The kisspeptin/KISS1R signaling system: Beyond the brain

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Reproduction is a biological process by which an organism propagates itself and it a fundamental feature of all known life. By understanding the factors that regulate reproduction we can enhance the breeding programs of important domestic and wildlife species. Similarly, through intervention we can develop novel strategies to reduce the population of wildlife species that pose a threat to fragile ecosystems and induce sterility among female cats and dogs as part of a global effort to regulate the population of both feral animals and pets. Strategies aimed at regulating reproduction often target the brain, to increase or decrease the availability of a hormone called the gonadotropin-releasing hormone (GnRH). GnRH is also called the master regulator of reproduction and is responsible for the production of the egg and sperm. When an egg is fertilized by a sperm it develops into an embryo which attaches itself to the wall of the uterus and develops into the fetus. The attachment process is called implantation and it is a critical rate-limiting step in achieving a successful pregnancy. Recently, we discovered that two proteins, kisspeptin (KP) and the kisspeptin receptor (KISS1R), are found in the uterus of mice and appear necessary for successful embryo implantation. However, before we can confidently say that KP and KISS1R regulate embryo implantation in the uterus more studies are required. Given their potential biological function, it is important to conduct these studies to understand how KP and KISS1R regulate implantation and thereby reproduction. To do this, we will create a mouse that lacks the ability to produce KP and KISS1R in its uterus and then ask what effect this has on the ability of the embryo to implant. If the embryo fails to implant this will be irrefutable proof that KP and KISS1R regulate implantation. If we make those observations we will then ask what regulates KP and KISS1R levels in the uterus. Here we will focus on the sex steroids, estrogen (E) and progesterone (P). E and P are made by the ovaries and are critical for embryo implantation and survival. Thus, it is possible that ovarian E and/or P regulate uterine KP and KISS1R levels. Using mice in which we have removed the ovaries and hence the internal source of E and P, we will add back E and P and determine what effect this has on the levels of KP and KISS1R. If we find that KP and KISS1R levels are altered we will conclude that uterine KP and KISS1R are E2- and P4-regulated proteins. Understanding what regulates KP and KISS1R levels and what KP and KISS1R regulate in turn, are the first critical steps towards targeting KP and KISS1R in the uterus in order to enhance or inhibit implantation and thereby reproduction.