INTRODUCTION

An indispensable precondition for successful implantation of the mammalian blastocyst into the endometrium is precise synchronization of the physiological and cell biological events of the developing blastocyst and the endometrium for successful interaction with one another. Disruption of this synchrony in the differentiation process leads to failure in implantation. The molecular signals involved are of clinical relevance, because understanding the nature of these signals may lead to strategies for correcting implantation failure or developing novel contraceptive approaches. In humans, approximately 20% of spontaneous abortions during pregnancy are estimated to occur before the pregnancy has been detected clinically, and the pregnancy rate in in vitro fertilization programs remains as low as 20-30% in spite of the high rate of successful fertilization.

Uterine receptivity is defined as a restricted time period when the uterus is conducive to blastocyst attachment and implantation. The establishment of this endometrial transition, which supports embryo implantation, is primarily coordinated by ovarian hormones, progesterone and estrogen, that modulate uterine events in a spatiotemporal manner and that prepare the endometrium to respond to blastocyst signals. In addition to the physical interaction of the embryonic tissue with the uterine cells, various substances such as steroid hormones, prostaglandins (PGs), and growth factors have been proposed to play a role in embryonic signaling. Although numerous molecules involved in implantation have been identified in rodents and humans, microarray analysis of human endometrium from the receptive phase has given insight regarding involvement of certain molecules, but the molecular mechanisms, regulation of genes, and signal cascades that govern this process of endometrium-blas-tocyst interaction remain poorly understood.

In previous studies, we showed that gap junction connexin expression is regulated in a precise spatiotemporal pattern during the receptive phase in rat endometrium as well as during cycling in humans. Gap junction channels mediate direct intercellular communication and allow transfer of small molecules (< 1 kDa) between the cytoplasm of neighboring cells, thereby coupling those cells both electrically and metabolically. They are composed of transmembrane proteins (connexins), with 19 members identified in the murine and 20 in the human genome that belong to one multigene family and show a very high sequence identity between different species.

We demonstrated a strong correlation between expression of connexins (Cx) 26 and 43 and the implantation reaction in rat endometrium: Expression of both connexins is regulated by ovarian hormones during preimplantation, leading to a suppression during the receptive phase, and is induced by the blastocyst shortly before and during implantation. In the present study, we demonstrate that endometrial expression of Cx26 and Cx43 during preimplantation utilizes an estrogen receptor (ER) a-regulated mechanism. The same genes are induced, however, via an ER-independent blastocyst signaling pathway before and during embryo recognition.