Identification of Novel Genes Regulated by Chorionic Gonadotropin in Baboon Endometrium during the Window of Implantation

Abstract

Chorionic gonadotropin (CG) is an early embryo-derived signal that is known to support the corpus luteum. An in vivo baboon model was used to study the direct actions of human CG (hCG) on the endometrium, during the periimplantation period. Endometrial gene expression was analyzed using microarrays. The endometrial biopsies were taken from hCG-treated (n = 5) and control (n = 6) animals on d 10 after ovulation. Class comparison identified 61 genes whose transcript levels differed between control and hCG-treated samples (48 increased, 13 decreased in mean expression level more than 2.5-fold; P < 0.01). Real-time PCR of transcript abundance confirmed up-regulation of several of these, including SerpinA3, matrix metalloproteinase 7, leukemia inhibitory factor (LIF), IL-6, and Complement 3 (P </= 0.05). Analysis of protein abundance in endometrial flushings showed increased LIF and IL-6 protein in uterine flushings from hCG-treated animals compared with controls. Complement C3 and Superoxide dismutase 2 that were also up-regulated, were further evaluated by immunocytochemistry. Complement C3 showed a marked increase in stromal staining in response to hCG, whereas and superoxide dismutase 2 localization was most markedly increased in the glandular epithelial cells. Expression of Soluble Frizzled Related Protein 4, the most highly down-regulated gene, was also validated by PCR. Our experiments have shown that hCG induces alterations in the endometrial expression of genes that regulate embryo attachment, extracellular matrix remodeling and the modulation of the immune response around the implanting blastocyst. Several of these genes, including LIF and gp130, have been shown to be essential for implantation in other species. This study provides strong evidence that the preimplantation embryo itself influences the development of the receptive endometrium via secreted paracrine signals.

Complement component C3 functions as an embryotrophic factor in early postimplantation rat embryos

“…It has been indicated that C3, mostly synthesized in the liver, is also synthesized in the uterine endometrium of various species including rats (Sundstrom et al, 1989) and humans (Sayegh et al, 1996), which is stimulated by estradiol or chorionic gonadotropin and inhibited by progesterone (Brown et al, 1990;Sherwin et al, 2007). It is suggested from the present findings that uterine C3 functions as an embryotrophic factor at earlier embryonic stages when the maternal blood sinus is not yet formed.…”

The role of chorionic gonadotropin and Notch1 in implantation

“…CG has a direct luteotrophic effect on the corpus luteum, increasing its life span. Concurrently, CG also leads to alterations in morphology and endometrial gene expression by modulating the endometrium in preparation for implantation [9].…”

Dominant Activation of Hedgehog Signaling Alters Development of the Female Reproductive Tract.

“…Here, the embryo produces cytokines that induce inflammatory pathways in the endometrium (Sherwin et al, 2007). A similar response to that generated by the embryo can be stimulated by scratching the uterus, or injecting oil into the tract of females primed by treatment with progesterone and estrogen (Dekel et al, 2010).…”