Chromatin modifications that regulate transcription at the neuromuscular synapse

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DESCRIPTION (provided by applicant): The proposed research focuses on a signaling pathway that helps to direct the formation and organization of neuromuscular synapses and addresses how this pathway might regulate transcription by inducing modifications to certain regions of chromatin. Localization of acetylcholine receptors (AChRs) to the postsynaptic region of muscle, which is studied as a basis for understanding how synapses form, is believed to be mediated in part by transcriptional mechanisms because the genes encoding AChR subunits are transcribed selectively in synaptic myofiber nuclei. Neuregulin-1 (NRG-1) is a potential extracellular ligand that stimulates synapse-specific transcription. NRG-1-induced AChR transcription requires two transcriptional regulatory elements, one that binds GA-binding protein (GABP) and another that binds early growth respone-1 (Egr-1), but the mechanisms by which GABP and Egr-1 induce transcription in response to NRG-1 are not known. Transcriptional activation can be mediated by local modifications to chromatin, and proteins that perform these modifications typically are recruited to specific regions of chromatin by forming complexes with DNA-binding proteins. NRG-1 induces a modification to chromatin typically associated with transcriptional activation where an AChR gene is located; raising the possibility that NRG-1 activates transcription in part by modifying specific regions of chromatin. Experiments in the proposed research will analyze NRG-1-induced modifications to chromatin and the roles of GABP, Egr-1, and their interacting proteins in facilitating these modifications. In addition to providing information on neuromuscular synapse development, this research may also yield insight into synapses in the central nervous system (CNS), which are structurally similar. Changes to synapses and their connectivity in the CNS mediate learning and memory, and similar mechanisms may control their formation and organization. Because synapses in the CNS become defective in many neurodegenerative diseases, understanding these mechanisms might be useful for restoring proper synapses.