The functioning of the nervous system depends upon the underlying highly stereotyped patterns of neuronal connectivity. How these precise patterns of synaptic connections form during development is the subject of the research funded by this grant. The fruitfly Drosophila was chosen for these studies because of the relative ease with which molecular genetic and classical genetic approaches can be used to address these issues. Once genes are discovered in Drosophila, and their functions determined using genetic analysis, it is possible to identify the homologous genes and functions in mammals, including human. To identify candidate recognition molecules, monoclonal antibodies were generated which recognize surface antigens expressed on subsets of axon pathways in the embryo. Five surface glycoproteins were identified, and the genes encoding them cloned. Further analysis showed that these genes encode recognition molecules that function as both attractants and repellents/inhibitors. Present and future studies focus on two of these recognition molecules: fasciclin II and semaphorin II. Fasciclin II is a contact-mediated attractive guidance molecule of the immunoglobulin superfamily and is closely related to mammalian NCAM. Semaphorin II is a chemorepellent/inhibitor and is closely related to mammalian semaphorin III/collapsin and other secreted members of the semaphorin family. Genetic analysis is used to study the function of these two molecules, and to identify other proteins that interact with them (e.g.., receptors and downstream signal transduction molecules) during growth cone guidance, target recognition, synapse formation, and synaptic plasticity. Since molecules highly related to fasciclin II and semaphorin II exist in humans, and are thought to play major roles in human brain development and plasticity, the results learned about their function and interacting components using this model genetic system should have broad implications for our understanding of normal and abnormal human nervous system development, including neurodegenerative disease, neurological disease, and the lack of regeneration after injury.
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