Embryonic lethality and defective mammary gland development of activator‐function impaired conditional knock‐in Erbb3^V943R mice

Abstract

ERBB3 is a pseudokinase domain-containing member of the ERBB family of receptor tyrosine kinases (RTKs). Following ligand binding, ERBB receptors homo-or heterodimerize, leading to a head-to-tail arrangement of the intracellular kinase domains, where the "receiver" kinase domain of one ERBB is activated by the "activator" domain of the other ERBB in the dimer. In ERBB3, a conserved valine at codon 943 (V943) in the kinase C-terminal domain has been shown to be important for its function as an "activator" kinase in vitro. Here we report a knock-in mouse model where we have modified the endogenous Erbb3 allele to allow for tissue-specific conditional expression of Erbb3 V943R (Erbb3 CKI-V943R). Additionally, we generated an Erbb3 D850N (Erbb3 CKI-D850N) conditional knock-in mouse model where the conserved aspartate in the DFG motif of the pseudokinase domain was mutated to abolish any potential residual kinase activity. While Erbb3 D850N/D850N animals developed normally, homozygous Erbb3 V943R/V943R expression during development resulted in embryonic lethality. Further, tissue specific expression of Erbb3 V943R/V943R in the mammary gland epithelium following its activation using MMTV-Cre resulted in delayed elongation of the ductal network during puberty. Single-cell RNA-seq analysis of Erbb3 V943R/V943R mammary glands showed a reduction in a specific subset of fibrinogen-producing luminal epithelial cells.

The Signaling of Neuregulin-Epidermal Growth Factor Receptors and Its Impact on the Nervous System

“…Conversely, ErbB4 plays a critical role in the assembly of GABAergic circuitry [29][30][31][32], while ErbB3 is necessary for myelination in the central and peripheral nervous systems [33][34][35] (Figure 2). Although ErbB3 is expressed in the developing brain, its role in central nervous system development remains unknown due to the embryonic lethality caused by null mutation [36]. The NRG-ErbB signaling pathway appears to be common among mammals, functioning in both mice and humans.…”

“…The mutant not only lacks Schwann cells but also exhibits a loss of ErbB3-negative sensory dorsal root ganglia (DRG) neurons and spinal motor neurons [76][77][78]. The first in vivo evidence for the critical function of NRG1/ErbB signaling in the PNS came from mutant mice lacking Erbb3 [36]. Some mutant embryos develop until birth but die shortly after, exhibiting lethal neuropathy characterized by breathing defects and defects in the regulation of functional Transient Receptor Potential Vanilloid 1-Receptor (TRPV1) along sensory neuron axons [78].…”