erbB genes in the mouse uterus: cell-specific signaling by epidermal growth factor (EGF) family of growth factors during implantation.

We previously described spatiotemporal expression of various epidermal growth factor (EGF)-like ligands and receptor subtypes, ErbB1 and ErbB2, during the peri-implantation period. To better understand the roles of these ligands and their possible signaling schemes in implantation, it is important to define the status of all the ligands and receptor subtypes in the uterus/embryo. No information is available about uterine and embryonic status of ErbB3 or ErbB4 during implantation. We cloned mouse erbB3 and erbB4 cDNAs and examined their expression and bioactivity in the peri-implantation uterus (days 1-8). Two erbB3 (cytoplasmic and extracellular) and three erbB4 (two cytoplasmic and one extracellular) clones were generated. Both forms of the erbB3 clone showed similar transcript profiles, while different transcript profiles were obtained with erbB4 clones. The steady-state levels of erbB3 and erbB4 mRNAs in whole uterine poly(A)+ RNA samples showed little changes during the peri-implantation period, while their unique cell-specific accumulation was noted. erbB3 is predominantly expressed in the epithelial cells, although decidual and embryonic cells also accumulate this mRNA. In contrast, the erbB4 mRNA is primarily expressed in the submyometrial stroma and myometrial connective tissues during this period. Additionally, the extracellular form of the erbB4 clone detected signals in a subpopulation of stromal cells. Autophosphorylation and immunoprecipitation studies provided evidence that uterine ErbB3 and ErbB4 are biologically active. This study provides a comprehensive analysis of possible ligand-receptor signaling schemes for EGF-like ligands in implantation.