Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development

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 ␣-AChR, AChE, ⑀-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.

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…In addition, mice deficient in ErbB2 show defects in cranial sensory ganglia likely due to defects in cranial neural crest [119,123]. ErbB2 plays a role in the terminal differentiation of oligodendrocyte precursors to mature oligodendrocytes in the spinal cord [124] as well as in the myelination of peripheral nerves by Schwann cells [125][126][127]. Rescue of the embryonic lethal cardiac defects of ErbB2-deficient mice by myocardium-restricted expression of wild-type ErbB2 results in mice with severe defects in Schwann cell migration in the peripheral nervous system with loss of sensory and motor neurons [125,126].…”

“…Neuregulin-1 is expressed in the endocardium and appears to act in a paracrine fashion through myocardium-restricted ErbB2 and ErbB4 to stimulate myocardial trabeculae formation [129,137]. Neuregulin-1-deficient mice also have deficient Schwann cell and cranial ganglia formation similar to those seen in ErbB2 and ErbB3 mutant mice [120,[125][126][127][128]137]. Similarly, deletion of HB-EGF, a ligand for both EGFR and ErbB4, leads to dilated cardiomyopathy similar to conditional mutant mice lacking ErbB2 or ErbB4 in the ventricular myocardium [138].…”

“…Table 1 ErbB receptor-ligand binding specificity. [125,126] Ventricular cardiomyocyte specific deletion Dilated cardiomyopathy Cardiomyocyte sensitivity to anthracycline toxicity [121,122] Cell Mol Life Sci. Author manuscript; available in PMC 2011 March 17.…”

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…In particular, the myelinating glia of the PNS, Schwann cells, depend on Nrg1, and we concentrate on discussing this function here. In Schwann cells, the Nrg1 signal is mediated by two receptors, ErbB2 and ErbB3 (Woldeyesus et al, 1999), and these receptors are unusual in the respect that ErbB3 lacks tyrosine kinase activity, whereas ErbB2 is a ligand-less receptor (Citri et al, 2003). They function as heterodimers where ErbB2 and ErbB3 provide the tyrosine kinase and the ligand binding activity, respectively.…”

Neuregulin 1 Role in Schwann Cell Regulation and Potential Applications to Promote Peripheral Nerve Regeneration

“…The absence of NRG1-type III (Wolpowitz et al, 2000) or of the co-receptors ErbB3 or ErbB2 (Morris et al, 1999;Woldeyesus et al, 1999) give rise to animals without or with severely reduced SC precursors; the absence of NRG1-type I/II give rise to normal SC (Meyer et al, 1997), suggesting that NRG1-type III is the most important isoform for SC development. Nevertheless, it has been shown -in the embryonic chick -that soluble NRG1 is also released by axons during the critical period of SC survival (Ma, Wang, Song, & Loeb, 2011).…”