Beyond the brain-Peripheral kisspeptin signaling is essential for promoting endometrial gland development and function

Abstract

Uterine growth and endometrial gland formation (adenogenesis) and function, are essential for fertility and are controlled by estrogens and other regulators, whose nature and physiological relevance are yet to be elucidated. Kisspeptin, which signals via Kiss1r, is essential for fertility, primarily through its central control of the hypothalamic-pituitary-ovarian axis, but also likely through peripheral actions. Using genetically modified mice, we addressed the contributions of central and peripheral kisspeptin signaling in regulating uterine growth and adenogenesis. Global ablation of Kiss1 or Kiss1r dramatically suppressed uterine growth and almost fully prevented adenogenesis. However, while uterine growth was fully rescued by E2 treatment of Kiss1−/− mice and by genetic restoration of kisspeptin signaling in GnRH neurons in Kiss1r−/− mice, functional adenogenesis was only marginally restored. Thus, while uterine growth is largely dependent on ovarian E2-output via central kisspeptin signaling, peripheral kisspeptin signaling is indispensable for endometrial adenogenesis and function, essential aspects of reproductive competence.

Uterine Gα q/11 signaling, in a progesterone‐dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse

“…To determine whether gland development and function were impaired in the KO uterus, the expression of FOXA2 was assessed by immunohistochemistry (IHC) in the d 4pregnant CTRL and KO uteri. FOXA2 is strongly expressed on the glandular epithelium and is a critical regulator of endometrial gland development and function (15,27,28). Results indicate that FOXA2 expression was similar between the CTRL and KO uteri ( Fig.…”

“…Perhaps the first evidence was from the study by Warsop et al (38), which reported that during early pregnancy in the guinea pig, Ga q/11 uterine membrane content dropped in early pregnancy relative to the nonpregnant uteri but rose significantly as pregnancy progressed. Later studies from genetically modified mice lacking Ga q/11 -coupled LPAR3 and KISS1R further suggested possible roles in regulating the final acquisition of uterine receptivity and embryo implantation (12,13,15). However, because LPAR3 also couples to Ga i/0 , it could not be ruled out that it was a disruption of the LPAR3/ Ga i/0 signaling pathway in the LPAR3 KO that prevented the full acquisition of uterine receptivity.…”

“…Taken together, these results suggest that P4 levels (albeit reduced) in the Gnaq Pgr-Cre -KO mouse on d 4 are not likely the underlying cause of the implantation failure, and this failure instead likely reflects a uterine defect. Endometrial glands produce and secrete substances that are essential for embryo implantation (13,15). To determine whether gland development and function were impaired in the KO uterus, the expression of FOXA2 was assessed by immunohistochemistry (IHC) in the d 4pregnant CTRL and KO uteri.…”

“…To date, despite the fact that several GPCRs are expressed in the uterus during the peri-implantation period, only a few have been identified as critical regulators of uterine receptivity and embryo implantation. These are leucine-rich repeat-containing GPCR 4 (LGR4) (9)(10)(11), lysophosphatidic acid receptor 3 (LPAR3) (12), and the kisspeptin receptor (KISS1R) (13)(14)(15)). LGR4 appears to couple to Ga s, LPAR3 couples to Ga q/11 and Ga i/0 (16), and KISS1R couples to Ga q/11 (16,17).…”

“…Deletion of LPAR3 results in persistent epithelial PR signaling and the inability to exit the prereceptive phase of early pregnancy (12). Deletion of KISS1R or its ligand kisspeptin results in reduced and defective adenogenesis and the inability of the blastocyst to adhere to the LE, thereby disrupting implantation (13)(14)(15)18). In the rat, down-regulation of uterine calcitonin expression also blocks implantation (19).…”