The goal of this project is to elucidate the mechanisms by which neuregulin (NRG-1), acting through heterodimers or homodimers of erbB receptor tyrosine kinases (erbB2, erbB3 and erbB4), regulates synaptic gene expression at neuromuscular junctions (NMJs). Several lines of evidence suggest that NRG-1 signaling pathways play an important role in Schwann cell development and AChR gene expression. NMJs are comprised of precisely aligned nerve terminals, Schwann cells and muscle cells. A cardinal feature of the NMJ is the presence of a postsynaptic apparatus containing high concentrations of acetylcholine receptors (AChRs) closely associated with numerous extracellular, transmembrane, and cytoplasmic scaffolding and signaling components. The AChR complex in embryonic muscle is organized as a pentamer comprised of four distinct subunits, alpha, beta, gamma, and delta, in the stoichiometry alpha2, beta, gamma, delta. The composition of the AChR undergoes a postnatal switch from alpha2, beta, gamma, delta (embryonic form) to alpha2, beta, epsilon, delta (adult form). The switch from gamma to epsilon subunit occurs during the first two postnatal weeks. Regulation of embryonic and adult AChR subunit gene expression has been an excellent model to understand synapse-specific gene expression. In the present proposal, we will determine the physiological role of erbB receptors in synapse-specific AChR gene expression by generating mice deficient in different erbB receptor heterodimers or homodimers during development or after birth. Furthermore, primary muscle cells will be established from these mutant mice to elucidate signal transduction pathways underlying synapse-specific AChR gene expression.
The aims are:
Aim 1. To determine the role of the neuregulin signaling pathway in AChR gene expression during embryonic development Aim 2. To determine the role of the neuregulin signaling pathway in regulating expression of adult AchRe subunit Aim 3. To determine the role of protein phosphorylation/dephosphorylation in neuregulin-regulated AchR gene expression Elucidating the mechanisms in the control of neuromuscular synapse formation will further our understanding of general principles governing synapse formation and, hence, the basis of nervous system development and function. These results will undoubtedly provide crucial information in designing strategies to treat neuromuscular diseases and spinal cord injury.
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