Pre- and postsynaptic cells generate signals that organize each other's differentiation. Considerable progress has been made in identifying some of these signals at the neuromuscular junction, and in elucidating their signal transduction mechanisms. Less is known about three other critical factors: electrical activity, which modulates numerous aspects of synaptic maturation; Schwann (glial) cells, which influence both nerve and muscle; and differences among muscles that bias synapse formation in favor of appropriate partners. This application proposes to apply transgenic technology to these issues.
The first aim i s to generate and analyze mice in which activity is blocked in three different ways: depletion of neurotransmitter, blockade of vesicle fusion, or deletion of the postsynaptic receptor. Comparison of these strains will allow us to assess which aspects of activity are important for each stage of synaptic development. In addition, each transgene will be conditional, allowing us to block activity at various stages of development (so we can bypass early lethality to study late steps in development) or in subsets of axons (so we can assay competitive interactions).
The second aim applies the same methods to mice in which all or some Schwann cells are deleted. IN the third aim, we will use new transgenic lines in which a few of the motor axons that innervate a muscle are indelibly marked with a fluorescent label. By visualizing entire motor units in these mice, we will learn how they are arranged, how they develop, and whether their component synapses resemble each other. Finally, we will focus on one aspect of motor unit arrangement: the orderly mapping of a motor pool into a muscle's rostrocaudal axis. We recently found that mapping is degraded in transgenic mice over-expressing or lacking ephrins, protein previous implicated in retinotectal mapping. By analyzing the arrangement and development of motor units in ephrin mutant mice, we will learn how factors that promote selective synapse formation interact with the """"""""nuts and bolts"""""""" that are shared by and play major roles in formation of all synapses of a class.
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