DIFFERENTIAL EXPRESSION OF THE ERBB2 GENE IN THE PERIIMPLANTATION MOUSE UTERUS - POTENTIAL MEDIATOR OF SIGNALING BY EPIDERMAL GROWTH FACTOR-LIKE GROWTH-FACTORS

Ligand-receptor signaling with the epidermal growth factor (EGF) famil y of growth factors in the uterus and embryo is considered to be impor tant for implantation. The EGF family includes EGF, transforming growt h factor-alpha, heparin binding-EGF, amphiregulin, beta-cellulin, epir egulin, and heregulins, whereas the receptor family (the erbB genes) c onsists of erbB1 (EGF-receptor, EGF-R), erbB2, erbB3, and erbB4. Inter actions of uterine EGF-R with EGF-like ligands have been examined, but limited information is available regarding the status of other recept or subtypes. Thus, we examined the expression of the erbB2 gene in the mouse uterus during the periimplantation period (days 1-8 of pregnanc y) and after 17 beta-estradiol and/or progesterone stimulation. Northe rn blot hybridization detected two transcripts (similar to 4.0 and 5.0 kb) of erbB2 messenger RNA (mRNA) in day 1-8 uterine polyadenylated R NA samples. In situ hybridization experiments showed unique uterine ce ll-specific erbB2 mRNA distribution On days 1-4, unlike the full-lengt h erbB1 mRNA which is not expressed in the uterine epithelium, the erb B2 mRNA was detected primarily in epithelial cells; the day 1 uterus s howed the highest accumulation. On day 5, the epithelium and the decid ualizing stromal cells around the implanting blastocyst exhibited accu mulation of this mRNA On days 6-8, the accumulation persisted in the e pithelium at both the implantation and interimplantation sites in addi tion to modest levels of signals in the secondary decidual zone. On da ys 7 and 8, accumulation of the erbB2 mRNA was also prominent in the t rophoblastic giant cells. Western blotting detected a predicted protei n of 185 kDa in day 4 uterine membrane preparations. Results of immuno cytochemistry demonstrated colocalization of the erbB2 protein with it s mRNA in the periimplantation uterus. The uterine ErbB2 underwent pho sphorylation by several members of the EGF family. Treatment of adult ovariectomized mice with 17 beta-estradiol, but not progesterone, up-r egulated the expression of the erbB2 mRNA by more than 3.5-fold, as de termined by quantitative reverse transcription-PCR, and this increase was Limited to the epithelium, as revealed by in situ hybridization. C ollectively, the results place ErbB2 as a potential candidate receptor subtype for interaction with the EGF-related Ligands in epithelial ce ll proliferation/differentiation during the preimplantation period and stromal cell proliferation/decidualization during the postimplantatio n period.