The objective is to understand how neurons in the vertebrate central nervous system (CNS) make proper connections with each other. This is one of the fundamental problems in development neurobiology. Answers to this problem should have important implications for many developmental diseases of the nervous system and problems concerning regeneration following injury to the CNS. One important aspect of how neurons become properly wired is how their growth cones navigate through the developing embryo to find their correct target neurons. However, the mechanisms which guide neuronal growth cones to their targets in the vertebrate CNS have been difficult to study primarily due to the complexity and large number of neurons found in the CNS of most vertebrates. I propose to study this problem in the embryonic spinal cord of the fish, the simplest part of the CNS of a relatively simple vertebrate. The early embryonic spinal cord of fish is an excellent preparation for pursuing this question since it contains a relatively small number of neurons which are easily visualized in the living embryo, can be identified as individuals or members of a small pool of homogeneous neurons, and studied with methods allowing analysis of single neurons.
The aims of this proposal are to describe the behavior of single identified growth cones and to delineate the cellular mechanisms which guide these growth cones to their targets. This will be accomplished by intracellular injection of a variety of dyes into individual embryonic neurons, analyzing their growth cones and the substrates of these growth cones with light and electron microscopy, and manipulating the environment of these growth cones by selectively ablating individual cells with a laser microbeam.
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