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...

SUMMARY1. The nerves to cat peroneus longus and tenuissimus muscles were either cut or crushed close to the muscle and the afferent and efferent nerve supply to the muscle spindles was studied electrophysiologically between 2 and 32 weeks later.2. Recovery was more rapid and complete after crush than section for both afferent and efferent fibres. After recovery from either procedure normal primary and secondary afferents and static and dynamic y efferent fibres were found.

1. The site of termination of static and dynamic fusimotor fibres has been mapped by finding which intrafusal muscle fibres have been depleted of glycogen as a result of tetanic stimulation of single γ fibres. Long periods of stimulation coupled with occlusion of the blood supply were necessary to cause glycogen depletion. 2. In cat tenuissimus muscle, dynamic γ motor fibres always activated bag intrafusal muscle fibres, and occasionally chain fibres. Static γ fibres always activated chain fibres and frequently activated bag fibres as well. 3. It is argued that these results can be fitted into the hypothesis of the mechanism of internal functioning of the spindle originally proposed by Jansen & Matthews (1962). It is also pointed out that the results raise problems concerning the mechanism of development of the spindle motor innervation.

Background-Skeletal muscle structure and function are dependent on intact Richard Butler, Ph.D. innervation. Prolonged muscle denervation results in irreversible muscle fiber James R. Bain, M.D. atrophy, connective tissue hyperplasia, and deterioration of muscle spindles, Margaret Fahnestock, Ph.D. specialized sensory receptors necessary for proper skeletal muscle function. The protective effect of temporary sensory innervation on denervated muscle, before motor nerve repair, has been shown in the rat. Sensory-protected muscles exhibit less fiber atrophy and connective tissue hyperplasia and maintain greater functional capacity than denervated muscles. The purpose of this study was to determine whether temporary sensory innervation also protects muscle spindles from degeneration.