| Embryonic implantation into the mother’s uterus is an indispensable step in mammalian reproduction.Abnormal embryo implantation can cause a series of adverse reactions to pregnancy,leading to harmful pregnancy outcomes such as fetal development defects,miscarriage,and infertility.In the process of embryo implantation and decidualization,many growth factors,cytokines,transcription factors,etc.participate in and regulate this process,and tyrosine phosphatase Shp2 can transduce signals transmitted by growth factors,cytokines,hormones,etc.Thus we speculate that Shp2 may be involved in this process.Professor Wang Haibin’s group collaborated with us to use PR-Cre to knock out Shp2 in epithelial and stromal cells.It was found that the receiving state of the mouse uterus was destroyed,the embryo could not be planted,and the female mice were completely infertile.These results confirm that Shp2 is a key factor for embryo implantation,but the effect of Shp2 deletion on the subsequent decidualization is not yet clear,and therefore further studies are needed.In this article,we first explored the expression pattern of Shp2 in early pregnancy events and found that the expression of Shp2 showed dynamic changes and increased significantly during embryo implantation and decidualization.To further investigate the function of Shp2 in mouse pregnancy events,we knocked out Shp2 specifically in uterine stromal cells using Amhr2-Cre.In a 6-month breeding experiment,male mice were found to have about half the fertility of Shp2 knockout mice compared to wild-type mice.Through the mouse tail vein injection of Chicago Blue to analyze embryo implantation,it was found that embryos had already been implanted in control mice at 2 am D5,but knockout mice do not implantation until At 9 o’clock in the morning,suggesting a delay in embryo implantation.Detection of estrogen-progesterone-responsive genes by QPCR revealed that the expression of the estrogen-regulated genes Mucl and Ltf was abnormally elevated in the Shp2 knock-out group;progesterone-regulated genes,Hand2,Areg,and Lif,were also abnormally,indicating that the uterus in the knockout mice was disorderly.Further research found that the development of the fetus in Shp2 knockout mice was ultimately fatal.The uterine decidualization of the embryos at the D6 attachment site in the wild-type mice was revealed by uterine HE staining at day 6-8 of pregnancy.The thickening was obvious,and decidualization was sufficient at D8,but decidualization did not occur at the time of knockout of mouse D6,and the process was obviously delayed,indicating that the delayed decidual development.At the same time,the mRNA detection of decidual marker molecules also showed that the expression of the decidual marker such as CX43 was significantly decreased in the knockout mouse group,and these all indicate that the stromal cells knocked out Shp2 caused defects in decidual development.The artificially induced decidualization model also confirmed the adverse effects of Shp2 deletion on decidualization.The proliferation of marker Ki67 on the 8th day of gestation and flow cytometry of decidual cells showed that the decidual defect caused by Shp2 deletion mainly showed a decrease in the proliferative capacity of the stromal cells and a decrease in the number of ploidy cells.Current experiments show that Shp2 down-regulates ERK expression after stromal cell knockout,suggesting that stromal cells Shp2 participates in the regulation of proliferative signaling by activating ERK signal during decidualization,but the mechanism of Shp2 regulating stromal cell proliferation needs further investigation.In summary,Shp2 may regulate decidualization of the uterus by regulating the proliferation of stromal cells.Our results indicate that Shp2 is essential for embryo implantation and decidualization.It establishes a certain basis for elucidating the molecular regulation mechanisms of decidualization,and it also provides clinical support for the diagnosis and treatment of decidua. |
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