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

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

PROVIDER: PRJNA610579 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11245007_1.fastq.gz	Fastqsanger.gz
	SRR11245007_2.fastq.gz	Fastqsanger.gz
	SRR11245008_1.fastq.gz	Fastqsanger.gz
	SRR11245008_2.fastq.gz	Fastqsanger.gz
	SRR11245009_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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

Project description: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.

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