Roles of PLCβ1 in female reproduction

Abstract

In mammals, development of a new organism requires fertilisation of the female egg by sperm. The resulting zygote develops into the blastocyst stage as it travels towards the uterus. Within the uterus, the blastocyst invades the maternal tissues and establishes access to the maternal blood supply. This process is called implantation and is absolutely essential for the further development of the conceptus and establishment of pregnancy. Successful implantation requires a proper preparation of the uterus and the embryo as well as a molecular dialogue between the embryo and the uterine tissues. Female mice that have a disruption in the Plcβ1 gene are infertile. In the course of this Thesis it became apparent that the main cause of their infertility is their inability to implant their embryos. PLCβ1 protein is a mediator of G-protein coupled receptor (GPCR) signalling and it is involved in the production of second messengers essential for downstream transmission of signals. A host of reproductive functions are under the control of GPCR signalling. In this PhD Thesis the infertile phenotype of Plcβ1 knockout (KO) female mice was investigated to identify the reproductive processes affected by the lack of a functional PLCβ1 protein. A combination of histological, molecular biology and in vivo techniques were utilised to show that at the time of implantation, embryos fail to attach to the uterine epithelium of KO uteri. In addition, it was demonstrated that estrogen signalling and components of the endocannabinoid metabolism, both key processes for successful implantation are severely altered in KO uteri. These observations show that KO uteri fail to prepare for implantation. In addition, the KO reproductive tract exerts a detrimental effect on pre- and peri- implantation embryo development. Currently, failure of implantation is thought to be one of the major causes of infertility in women and up to this date there are no successful treatments. The results of this project expand our current knowledge on the physiology of implantation and provide cues for the development of diagnostic markers and treatments for the women who are unable to conceive.