HB-EGF: a unique mediator of embryo-uterine interactions during implantation

Abstract

An implantation-competent blastocyst, several hours prior to its attachment on the uterine wall, transmits signals to surrounding uterine cells and vice-versa to initiate a two-way interaction. The language of this precocious dialogue is versatile, taking advantage of secreted molecules for long-range interactions and membrane-bound molecules for more immediate interactions. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) was identified as an early messenger of implantation which uses both modes of communication. In this review, we discuss the footprint of HB-EGF as to how it was initially identified as a mediator of implantation and how it initiates embryo-uterine interactions during this process.

Fig. 1

Expression of ErbB1 and ErbB4 in day 4 and day 7 delayed blastocysts. Day 4 pregnant mice were ovariectomized and received daily P₄ injections from day 4 to day 6. On day 7, dormant blastocysts were obtained by uterine flushing. Immunoreactive ErbB1 and ErbB4 show red deposits mainly in the trophectoderm of day 4 normal blastocysts. In dormant blastocysts, both ErbB1 and ErbB4 are downregulated (reproduced from [18, 19]).

Fig. 2

Altered uterine expression of Ar, HB-EGF and Ereg around the time of implantation in wildtype and Lif^−/− mice. Photomicrographs of representative uterine sections showing in situ hybridization of Areg, Hbegf, and Ereg mRNAs on day 5 of pregnancy are shown at 100X. Arrows indicate the location of blastocysts (reproduced from [34]).

Fig. 3

A schematic landscape of signaling by HB-EGF_™ and mature HB-EGF. HB-EGF takes advantage of autocrine, paracrine, and juxtracrine modes of signaling to regulate both embryonic and uterine functions. HB-EGF affects trophoblast growth and adhesion during implantation. In the uterine stroma, HB-EGF increases DNA synthesis and cell cycle progression. This versatility of HB-EGF synergizes upon the process of successful implantation.