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Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development
M T Woldeyesus1, S Britsch, D Riethmacher
1Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany.
Abstract:
The ErbB2 tyrosine kinase functions as coreceptor for the neuregulin receptors ErbB3 and ErbB4 and can participate in signaling of EGF receptor (ErbB1), interleukin receptor gp130, and G-protein coupled receptors. ErbB2(-/-) mice die at midgestation because of heart malformation. Here, we report a genetic rescue of their heart development by myocardial expression of erbB2 cDNA that allows survival of the mutants to birth. In rescued erbB2 mutants, Schwann cells are lacking. Motoneurons form and can project to muscle, but nerves are poorly fasciculated and disorganized. Neuromuscular junctions form, as reflected in clustering of AChR and postsynaptic expression of the genes encoding the alpha-AChR, AChE, epsilon-AChR, and the RI subunit of the cAMP protein kinase. However, a severe loss of motoneurons on cervical and lumbar, but not on thoracic levels occurs. Our results define the roles of Schwann cells during motoneuron and synapse development, and reveal different survival requirements for distinct motoneuron populations.
Insights
Genetic rescue of ErbB2 tyrosine kinase in mice allowed survival to birth, revealing Schwann cells are crucial for motoneuron development and survival, particularly in specific nerve populations.
Area of Science:
- Developmental biology
- Neuroscience
- Molecular biology
Background:
- ErbB2 tyrosine kinase is essential for heart development, and its absence leads to embryonic lethality.
- ErbB2 functions as a coreceptor in various signaling pathways, including those involving neuregulin receptors.
Purpose of the Study:
- To investigate the role of ErbB2 in heart development and survival.
- To determine the consequences of lacking Schwann cells, which are absent in rescued ErbB2 mutants, on motoneuron and neuromuscular junction development.
Main Methods:
- Genetic rescue of ErbB2 deficiency by expressing erbB2 cDNA in the myocardium.
- Analysis of heart development, peripheral nerve formation, and neuromuscular junctions in rescued ErbB2 mutant mice.
Main Results:
- Myocardial expression of erbB2 cDNA rescued heart development, allowing ErbB2(-/-) mice to survive to birth.
- Rescued mutants lacked Schwann cells, leading to disorganized peripheral nerves and neuromuscular junctions.
- Despite synapse formation, a significant loss of motoneurons occurred in cervical and lumbar regions, but not thoracic levels.
Conclusions:
- Schwann cells play a critical role in the proper development and organization of peripheral nerves and neuromuscular junctions.
- Distinct motoneuron populations exhibit differential survival requirements, highlighting the complexity of neuronal development and maintenance.