Synapse formation between a developing axon and its target involves the coordinated differentiation of the pre- and postsynaptic components that mediate synaptic transmission. At developing neuromuscular synapses, acetylcholine receptors (AChRs) are among the proteins that become localized to the postsynaptic region in muscle, and their localization to this small patch of the myofiber membrane during development is a hallmark of the inductive events of synapse formation. It is believed that the localization of AChRs is mediated in part by transcriptional mechanisms because the genes encoding AChR subunits are transcribed selectively in the few muscle nuclei that are situated at synaptic sites. Neuregulins (NRGs) are the best candidates for ligands that stimulate synapse-specific gene expression, because NRGs are concentrated at synaptic sites and can induce AChR synthesis in cultured muscle cells. NRG-1-induced AChR transcription requires two transcriptional regulatory elements, one that binds GA-binding protein (GABP), a heterodimer of the Ets protein GABP alpha and GABP beta, and another that binds Sp1, a zinc finger protein. The proposed research addresses the mechanisms by which NRGs signal through GABP and Sp1 to mediate a transcriptional response.
The specific aims are to determine if GABP is required for NRG-1-induced transcription; determine if NRG-1-stimulated phosphorylation of GABP alpha is critical for inducing transcription; determine if a transcriptional activation domain of GABP beta is required for inducing transcription in response to NRG-1; identify the region of Sp1 that is sufficient for regulating DNA binding in response to NRG-1. In addition to providing information on development of the neuromuscular synapse, the proposed experiments may also yield insight into other processes which are influenced by neuregulin signaling, such as cellular transformation.
| Herndon, Carter A; Fromm, Larry (2008) Neuregulin-1 induces acetylcholine receptor transcription in the absence of GABPalpha phosphorylation. J Neurosci Res 86:982-91 |
| Herndon, Carter A; Fromm, Larry (2007) Directing RNA interference specifically to differentiated muscle cells. J Muscle Res Cell Motil 28:11-7 |
| Fromm, Larry; Rhode, Monika (2004) Neuregulin-1 induces expression of Egr-1 and activates acetylcholine receptor transcription through an Egr-1-binding site. J Mol Biol 339:483-94 |
