Determining the role of kisspeptins in the peripheral control of ovarian physiology and pregnancy.

Puberty is an important developmental milestone for all mammals but until recently, very little was know about the molecules that initiated this event. We have shown that a novel protein (GPR54) and the molecules that bind to this protein (kisspeptins) are essential for puberty. Mice lacking these proteins fail to undergo puberty and are sterile. Kisspeptins and GPR54 are expressed in a part of the brain known as the hypothalamus, which is known to play a crucial role in regulating fertility. The expression pattern of these genes, however, suggest that they may also function outside the brain to regulate the function of the ovaries and in pregnancy. The aim of this project is to define these roles by comparative studies using mutant mice lacking kisspeptins or GPR54. The mutant mice will be given hormonal treatments to induce fertility and the physiological and molecular responses examined. These studies will establish the function of kisspeptin/GPR54 in ovary and uterine physiology and provide an insight into the role of these genes in reproductive disorders such as early gestational abortions and premature hypogonadism.

Kisspeptins, encoded by the Kiss1 gene, bind to the G-protein coupled receptor GPR54 and act as central mediators of mammalian puberty and fertility. The expression profile of these genes and preliminary experimental data suggest that they may also function outside the central nervous system to regulate ovarian physiology and pregnancy. The aim of this project is to define these roles by comparative studies using Kiss1 and Gpr54 null mice. These mutant mice are sterile due to a failure of the hypothalamus to initiate GnRH secretion at puberty. To study the role of kisspeptin signalling in gonadal function, the mutant mice will be induced to proceed through puberty by hormonal treatment and the ability of the mice to undergo oogenesis studied by histological and molecular analysis. Cell or tissue-specific autonomous defects will be examined by reciprocal transplantation of ovaries etween mutant mice and normal mice. To determine the role of kisspeptins/Gpr54 in placentation and pregnancy, mutant female mice will be treated with gonadotrophic hormones to induce maturation of the reproductive tract and ovulation. These mice will be paired with males and sacrificed at different stages of gestation to assess implantation and subsequent fetal development. Placenta function will be assessed by histological analysis and morphometric measurements of uteroplacental units. A mechanistic insight into deviations from normal placenta development will be obtained by a molecular comparison of early placentation genes. These studies will establish the function of kisspeptin/Gpr54 in ovarian and uterine physiology and provide an insight into the role of these genes in reproductive disorders such as early gestational abortions and premature hypogonadism.