Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor
Tang-Cheng Lee1, David W Threadgill
1Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Abstract:
The epidermal growth factor receptor (EGFR) is important for normal homeostasis in a variety of tissues and, when abnormally expressed or mutated, contributes to the development of many diseases. However, in vivo functional studies are hindered by the lack of adult mice lacking EGFR because of the pre- and postnatal lethality of EGFR deficient mice. We generated a conditional allele of Egfr (Egfr(tm1Dwt)) by flanking exon 3 with loxP sites in order to investigate tissue-specific functions of this widely expressed receptor tyrosine kinase. The activity of the Egfr(tm1Dwt) allele is indistinguishable from wildtype Egfr. Conversely, the Egfr(Delta) allele, generated by Cre-mediated deletion of exon 3 using the germline EIIa-Cre transgenic line, functions as a null allele. Egfr(Delta/Delta) embryos that have complete ablation of EGFR activity and die at mid-gestation with placental defects identical to those reported for mice homozygous for the Egfr(tm1Mag) null allele. We also inactivated the Egfr(tm1Dwt) allele tissue-specifically in the skin epithelium using the K14-Cre transgenic line. These mice were viable but exhibited wavy coat hair remarkably similar to mice homozygous for the Egfr(wa2) hypomorphic allele or heterozygous for the Egfr(Wa5) antimorphic allele. These results suggest that the hairless phenotype of Egfr nullizygous mice is not solely due to absence of EGFR in the epithelium, but that EGFR activity is required also in skin stromal cells for normal hair morphogenesis. This new mouse model should have wide utility to inactivate Egfr conditionally for functional analysis of EGFR in adult tissues and disease states.
Insights
Researchers developed a new conditional mouse model to study epidermal growth factor receptor (EGFR) functions in adult tissues. This model overcomes the lethality issues of EGFR-deficient mice, enabling new insights into EGFR
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) is crucial for tissue homeostasis.
- Abnormal EGFR expression or mutations are linked to various diseases.
- Studying EGFR's in vivo function in adult tissues is challenging due to embryonic lethality of EGFR-deficient mice.
Purpose of the Study:
- To generate a conditional mouse model for tissue-specific inactivation of the epidermal growth factor receptor (EGFR) gene (Egfr).
- To investigate the role of EGFR in adult tissues, particularly in skin and hair development.
- To overcome the limitations of embryonic lethality associated with EGFR deficiency.
Main Methods:
- Generated a conditional Egfr allele (Egfr(tm1Dwt)) by flanking exon 3 with loxP sites.
- Created a null allele (Egfr(Delta)) via Cre-mediated deletion of exon 3 using the EIIa-Cre line.
- Used K14-Cre transgenic mice to achieve tissue-specific inactivation of Egfr in the skin epithelium.
Main Results:
- Egfr(Delta/Delta) embryos exhibited mid-gestation lethality with placental defects, confirming EGFR's essential role.
- Tissue-specific inactivation of Egfr in skin epithelium (K14-Cre) resulted in viable mice with wavy coat hair.
- The hair phenotype suggests EGFR activity is required in both skin epithelium and stromal cells for normal hair morphogenesis.
Conclusions:
- The novel conditional Egfr allele provides a valuable tool for studying EGFR function in adult tissues.
- EGFR plays a critical role in hair morphogenesis, requiring its activity in both epithelial and stromal compartments of the skin.
- This mouse model will facilitate research into EGFR's role in various physiological processes and disease states.
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