ErbB2 Is Required for Muscle Spindle and Myoblast Cell Survival

Abstract

Signaling mediated by ErbB2 is thought to play a critical role in numerous developmental processes. However, due to the embryonic lethality associated with the germ line inactivation of erbB2, its role in adult tissues remains largely obscure. Given the expression of ErbB2 at the neuromuscular junction, we have created a muscle-specific knockout to assess its role there. This resulted in viable mice with a progressive defect in proprioception due to loss of muscle spindles. Interestingly, a partial reduction of ErbB2 levels also reduced the number of muscle spindles. Although histological analysis of the muscle revealed an otherwise normal architecture, induction of muscle injury revealed a defect in muscle regeneration. Consistent with these observations, primary myoblasts lacking ErbB2 exhibit extensive apoptosis upon differentiation into myofibers. Taken together, these results illustrate a dual role for ErbB2 in both muscle spindle maintenance and survival of myoblasts.ErbB2 (also known as Neu and HER2) is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (7,13,23). This family is comprised of EGFR (48), ErbB2 (4,12,36,39,48,51), ErbB3 (27), and ErbB4 (35). Gene targeting experiments have revealed that each of these EGFR family members plays a critical role in regulating embryonic development. For example, germ line elimination of erbB2 or erbB4 results in embryonic lethality at day 10.5 of embryogenesis due to defects in cardiac and neural development (19, 28). Although inactivation of erbB3 function has a less severe impact on cardiac development, embryonic lethality is also observed due to defects in neural and Schwann cell differentiation (5,14,38). Interestingly, elimination of EGFR receptor function results in a strain-dependent perinatal lethality (21,41,46).Given the importance of EGFR family members in embryonic development, it has been difficult to elucidate the relative contribution of this family to the maintenance and development of adult tissues. The embryonic lethality associated with inactivation of erbB2 has previously been rescued by myocardial expression of an erbB2 transgene (29,33,49). However, these mice die at birth due to loss of motor neurons and defects in Schwann cell development. To avoid this perinatal lethality, specific deletions may be created to address the role of ErbB2 in various adult tissues through the use of the Cre/ LOXP1 recombinase system. Indeed this approach has been used to generate a peripheral-nerve-specific deletion of erbB2 that resulted in the extensive demyelination of the nerves (17, 18).In addition to its role in Schwann cell development, ErbB2 is expressed in skeletal muscle and is concentrated at the neuromuscular junction (NMJ) along with ErbB3 and ErbB4 EGFR family members (1, 34, 52). Indeed, EGFR family members have been implicated as important functional components of the NMJ (24). Neuregulins serve as ligands for ErbB3 and ErbB4 and are released from the motor neuron end plate, where they are thought to act...

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

“…32 The expression of EGFR has been also demonstrated in rhabdomyosarcoma cell lines, in which abrogation of EGFR expression was found to impair proliferative ability. 23 Likewise, ErbB-2 is required for myoblast cell survival, 33 and ectopic expression of ErbB-2 in a transgenic mouse that lacks the p53 tumor suppressor gene has been shown to promote rhabdomyosarcoma development 34 (although p53 mutation frequency has been found to be extremely low in rhabdomyosarcoma tumors 35 ). Therefore, EGFR and ErbB-2 seem to be associated with rhabdomyogenesis and appear to play a role in rhabdomyosarcoma development in the mouse.…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Proprioceptive defect due to loss of muscle spindles Decreased myoblast survival [191] Colonic epithelial and enteric nervous system deletion Enteric neuron and glia loss postnatally Colonic distension [192] Mammary epithelial deletion…”

Skeletal muscle stem cells express anti-apoptotic ErbB receptors during activation from quiescence

“…Within myoblasts, the functions attributed to erbB signalling 669 include neuregulin/erbB3-mediated promotion of differentia-670 tion and fusion [33] and erbB2-dependent survival of differ-671 entiating myoblasts [21]. Specifically, erbB2 conditional 672 knockout mice have been created, in which the muscle 673 creatine kinase promoter (MCK) drives Cre-mediated excision 674 of floxed erbB2 exclusively in heart and skeletal muscles [21].…”

“…Specifically, erbB2 conditional 672 knockout mice have been created, in which the muscle 673 creatine kinase promoter (MCK) drives Cre-mediated excision 674 of floxed erbB2 exclusively in heart and skeletal muscles [21].…”

“…However, MCK is not 677 expressed by undifferentiated satellite cells [58] and only 678 becomes expressed during myoblast differentiation [21], so 679 the role of erbB2 during the early stages of muscle regenera-680 tion could not be assessed in that model.…”