Yap is essential for uterine decidualization through Rrm2/GSH/ROS pathway in response to Bmp2

Abstract

Yap is required for ovarian follicle and early embryo development, but little information is available regarding its physiological significance in decidualization. Here we determine the effects of YAP on decidualization, mitochondrial function, cell apoptosis and DNA damage, and explore its interplay with Bmp2, Rrm2, GSH and ROS. The results exhibited that Yap was abundant in decidual cells and its inactivation impaired the proliferation and differentiation of stromal cells along with the deferral of G1/S phase transition, indicating Yap importance in decidualization. Bmp2 via Alk2 receptor promoted nuclear translocation of Yap where it might interact with Tead and then bind to the promoter of Rrm2 whose activation rescued the faultiness of differentiation program and attenuated oxidative DNA damage caused by Yap impediment. Meanwhile, Yap had an important part in the crosstalk between Bmp2 and Rrm2. Furthermore, inactivation of Yap resulted in an obvious accumulation of intracellular ROS followed by the abnormal GR activity and GSH content dependent on Rrm2. Replenishment of GSH counteracted the regulation of Yap inactivation on stromal differentiation and DNA damage with distinct reduction for intracellular ROS. Additionally, blockage of Yap caused the enhancement of stromal cell apoptosis and brought about mitochondrial dysfunction as indicated by the aberration for ATP level, mtDNA copy number and mitochondrial membrane potential concomitant with the opening of mitochondrial permeability transition pore, but these abnormalities were neutralized by GSH. Administration of mitochondrial antioxidant Mito-TEMPO rescued the fault of stromal differentiation conferred by Yap inactivation. Collectively, Yap was essential for uterine decidualization through Rrm2/GSH/ROS pathway in response to Bmp2.

Transcriptome‐wide high‐throughput m6A sequencing of differential m6A methylation patterns in the decidual tissues from RSA patients

“…Cytokine–cytokine receptor interaction, including canonical TGF‐β/BMP signaling, targets like BMP2 and inhibin beta‐A chain (INHBA) and interleukin‐11 receptor subunit alpha (IL11RA), a receptor for interleukin‐11. Both BMP2 and INHBA protein have a direct relationship with the processes of embryo implantation and endometrial decidualization, 42–44 which may play a role in the occurrence of RSA. Several studies reported that IL‐11/IL11RA is critical for decidualization of the endometrial stromal cells in early pregnancy 45,46 .…”

IHH, SHH, and primary cilia mediate epithelial-stromal cross-talk during decidualization in mice

“…A previous study showed that SHH secreted from mesenchymal cells can induce osteoblast differentiation by activating YAP ( 59 ), which, in endometrial cancer cells, promotes malignancy by inducing IL-11 ( 57 ). YAP, IL-11, and IL-11Rα are present in mouse decidua, and YAP and IL-11Rα are required for proper decidualization ( 9 , 58 , 68 ). It is possible that SHH stimulates IL-11 production through activating YAP.…”

“…IL-11 and IL-11Rα are essential for mouse decidualization (7)(8)(9). Previous studies showed that SHH can induce IL-11 through the transcriptional coactivator YAP (57)(58)(59). Therefore, we asked whether SHH may activate IL-11 and IL-11Rα to induce decidualization.…”

Melatonin modulates endometrial decidualization via NOTCH1–NRF2–FOXO1–GSH pathway

“…Total RNAs from ESCs were extracted using TRIPURE reagent (Roche) and then synthesized into cDNA using M-MLV reverse transcriptase. Afterwards, cDNA was amplified using SYBR Green Premix (Roche) and corresponding primers on LightCycler 96 Real-Time Detection System to reckon the expression levels of various gene as represented previously [14]. Followed by the analysis of 2 -ΔΔCt method, data were normalized to GAPDH expression.…”