AbstractDimerization and activation of ErbB receptors by their ligands play crucial roles in organogenesis. Epithelial morphogenesis of embryonic mouse submandibular gland (SMG) has been shown to depend on intraepithelial signaling mediated by the epidermal growth factor (EGF) family of molecules and the EGF receptor (ErbB1). Here, we report on the neuregulin (NRG) ‐1 protein and its receptors ErbB2 and ErbB3 in the developing SMG. The expression of these molecules was demonstrated by reverse transcriptase‐polymerase chain reaction and Western blot analysis. Immunofluorescence microscopy showed that the two ErbB receptors as well as ErbB1 were expressed mainly in the epithelium, whereas NRG‐1 was exclusively found in the mesenchyme. Epithelial morphogenesis was retarded by anti–NRG‐1 neutralizing antibody and promoted by recombinant NRG‐1 protein. We suggest that, in the developing SMG, both mesenchyme‐derived NRG molecules and epithelium‐derived EGF molecules regulate ErbB signaling in the epithelium to participate in tissue morphogenesis. Developmental Dynamics 230:591–596, 2004. © 2004 Wiley‐Liss, Inc.