IBN: 9631745 PI: Schnaar Nerve cells send signals to other nerve cells and to target tissues (such as muscle) through long cellular extensions, or "wires," called axons. In the developing brain, billions of growing axons weave their way to their appropriate targets through a free-wheeling process of extension and migration. After appropriate connections are established, many of the axons are wrapped by layers of insulation, called myelin, which is made by support cells in the brain. In addition to insulating the axons, myelin signals them to stop extending and migrating, thereby stabilizing the pattern of connections in the mature brain. Specific molecules on myelin interact with complementary molecules on the axon, like a lock and key, to trigger the axon to stop extending or migrating. This proposal investigates the structures and functions of these interacting molecules. Specifically, a well-defined protein on myelin, called myelin-associated glycoprotein (MAG for short) is one of the myelin molecules responsible for signaling axons to stop growing. We discovered complementary sugar molecules on the surface of axons which bind to MAG, and which may be responsible for initiating the "stop growing" signal. Experiments detailed in this proposal will test whether these axon sugar molecules, termed gangliosides, are required in order for MAG to halt axon extension and migration. Gangliosides with different structural variations will be tested, to define the specific chemical determinants required for MAG's binding and actions. These studies may elucidate basic molecular mechanisms for stabilization of neuronal connections in the mature brain, and may help explain why central nervous system axons fail to regenerate in some vertebrates, including mammals.
