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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 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.

SUBMITTER: Senger K

PROVIDER: S-EPMC9744554 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Senger Kate K Yuan Wenlin W Sagolla Meredith M Doerr Jonas J Bolon Brad B Ziai James J Sun Kai-Hui KH Warming Soren S Roose-Girma Merone M Zhang Na N Tam Lucinda L Newman Robert J RJ Chaudhuri Subhra S Antony Aju A Goldstein Leonard D LD Durinck Steffen S Jaiswal Bijay S BS Lafkas Daniel D Modrusan Zora Z Seshagiri Somasekar S

Advanced genetics (Hoboken, N.J.) 20201205 1

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 ...[more]

PMID: 36618440

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Project description:IntroductionThe receptor ErbB3/HER3 is often over-expressed in human breast cancers, frequently in conjunction with over-expression of the proto-oncogene ERBB2/HER2/NEU. Although the prognostic/predictive value of ErbB3 expression in breast cancer is unclear, ErbB3 is known to contribute to therapeutic resistance. Understanding ErbB3 functions in the normal mammary gland will help to explain its role in cancer etiology and as a modulator of signaling responses to the mammary oncogene ERBB2.MethodsTo investigate the roles of ErbB3 in mouse mammary gland development, we transplanted mammary buds from ErbB3-/- embryos into the cleared mammary fat pads of wild-type immunocompromised mice. Effects on ductal outgrowth were analyzed at 4 weeks, 7 weeks and 20 weeks after transplantation for total ductal outgrowth, branch density, and number and area of terminal end buds. Sections of glands containing terminal end buds were analyzed for number and epithelial area of terminal end buds. Terminal end buds were also analyzed for presence of mitotic figures, apoptotic figures, BrdU incorporation, and expression of E-cadherin, P-cadherin, alpha-smooth muscle actin, and cleaved caspase-3.ResultsThe mammary ductal trees developed from ErbB3-/- buds only partly filled the mammary fat pad. In contrast to similar experiments with ErbB2-/- mammary buds, this phenotype was maintained through adulthood, pregnancy, and parturition. In addition, and in contrast to similar work with ErbB4-/- mammary buds, lobuloalveolar development of ErbB3-/- transplanted glands was normal. The ErbB3-/- mammary outgrowth defect was associated with a decrease in the size of the terminal end buds, and with increases in branch density, in the number of terminal end buds, and in the number of luminal spaces. Proliferation rates were not affected by the lack of ErbB3, but there was an increase in apoptosis in ErbB3-/- terminal end buds.ConclusionsEndogenous ErbB3 regulates morphogenesis of mammary epithelium.

Dataset Information

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

Publications

Embryonic lethality and defective mammary gland development of activator-function impaired conditional knock-in <i>Erbb3</i> <sup><i>V943R</i></sup> mice.

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