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A Reverse Genetic Approach to Test Functional Redundancy During Embryogenesis
Published on: August 11, 2010
Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor
M Gassmann1, F Casagranda, D Orioli
1Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Abstract:
Various in vitro studies have suggested that ErbB4 (HER4) is a receptor for the neuregulins, a family of closely related proteins implicated as regulators of neural and muscle development, and of the differentiation and oncogenic transformation of mammary epithelia. Here we demonstrate that ErbB4 is an essential in vivo regulator of both cardiac muscle differentiation and axon guidance in the central nervous system (CNS). Mice lacking ErbB4 die during mid-embryogenesis from the aborted development of myocardial trabeculae in the heart ventricle. They also display striking alterations in innervation of the hindbrain in the CNS that are consistent with the restricted expression of the ErbB4 gene in rhombomeres 3 and 5. Similarities in the cardiac phenotype of ErbB4 and neuregulin gene mutants suggest that ErbB4 functions as a neuregulin receptor in the heart; however, differences in the hindbrain phenotypes of these mutants are consistent with the action of a new ErbB4 ligand in the CNS.
Insights
ErbB4 (HER4) is vital for heart muscle development and central nervous system axon guidance in vivo. Mice lacking ErbB4 show severe cardiac defects and altered hindbrain innervation, highlighting its essential role in development.
Area of Science:
- Developmental Biology
- Neuroscience
- Cardiovascular Biology
Background:
- In vitro studies suggest ErbB4 (HER4) acts as a receptor for neuregulins, proteins involved in neural and muscle development.
- Neuregulins are implicated in mammary epithelial differentiation and oncogenic transformation.
Purpose of the Study:
- To investigate the in vivo function of ErbB4 in cardiac muscle differentiation and central nervous system (CNS) axon guidance.
- To elucidate the role of ErbB4 in embryonic development.
Main Methods:
- Generation and analysis of ErbB4-deficient mice.
- Phenotypic characterization of cardiac and CNS development in mutant embryos.
- Comparison with existing neuregulin gene mutant phenotypes.
Main Results:
- Mice lacking ErbB4 exhibit embryonic lethality due to failed myocardial trabeculae development in the heart ventricle.
- ErbB4 deficiency leads to significant alterations in hindbrain innervation within the CNS.
- Expression of ErbB4 is restricted to specific rhombomeres (3 and 5) in the developing hindbrain.
Conclusions:
- ErbB4 is an essential in vivo regulator of cardiac muscle differentiation and CNS axon guidance.
- ErbB4 likely functions as a neuregulin receptor in the heart, based on phenotypic similarities.
- Distinct hindbrain phenotypes suggest ErbB4 may interact with additional ligands in the CNS.
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