Two major signaling systems have a critical role at neuromuscular synapses. The first signaling system, synaptic transmission, requires the rapid and precise release of acetylcholine (ACh) from synaptic vesicles docked at the active zone and the reception of ACh by acetylcholine receptors (AChRs) positioned precisely across from the active zones and expressed in numbers that are sufficient to reliably generate a synaptic potential. The second signaling system is required to establish the number and distribution of AChRs in the postsynaptic membrane, thereby insuring the reliability of synaptic transmission. The second signaling system involves at least two pathways, one of which, synapse-specific gene expression, is important for inducing and maintaining AChR gene expression at synaptic sites. Neuregulin (NRG), a candidate for the signal that induces synapse-specific transcription, and its receptors, erbB3 and erbB4, are localized to synapses, but the role that these molecules might have at neuromuscular synapses in vivo is not known. Experiments described here are designed to determine the role that NRG/erbB-mediated signaling has in synapse formation. Because NRG and erbBs are required for heart development, it has not been possible to determine whether NRG and erbBs have a role in neuromuscular synapse formation by studying loss of function mutations in mice. To circumvent the problems associated with the early requirement for NRG-mediated signaling in embryonic development, they will use two different approaches to selectively inactivate erbBs in skeletal muscle cells. Moreover, they will use the same approaches to study the role that muscle-derived agrin and muscle-derived NRG might have in synapse formation. Experiments described here are also designed to determine how erbBs become localized to the postsynaptic membrane and how NRG/erbB signaling activates transcription of AChR genes. There is increasing evidence to suggest that plasticity in the central nervous system involves changes in the properties of synapses, including changes in the distribution and expression of neurotransmitter receptors. Thus, it seems likely that a better understanding of the molecules and mechanisms regulating gene expression at neuromuscular synapses will not only lead to a better understanding of neuromuscular synapse formation but will also provide insight into molecules and mechanisms that regulate plasticity in the central nervous system.
Showing the most recent 10 out of 27 publications
