Open AccessEmbryonic lethality and defective mammary gland development of activator‐function impaired conditional knock‐in Erbb3 V943R mice
Author(s) -
Senger Kate,
Yuan Wenlin,
Sagolla Meredith,
Doerr Jonas,
Bolon Brad,
Ziai James,
Sun KaiHui,
Warming Soren,
RooseGirma Merone,
Zhang Na,
Tam Lucinda,
Newman Robert J.,
Chaudhuri Subhra,
Antony Aju,
Goldstein Leonard D.,
Durinck Steffen,
Jaiswal Bijay S.,
Lafkas Daniel,
Modrusan Zora,
Seshagiri Somasekar
Publication year - 2021
Publication title -
advanced genetics
Language(s) - English
Resource type - Journals
ISSN - 2641-6573
DOI - 10.1002/ggn2.10036
Subject(s) - erbb , biology , receptor tyrosine kinase , microbiology and biotechnology , activator (genetics) , tyrosine kinase , erbb3 , kinase , receptor , signal transduction , genetics
ERBB3 is a pseudokinase domain‐containing member of the ERBB family of receptor tyrosine kinases (RTKs). Following ligand binding, ERBB receptors homo‐ or hetero‐dimerize, 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.