Neuregulin receptors, erbB3 and erbB4, are localized at neuromuscular synapses.

Abstract

Neuregulin (NRG) is concentrated at synaptic sites and stimulates expression of acetylcholine receptor (AChR) genes in muscle cells grown in cell culture. These results raise the possibility that NRG is a synaptic signal that activates AChR gene expression in synaptic nuclei. Stimulation of NRG receptors, erbB3 and erbB4 initiates oligomerization between these receptors or between these receptors and other members of the epidermal growth factor (EGF) receptor family, resulting in stimulation of their associated tyrosine kinase activities. To determine which erbBs might mediate synapse‐specific gene expression, we used antibodies against each erbB to study their expression in rodent skeletal muscle by immunohistochemistry. We show that erbB2, erbB3 and erbB4 are concentrated at synaptic sites in adult skeletal muscle. ErbB3 and erbB4 remain concentrated at synaptic sites following denervation, indicating that erbB3 and erbB4 are expressed in the postsynaptic membrane. In addition, we show that expression of NRG and erbBs, like AChR gene expression, increases at synaptic sites during postnatal development. The localization of erbB3 and erbB4 at synaptic sites is consistent with the idea that a NRG‐stimulated signaling pathway is important for synapse‐specific gene expression.

Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle

“…Consistent with other investigators, we have demonstrated the expression and localization of ErbB2, ErbB3, and ErbB4 proteins in skeletal muscle and the enrichment of these receptors at the NMJ (2,14,15,25,40,48). A novel finding in our study is the increased expression of ErbB3 in the EDL, a predominantly fasttwitch, glycolytic muscle compared with the soleus, a predominantly slow-twitch, oxidative muscle.…”

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

“…Frozen sections (10 µm) from fixed, adult leg muscles were stained with antibodies as described previously (DeChiara et al, 1996;Zhu et al, 1995). The following primary antibodies were used: affinitypurified rabbit anti-rapsyn (1:500) (Herbst and Burden, 2000), mouse anti-utrophin C terminus (1:20, Vector Labs), rabbit anti-Na + channel (1:1000, Upstate), rabbit anti-ErbB4 (antibody # 616) (Zhu et al, 1995), rabbit anti-synaptophysin (1:20, Zymed), mouse anti-SV2 (1:10) (Buckley and Kelly, 1985) and rabbit anti-Musk (#83033, 1:4000 and #24908, 1:50) (Watty et al, 2000).…”

“…The following primary antibodies were used: affinitypurified rabbit anti-rapsyn (1:500) (Herbst and Burden, 2000), mouse anti-utrophin C terminus (1:20, Vector Labs), rabbit anti-Na + channel (1:1000, Upstate), rabbit anti-ErbB4 (antibody # 616) (Zhu et al, 1995), rabbit anti-synaptophysin (1:20, Zymed), mouse anti-SV2 (1:10) (Buckley and Kelly, 1985) and rabbit anti-Musk (#83033, 1:4000 and #24908, 1:50) (Watty et al, 2000). We were unable to detect fluorescence from the Musk-GFP transgene.…”

Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation

“…For example, the common transmembrane topology of mesenchymal isoforms, which is not shared by most neuronal factors, may enhance binding and increase availability of the lower a nity ligands. This proposition is supported by the apparent short range of NDF/neuregulin action in vivo, including its involvement in cardiac development (Gassmann et al, 1995;Lee et al, 1995;Meyer and Birchmeier, 1995), contact-induced mitosis of Schwann cells by neuron-expressed neuregulins (Morrissey et al, 1995), co-localization of neuregulin and its receptors in the neuromuscular synapse (Zhu et al, 1995), and mesenchyme-epithelia interaction during mammary gland development (Yang et al, 1995).…”