The AChR subunit genes, including the delta subunit gene, are transcribed selectively in myofiber nuclei located near the synaptic site. It has been shown that erbB2, erbB3 and erbB4 receptor tyrosine kinases are clustered at synaptic sites in skeletal myofibers in vivo. However, it is not known if activation of these receptor tyrosine kinases leads to activation of AChR gene expression. This proposal will determine which of the erbB receptors, if any, are required for synapse specific AChR gene expression in vivo. First dominant negative form of erbB2 will be expressed in skeletal muscle in vivo. A decrease in transcription from the AChR-delta subunit gene will implicate erbB receptor signalling in synapse-specific gene expression. To determine which of these receptors or combination of receptors are required for synapse specific gene expression, the erbB3 and erbB4 genes will be deleted selectively in mouse skeletal myofibers using the cre-lox system. Synaptic expression of AChR subunits will be assayed in muscle fibers from mutant mice using in situ hybridization. Decreased expression of AChR subunits in mutant myofibers will implicate specific receptors in the neuregulin stimulated transcriptional pathway. An understanding of AChR gene regulation at skeletal neuromuscular junction will provide important information about the mechanisms used to regulate erbB dependent expression of other genes in muscle and in other postsynaptic tissues in the CNS.
| Bothe, G W; Haspel, J A; Smith, C L et al. (2000) Selective expression of Cre recombinase in skeletal muscle fibers. Genesis 26:165-6 |
