Proper nervous system function depends on precise contacts between nerve cells and their targets. The objective of this study is to learn how the development of specific synaptic connections is regulated. We propose cellular, molecular and genetic analyses of the interactions between particular motoneurons and muscle cells in an embryonic vertebrate, the zebrafish. By studying and perturbing the early development of these cells, we will learn how targets function in specifying the formation of synaptic connections. We propose three specific aims: a) We will identify the particular subset of muscle cells with which the motoneurons first interact and characterize their early development, using a variety of molecular markers. From this we will learn how they differentiate and when they express particular genes that may be important for their developmental functions. b) We will ablate and transplant these cells early in development to see if they function in the patterning of body muscle segments. c) We will characterize and study genes expressed by these muscle cells during early development to learn how they may function in the specification of neuromuscular synapses. Although much work has been done to describe how synapses form, very little is known about what regulates the formation of specific synaptic connections; that is, how does a neuron know which cells it should and should not innervate? In humans, neurons sometimes make mistakes. For example, there are a number of congenital defects (such as infantile Muscular Dystrophies) that are due to incorrect connections between nerve cells and their targets. By learning how these connections normally develop we will gain insights into what goes awry to cause developmental abnormalities.
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