The formation of synapses between neurons and the regulation of signaling through these synapses is fundamental to the function of the nervous system. We are studying mechanisms of synapse formation and regulation of neurotransmitter receptors in the genetic model organism C. elegans using a combination of genetic, cell biological, and biochemical techniques. Analysis of the C. elegans nervous system is relatively easy due to the small number of neurons (302) and the fact that the connectivity between these neurons is known and identical in every animal. To visualize synapses, GFP- or RFP-tagged synaptic proteins can be expressed in subsets of neurons, for example the cholinergic or GABAergic motorneurons, or glutamatergic interneurons.

Recent evidence indicates that regulated degradation of synaptic proteins is an important mechanism to control synapse formation and function. Ubiquitin-dependent degradation is a major pathway for regulated protein degradation. In this pathway, ubiquitin ligases conjugate the small protein ubiquitin to target proteins destined for degradation. We are currently characterizing the function of ubiquitin ligase mutants that affect synapse structure and synaptic transmission at various synapses. The activity of ubiquitin ligases is antagonized by deubiquitinating enzymes that remove ubiquitin from target proteins (in a similar way, protein kinases and phosphatases antagonize each other). Deubiquitinating enzymes are probably as important as ubiquitin ligases in regulating protein degradation, but very few have been characterized to date. The C. elegans genome encodes about 300 ubiquitin ligases and 50 deubiquitinating enzymes. In RNAi based screens, we are now identifying deubiquitinating enzymes that affect synaptic transmission and synapse structure.

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