ErbB3 Mouse
Description
Cardiac Development
ErbB3 is essential for atrioventricular (AV) cushion morphogenesis:
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Phenotype in ErbB3 Knock-In Mutants: Reduced mesenchymal cell proliferation in AV cushions due to impaired AKT/ERK activation .
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Embryonic Lethality: Defects in Schwann cell precursors and sensory/motor neurons in Erbb3−/− mice .
Mammary Gland Morphogenesis
Conditional deletion in luminal epithelium (MMTV-Cre) disrupts ductal elongation and epithelial cell balance:
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Delayed Ductal Growth: Reduced Ki67+ proliferative cells in terminal end buds (TEBs) .
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Basal Epithelium Expansion: Increased cytokeratin 5 (CK5)+ cells and interleukin 6 (IL-6) production, promoting basal cell growth .
Skin and Wound Healing
ErbB3 is dispensable for epidermal development but critical for tumor promotion and repair:
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Wound Healing: Impaired keratinocyte proliferation post-TPA (12-O-tetradecanoylphorbol-13-acetate) stimulation in Erbb3del mice .
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Tumor Progression: Reduced squamous cell carcinoma burden in Erbb3del mice under DMBA/TPA carcinogenesis .
Mammary Tumorigenesis
In PyVmT (polyomavirus middle T)-driven models, ErbB3 deletion delays tumor onset and reduces metastasis:
| Parameter | Control (ErbB3+/+) | ErbB3-deficient (fl/fl.MCre) |
|---|---|---|
| Tumor Latency (T₅₀) | 42.5 days | 57.5 days |
| Metastasis Incidence | 100% | 62% |
| Total Tumor Weight | 5.93 ± 1.88 g | 3.73 ± 0.99 g |
Skin Carcinogenesis
Erbb3del mice exhibit reduced tumor burden under DMBA/TPA protocols:
| Parameter | Control | Erbb3del |
|---|---|---|
| Tumor Onset | 5 weeks | 10 weeks |
| Tumors per Mouse (20w) | 7.5 | 1.5 |
| Tumor Size (20w) | ~4 mm | ~1 mm |
Therapeutic Targeting
ErbB3 inhibition via antibodies (e.g., seribantumab) blocks HRG/BTC-induced signaling, showing promise in PI3K/Akt-dependent cancers .
Research Implications and Future Directions
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Clinical Relevance: ErbB3 overexpression correlates with resistance to HER2, EGFR, and hormone therapies .
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Biomarker Potential: Activated ErbB3 and downstream p-Akt levels may predict therapeutic response .
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Model Limitations: Conditional knockout models require Cre-driver specificity to avoid off-target effects .
Product Specs
Q&A
What is ErbB3 and what is its expression pattern in mouse tissues?
ErbB3 (HER3) is a receptor tyrosine kinase structurally related to the epidermal growth factor receptor (EGFR). While it has weak kinase activity, it strongly activates downstream signaling pathways through heterodimerization with other ErbB receptor tyrosine kinases .
In the skin, ErbB3 is expressed in all epidermal layers, with highest levels in the suprabasal and spinous layers . In mammary tissue, ERBB3 mRNA expression is highest in luminal epithelial populations and lowest in basal/stem cell populations . Notably, mammary ErbB3 expression peaks during mid-to-late puberty (6-7 weeks), coinciding with maximal specification and maintenance of the luminal epithelium .
What mouse models are available for studying ErbB3 function?
Several genetic mouse models have been developed to study ErbB3 function:
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Conditional knockout models: Mice carrying floxed Erbb3 alleles can be crossed with tissue-specific Cre lines to achieve targeted deletion:
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Embryonic transplantation model: Mammary buds from Erbb3^-/- embryos can be transplanted into cleared mammary fat pads of immunocompromised mice to study ductal morphogenesis .
Is ErbB3 essential for normal development of skin and mammary gland?
The requirement for ErbB3 differs between tissues:
Skin: ErbB3 is largely dispensable for skin development and homeostasis. Mice lacking ErbB3 specifically in keratinocytes (Erbb3^del) show no obvious skin abnormalities, normal tissue architecture, and normal expression patterns of epidermal differentiation markers (K14, K10, and loricrin) . This lack of phenotype may be due to compensatory upregulation of EGFR observed in these mice .
Mammary gland: ErbB3 plays a more critical role in mammary development. Loss of ErbB3 in the luminal mammary epithelium results in delayed ductal lengthening during puberty, decreased thickness of the terminal end bud (TEB) body cell layer, and disorganization of the luminal epithelium . These defects are associated with reduced luminal cell proliferation and survival .
How does ErbB3 loss affect cellular signaling in mouse tissues?
The signaling consequences of ErbB3 deletion vary by tissue:
Mammary epithelium: ErbB3 loss in the luminal mammary epithelium impairs Akt and MAPK signaling, reducing luminal cell proliferation and survival . These signaling defects shift gene expression patterns toward a mammary basal cell/stem cell signature .
Skin: Despite ErbB3 deletion in keratinocytes, major ErbB signaling pathways including MAPK, AKT, P38, and SAPK, as well as S6RP and P70SEK (downstream of AKT), show no significant changes in activation . This may be explained by the compensatory upregulation of EGFR observed in Erbb3^del skin .
What methodological approaches are used to study ErbB3 in wound healing?
For investigating ErbB3's role in wound healing, the following methodology is typically employed:
How does ErbB3 contribute to skin carcinogenesis in mouse models?
ErbB3 plays a significant role in promoting skin tumor development, as demonstrated using the two-step chemical carcinogenesis protocol:
Methodology:
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Tumor initiation: Single application of DMBA
Key findings in Erbb3^del mice:
This indicates that ErbB3 is required for proper tumor progression during chemical carcinogenesis in mice. Similar upregulation of ErbB3 has been observed in human skin tumor samples, including squamous cell carcinoma, condyloma, and malignant melanoma .
How does ErbB3 influence epithelial cell fate decisions in the mammary gland?
ErbB3 plays a crucial role in specifying and/or maintaining the luminal phenotype of breast epithelium, as evidenced by:
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Gene expression changes: ErbB3 loss shifts gene expression patterns away from previously defined luminal signatures toward basal cell signatures .
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Lineage marker alterations: The luminal progenitor population markers ELF5 and KIT decrease in response to ErbB3 loss, suggesting that hierarchical differentiation along the luminal lineage requires ErbB3 for luminal specification and/or maintenance .
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Cross-talk between epithelial compartments: Intriguingly, ErbB3 deletion in luminal epithelium leads to expansion of the basal epithelium through paracrine mechanisms involving cytokine production (including IL-6) . This effect only occurs when ErbB3 is deleted in luminal cells, not when deleted in basal cells .
What is the relationship between ErbB3 expression and breast cancer subtypes in translational mouse models?
ErbB3 expression correlates strongly with luminal differentiation in both normal tissues and cancer:
What controls should be included when studying ErbB3 conditional knockout mice?
When analyzing conditional ErbB3 knockout mice, appropriate controls should include:
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Heterozygous controls: ErbB3^FL/+ with the appropriate Cre recombinase. Heterozygotes typically show no change in mammary phenotype compared to wild-type mice and can serve as controls .
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Validation of deletion: Confirmation of successful recombination of the floxed ErbB3 allele by PCR analysis and validation of protein loss by immunohistochemistry or Western blot .
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Tissue-specific effects: When comparing phenotypes between different tissue-specific knockouts (e.g., MMTV-Cre vs. CK14-Cre), the genetic background and other experimental conditions should be standardized .
How can researchers dissect the compensatory mechanisms that occur in response to ErbB3 loss?
The research suggests several approaches to investigate compensatory mechanisms:
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Protein expression analysis: Western blot analysis should assess not only ErbB3 loss but also potential upregulation of other family members, such as EGFR .
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Signaling pathway analysis: Comprehensive evaluation of multiple signaling pathways (MAPK, AKT, P38, SAPK, S6RP, P70SEK) using phospho-specific antibodies .
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Rescue experiments: Testing whether activation of specific pathways (e.g., Akt and MAPK) can rescue the phenotypes induced by ErbB3 depletion .
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Cytokine analysis: Investigating paracrine mechanisms by analyzing cytokine production (e.g., IL-6) and testing their effects in co-culture systems .
What remains unknown about ErbB3 function in mouse development and disease?
Several important questions remain to be fully addressed:
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Molecular mechanisms: How does ErbB3 specifically regulate the specification and maintenance of the luminal lineage at the molecular level?
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Compensatory mechanisms: What determines whether compensatory mechanisms (like EGFR upregulation) are activated in response to ErbB3 loss in different tissues?
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Therapeutic implications: How can the knowledge of ErbB3's role in maintaining the luminal phenotype inform treatments for different breast cancer subtypes?
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Inter-tissue communication: Further exploration of the paracrine mechanisms by which ErbB3 loss in one epithelial compartment affects other compartments.
Product Science Overview
Tyrosine Kinase ErbB-3, also known as HER3, is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This protein plays a crucial role in cellular signaling pathways that regulate cell proliferation, differentiation, and survival. The recombinant form of ErbB-3, particularly from mouse models, is widely used in research to understand its function and role in various diseases, including cancer.
ErbB-3 is a membrane-bound protein that contains a neuregulin binding domain but lacks an active kinase domain . This means that while it can bind to its ligand, it cannot convey the signal into the cell through protein phosphorylation on its own. Instead, ErbB-3 forms heterodimers with other members of the EGFR family, such as ErbB-2 (HER2), which possess kinase activity . This heterodimerization leads to the activation of downstream signaling pathways that promote cell proliferation and differentiation .
ErbB-3 is expressed in various tissues, including epithelial tissues and the brain . Its expression is tightly regulated, and dysregulation can lead to pathological conditions. Overexpression or amplification of the ErbB-3 gene has been reported in numerous cancers, including prostate, bladder, and breast tumors . This overexpression is often associated with poor prognosis and resistance to certain therapies.
Recombinant ErbB-3 proteins, particularly those derived from mouse models, are invaluable tools in biomedical research. These proteins are typically produced in expression hosts such as HEK293 cells and purified to high levels of purity . Researchers use recombinant ErbB-3 to study its biochemical properties, interaction with other proteins, and role in signaling pathways. Additionally, recombinant ErbB-3 is used in drug discovery and development to screen for potential therapeutic agents that target this receptor.
The study of ErbB-3 has significant clinical implications. Given its role in cancer progression, ErbB-3 is a potential target for cancer therapies. Understanding the mechanisms by which ErbB-3 contributes to tumor growth and resistance to treatment can lead to the development of novel therapeutic strategies. For instance, therapies that disrupt the interaction between ErbB-3 and its heterodimer partners or inhibit its downstream signaling pathways are being explored as potential cancer treatments.
