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

• Published in: Genetics & genomics next Vol. 2; no. 1; p. e10036
• Main Authors: Senger, Kate, Yuan, Wenlin, Sagolla, Meredith, Doerr, Jonas, Bolon, Brad, Ziai, James, Sun, Kai-Hui, Warming, Soren, Roose-Girma, 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
• Format: Journal Article
• Language: English
• Published: United States 01-03-2021
• Subjects: basic medical sciences; genetics; animal genetics; genetics or genomics; molecular medicine; developmental genetics; medicine
• ISSN: 2641-6573; 2641-6573
• DOI: 10.1002/ggn2.10036

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
. Here we report a knock-in mouse model where we have modified the endogenous
allele to allow for tissue-specific conditional expression of
(
). Additionally, we generated an
(
) 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
animals developed normally, homozygous
expression during development resulted in embryonic lethality. Further, tissue specific expression of
in the mammary gland epithelium following its activation using
resulted in delayed elongation of the ductal network during puberty. Single-cell RNA-seq analysis of
mammary glands showed a reduction in a specific subset of fibrinogen-producing luminal epithelial cells.