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Differential Expression of the erbB2 Gene in the Periimplantation Mouse Uterus: Potential Mediator of Signaling by Epidermal Growth Factor-Like Growth Factors¹

Department of Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160-7336

Address all correspondence and requests for reprints to: Dr. S. K. Das, Department of Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160-7338.

Ligand-receptor signaling with the epidermal growth factor (EGF) family of growth factors in the uterus and embryo is considered to be important for implantation. The EGF family includes EGF, transforming growth factor-, heparin binding-EGF, amphiregulin, betacellulin, epiregulin, and heregulins, whereas the receptor family (the erbB genes) consists of erbB1 (EGF-receptor, EGF-R), erbB2, erbB3, and erbB4. Interactions of uterine EGF-R with EGF-like ligands have been examined, but limited information is available regarding the status of other receptor subtypes. Thus, we examined the expression of the erbB2 gene in the mouse uterus during the periimplantation period (days 1–8 of pregnancy) and after 17ß-estradiol and/or progesterone stimulation. Northern blot hybridization detected two transcripts (4.0 and 5.0 kb) of erbB2 messenger RNA (mRNA) in day 1–8 uterine polyadenylated RNA samples. In situ hybridization experiments showed unique uterine cell-specific erbB2 mRNA distribution. On days 1–4, unlike the full-length erbB1 mRNA which is not expressed in the uterine epithelium, the erbB2 mRNA was detected primarily in epithelial cells; the day 1 uterus showed the highest accumulation. On day 5, the epithelium and the decidualizing stromal cells around the implanting blastocyst exhibited accumulation of this mRNA. On days 6–8, the accumulation persisted in the epithelium at both the implantation and interimplantation sites in addition to modest levels of signals in the secondary decidual zone. On days 7 and 8, accumulation of the erbB2 mRNA was also prominent in the trophoblastic giant cells. Western blotting detected a predicted protein of 185 kDa in day 4 uterine membrane preparations. Results of immunocytochemistry demonstrated colocalization of the erbB2 protein with its mRNA in the periimplantation uterus. The uterine ErbB2 underwent phosphorylation by several members of the EGF family. Treatment of adult ovariectomized mice with 17ß-estradiol, but not progesterone, up-regulated the expression of the erbB2 mRNA by more than 3.5-fold, as determined by quantitative reverse transcription-PCR, and this increase was limited to the epithelium, as revealed by in situ hybridization. Collectively, the results place ErbB2 as a potential candidate receptor subtype for interaction with the EGF-related ligands in epithelial cell proliferation/differentiation during the preimplantation period and stromal cell proliferation/decidualization during the postimplantation period.

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