We are interested in the mechanisms by which the nervous system remodels its neuronal connectivity during development. The precise wiring of neuronal circuitry is essential for proper function of the nervous system. However, the developing nervous system often begins as an approximate prototype, which requires further remodeling to achieve the mature connectivity. Three basic remodeling mechanisms are commonly employed to reorganize the developing nervous system: neurogenesis, apoptosis and neuronal pruning. Pruning is a tightly controlled self-destructive process that selectively eliminates specific parts of neuronal processes without causing cell death. Thus, any mis-regulation of pruning activity would bring catastrophic consequence to the neurons that could be the pathological basis of neurodegenerative diseases. We plan to use the nervous system of Drosophila (fruit fly) as a model system to dissect the molecular mechanisms of neuronal pruning by various approaches, including biochemical, molecular and cellular biology, and genetics.
In Drosophila, extensive neuronal remodeling takes place during metamorphosis to reorganize the larval nervous system into adult patterns. Most of the larval neurons die, while few of them survive, prune and regenerate their neuronal processes. Some class IV dendritic arborization (da) neurons, a subset of larval peripheral sensory neurons, undergo a large-scale dendrite pruning to eliminate all their larval dendrites prior to the regeneration of adult dendrites, yet leave their axons intact. Dendrite pruning of class IV da neurons begins with severing the proximal dendrites, followed by removal of all severed dendrite by phagocytes. We have identified Ik2 kinase, a Drosophila IKK-related kinase, and katanin p60-like 1 (kat-60L1), a novel microtubule-severing molecule, and shown that both genes are essential to initiate dendrite severing. In the near future, we intend to study the molecular mechanisms of dendrite severing in the fly nervous system through addressing the following questions: 1) how to regulate the activity of Ik2 kinase and Kat-60L1 in dendrite pruning? and 2) how to confine pruning activity in the subcellular compartments of neurons?