Embryonic lethality and defective mammary gland development in activator function impaired conditional knock-in ErbB3V943R mice

ERBB3, a pseudo-kinase domain containing human epidermal growth factor receptor (ERBB/HER) family member, plays a key role in multiple cellular processes and is required for normal embryonic development. Following ligand binding, ERBB3 heterodimerizes preferentially with ERBB2, leading to allosteric kinase activation and signaling. ERBB3 has been shown to function primarily as an activator kinase that activates the receiver kinase in the asymmetric dimer activation complex. Structural studies of the activator-receiver interface have identified V943 as a key residue required for ERBB3 mediated activation of ERBB2. Here we report the generation of a knock-in mouse model where the endogenous ErbB3 allele was modified to allow tissue-specific conditional expression of ErbB3V943R (ErbB3CKI-V943R). Activation of ErbB3V943R expression during development resulted in embryonic lethality at around E12.0. Analysis of the embryos reveals thinning of the myocardium and reduced mesenchyme within the endocardial cushion of the heart, reminiscent of ErbB3 knockout mice. Tissue specific expression of ErbB3V943R in the epithelial cells of the mammary gland using an MMTV-Cre driver results in delayed elongation of the ductal network during puberty. Consistent with this, single cell RNA-seq analysis showed a reduction in a specific subset of fibrinogen-producing luminal epithelial cells. Our studies establish the importance in vivo of the allosteric interface in activation of the ERBB family and also provides an important tool that can be used to understand the role of ERBB3 in cancer development. Single-cell RNA sequencing of luminal epithelial cells from 6-week old wild-type or ErbB3 V943R conditional mutant mammary glands