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ErbB4 signaling during breast and neural development: novel genetic models reveal unique ErbB4 activities
Frank E Jones1, Jon P Golding, Martin Gassmann
1Tulane University Health Sciences Center, Tulane Cancer Center, Department of Structural and Cellular Biology, New Orleans, Louisiana, USA. fjones@tulane.edu
Abstract:
The erbB4 gene encodes one of the four members of the mammalian ErbB family of transmembrane tyrosine kinases. The ErbB4 protein plays a role as a receptor for the neuregulins, a large group of structurally related molecules and a few other epidermal growth factor (EGF)-related polypeptides, such as heparin-binding EGF, betacellulin and epiregulin. The importance of this receptor tyrosine kinase in development has been demonstrated by the generation of mice with a targeted inactivation of the erbB4 gene. Such mice die by embryonic day eleven due to defective trabeculation in the heart, precluding analysis of phenotypes at later stages in development and in the adult. Now, using two unique genetic approaches our laboratories succeeded in overcoming this obstacle. In the first approach, the heart defects of ErbB4 null mutant mice were rescued by transgenic expression of an ErbB4 cDNA under a cardiac-specific myosin promoter. This allowed the generation of ErbB4 mutants that develop into adulthood and are fertile. In the second approach, the role of ErbB4 during mammary gland development was specifically addressed by Cre-mediated deletion of both erbB4 alleles within the mammary epithelium. Below we discuss the progress made studying these genetic models in understanding the physiological roles of ErbB4 with a focus on the mammary gland and the nervous system.
Insights
Researchers developed genetic models to study the ErbB4 receptor tyrosine kinase. These models overcome early lethality, enabling analysis of ErbB4
Area of Science:
- Molecular and Cellular Biology
- Developmental Biology
- Genetics
Background:
- The ErbB4 gene encodes a receptor tyrosine kinase crucial for mammalian development.
- ErbB4 acts as a receptor for neuregulins and other epidermal growth factor (EGF)-related polypeptides.
- Previous studies showed ErbB4 deficiency causes embryonic lethality due to cardiac defects.
Purpose of the Study:
- To overcome embryonic lethality in ErbB4-deficient mice.
- To investigate the physiological roles of ErbB4 in adult mammals, particularly in the mammary gland and nervous system.
Main Methods:
- Generated heart-defect-rescued ErbB4 null mutant mice using transgenic ErbB4 cDNA expression.
- Utilized Cre-mediated deletion to specifically remove ErbB4 alleles in the mammary epithelium.
- Studied phenotypes in adult mice and during mammary gland development.
Main Results:
- Successfully generated viable and fertile adult ErbB4 mutant mice by rescuing cardiac defects.
- Established a model to specifically study ErbB4 function in the mammary gland.
- Enabled further investigation into ErbB4's roles in the nervous system.
Conclusions:
- Developed novel genetic models to study the essential roles of ErbB4 beyond embryonic development.
- These models facilitate detailed analysis of ErbB4 function in the mammary gland and nervous system.
- Further research using these models will elucidate the complex physiological functions of ErbB4.
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