Rescue of the Cardiac Defect in ErbB2 Mutant Mice Reveals Essential Roles of ErbB2 in Peripheral Nervous System Development

Abstract

ErbB2 receptor tyrosine kinase plays a role in neuregulin signaling and is expressed in the developing nervous system. We genetically rescued the cardiac defect of erbB2 null mutant embryos, which otherwise died at E11. These rescued erbB2 mutant mice die at birth and display a severe loss of both motor and sensory neurons. Motor and sensory axons are severely defasciculated and aberrantly projected within their final target tissues. Schwann cells are completely absent in the peripheral nerves. Schwann cell precursors are present within the DRG and proliferate normally, but their ability to migrate is decreased. Acetylcholine receptors cluster within the central band of the mutant diaphragm muscle. However, these clusters are dispersed and morphologically different from those in control muscle. Our results reveal an important role for erbB2 during normal peripheral nervous system development.

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“…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.…”

Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

“…ErbB2 or ErbB4 knockout mice died around E10.5 due to cardiac defects. Cardiac specific overexpression of the ErbB2 receptor in ErbB2 knockout mice restored normal ventricular trabeculation (Morris et al, 1999). These data suggest that the effects of Neuregulin1 proteins on cardiac development depend on both ErbB2 and ErbB4 receptors.…”

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).…”