The implantation process is a two-way interaction between the trophectoderm of the active blastocyst and luminal epithelium (LE) of the receptive uterus. Although this interaction primarily depends on the coordinated effects of estrogen (E) and progesterone (P4), the molecular basis for this process is ill-defined. Our central hypothesis is that the ligand-receptor signaling with EGF-like growth factors is important in implantation. EGF, TGF-alpha:, heparin-binding EGF-like growth factor (HB- EGF) and amphiregulin (AR) all belong to the EGF family and apparently mediate their functions via the EGF receptor (EGF-R). EGF-R expression in the mouse blastocyst is tightly regulated during implantation. Furthermore, homozygous mouse blastocysts with mutated EGF-R genes die around the time of implantation. These findings suggest the importance of blastocyst EGF-R in periimplantation processes. But the ligand(s) involved remains undefined. EGF is not expressed in the mouse uterus during implantation. The role of TGF-alpha; which is expressed in the uterus is questionable, since TGF-alpha; deficient mice show apparently normal implantation. HB-EGF is induced in the receptive LE at the blastocyst site before the attachment reaction. Preliminary results indicate that AR gene is expressed in the mouse uterine epithelium on the day of implantation under the influence of P4. Furthermore, blastocyst's state of activity is critical in determining the """"""""window"""""""" of implantation in the receptive uterus, and preliminary results also show that blastocyst's state of activity and uterine receptivity are differentially regulated by E. These results allow for the examination of regulation of embryonic and uterine events separately, as well as their cooperative interactions during implantation.
Our specific aims are to determine in the mouse: (i) Temporal and spatial expression of uterine AR gene during various stages of uterine sensitivity to implantation; (ii) Effects of ovarian steroids on this expression; (iii) Regulation of EGF-R gene in the blastocyst; (iv) Mechanism of E directed uterine preparation and blastocyst activation for implantation; and (v) Role of ligand-receptor signaling with EGF-like growth factors in implantation. Detection of growth factor and receptor mRNAs will employ Northern blot and in situ hybridization and RT-PCR, while immunostaining, Western blotting and pulse-labeling experiments will be used for detecting proteins. Autoradiography, cross-linking and phosphorylation studies will be used for receptor characterization. Physiological experiments will use embryo culture and blastocyst transfer. These results will enhance our understanding of embryo-uterine interactions during implantation and regulation of fertility in the female.
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