implantation when the blastocyst is implantation-competent and the uterus is receptive [3]
We show here that uterine peroxisome proliferator-activated receptor (PPAR)␦ is essential for normal implantation and decidualization, embryonic PPAR␦ via coordinated interaction with AKT and leukemia inhibitory factor (LIF)-signal transducer and activator of transcription 3 (STAT3) signaling is vital for specifying trophoblast cell differentiation during placentation
Ovulation and Fertilization Are Normal in PPAR␦Ϫ/Ϫ Mice— To examine ovulation and fertilization status in PPAR␦Ϫ/Ϫ mice, we recorded the number of ovulated eggs and fertilized two-cell embryos on day 2 of pregnancy

Summary

EXPERIMENTAL PROCEDURES

Reagents—Antibodies to anti-phospho-p38 MAPK (Thr180/Tyr-182), total p38 MAPK, phospho-extracellular signalregulated kinase (ERK) 1/2 (Thr-202/Tyr-204), total ERK1/2, phospho-AKT ( known as protein kinase B) (Ser-473), total. Mice were killed on day 2 of pregnancy and oviducts were flushed with Whitten’s medium to recovery eggs and embryos. Their morphology was examined under a dissecting microscope [5]. Immunostaining and Lectin Histochemistry—Immunofluorescence staining of PPAR␦ in preimplantation embryos was performed as described by us [26]. Immunolocalization of PPAR␦, COX-2, phospho-AKT, phospho-STAT3, cytokeratin, VCAM-1, PL-I, SOCS3, and CDX2 was performed in 10% neutral-buffered formalin or Bouin’s fixed and paraffin-embedded sections of uteri and placentas using a Histostain-SP kit as described [21]. Immunohistological and lectin binding analysis were performed on at least 4 – 6 different implantation sites or placentas at each developmental stage obtained from three different mice.

RESULTS

No of recipients

To test that a balance between

DISCUSSION