Grant: Operating Grant

The formation of synaptic connections between neurons is a key event during development. Netrins are secreted proteins that function as extracellular cues to direct cell migration. Many types of axons, the processes that connect one neuron to another, require netrin-1 to extend and find their synaptic targets. An important part of the mechanism that allows cells to respond to netrin-1 is a receptor called DCC which is located at the leading edge of a migrating cell. Without netrin-1 or DCC, nervous system development is highly abnormal. We have found that netrin-1 and DCC are made by neurons in the mature brain. While these proteins are absolutely essential for normal development, their significance in the mature brain is not known. In support of the idea that they are important, recent studies have found that mutations in the human genes encoding netrin-1 and DCC are predictive of the age of onset and susceptibility to develop Parkinson's disease and amyotrophic lateral sclerosis. Although this suggests an important role in degenerative diseases in the nervous system, how netrin-1 and DCC might be involved is not known. We have found that these proteins influence synapse formation between neurons in early neural development. Examining the mature brain, we have found that netrin-1 and DCC are located at synapses. Our studies indicate that ongoing expression of DCC regulates synapse structure, and is required for changes in synapse function thought to underlie learning and memory. Consistent with this, we have obtained behavioral evidence that DCC is required for certain forms of learning and memory. Our proposal aims to identify the mechanisms that underlie the contribution of netrin-1 and DCC to synapse formation during development, and their function at synapses in the mature brain. Investigating this newly discovered role for netrin-1 and DCC will contribute to our understanding of the mechanisms that regulate learning, memory, and neurodegenerative disease.