Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor.

Implantation requires communication between a receptive endometrium and a healthy blastocyst. This maternal-embryonic crosstalk involves local mediators within the uterine microenvironment. We demonstrate that a secreted protein, prokineticin 1 (PROK1), is expressed in the receptive endometrium and during early pregnancy. PROK1 induces expression of leukemia inhibitory factor (LIF) in endometrial epithelial cells and first trimester decidua via a Gq-Ca(2+)-cSrc-mitogen-activated protein kinase kinase-mediated pathway. We show that human embryonic chorionic gonadotropin (hCG) induces sequential mRNA expression of PROK1 and LIF in an in vivo baboon model, in human endometrial epithelial cells, and in first-trimester decidua. We have used micro RNA constructs targeted to PROK1 to demonstrate that hCG-mediated LIF expression in the endometrium is dependent on prior induction of PROK1. Dual immunohistochemical analysis colocalized expression of the luteinizing hormone/chorionic gonadotropin receptor, PROK1, PROKR1, and LIF to the glandular epithelial cells of the first trimester decidual tissue. PROK1 enhances adhesion of trophoblast cells to fibronectin and laminin matrices, which are mediated predominantly via LIF induction. These data describe a novel signaling pathway mediating maternal-embryonic crosstalk, in which embryonic hCG via endometrial PROK1 may play a pivotal role in enhancing receptivity and maintaining early pregnancy.

Large-scale gene expression studies of the endometrium: what have we learnt?

The endometrium is a dynamic tissue that undergoes coordinated changes under the influence of steroid hormones. This results in proliferation and differentiation culminating in a receptive state, followed by menstruation and endometrial repair. These functions involve complex interactions between the epithelium, stroma and leucocytes in the endometrium. Understanding the underlying causes of endometrial disorders, such as infertility, endometriosis and heavy menstrual bleeding, therefore represents a considerable challenge. Recently developed techniques, such as differential display and DNA microarrays permit the abundance of thousands of mRNA transcripts within cells or tissues to be measured simultaneously. This provides a new approach to understanding the complex interactions that underlie both healthy and disease states. Responses of the endometrium to hormones or drugs can be studied and the response of the system as an integrated whole can be assessed. Comparisons of endometrium from healthy women and those with endometrial dysfunction have advanced our understanding of key areas of endometrial physiology, including infertility, receptivity, endometriosis and cancer. Using this approach, novel genes controlling specific endometrial functions like receptivity have been identified for functional testing. This paper will review the impact of these techniques for transcript profiling on our understanding of selected areas of endometrial biology and discuss the potential applications in future.