Derek Sieburth

Assistant Professor,
Cell & Neurobiology
Zilkha Neurogenetic Institute
Keck School of Medicine

Research Topics

1. Mechanisms of presynaptic function
2. Systematic analysis of synapse structure
3. Regulation of neurotransmission
4. Neuropeptide secretion

Research Overview

The Sieburth lab is interested in identifying and characterizing molecules that regulate synaptic function. Synapses are specialized subcellular compartments that mediate rapid intercellular signaling in the brain. Synapses are surprisingly diverse in their structural and functional properties. For example, different synapses in the brain vary significantly in size, the number of neurotransmitter release sites, the pool of synaptic vesicles available for release and the probability of vesicle release. Beyond this diversity between synapses, the properties of each synapse are highly dynamic. This plasticity in synaptic properties is thought to underlie the specificity of neuronal wiring during development, and processes such as learning and memory.

Synapses are biochemically complex structures. Proteomic studies suggest that synapses are composed of hundreds of different proteins. However, very little is known about the changes in molecular composition and signal transduction properties that underlie the diversity of synaptic function.

In the Sieburth lab, we use C. elegans as a model organism for studying synaptic biology, because of its simple neuronal circuitry, the ability to visualize synapses in live animals, and its powerful genetics. We combine behavioral, genetic, RNA interference (RNAi), and live imaging techniques to dissect synaptic function at a systems and molecular level in C. elegans.

To identify new proteins required for synaptic transmission, we conducted a large scale screen for genes that decrease acetylcholine secretion using an RNAi feeding library. We identified 185 proteins, 132 of which have no previously reported role in synaptic function, and 163 have vertebrate homologs. Among the proteins identified include constituents of signal transduction pathways, as well as proteins that have roles in intracellular membrane trafficking, cytoskeleton dynamics, and lipid signaling.

We are focusing on conducting a detailed analysis of several genes identified in this screen. Using a hierarchical clustering strategy (Panel c in figure) to find genetically related genes, we have identified a group of proteins that appear to be essential regulators of the synaptic vesicle cycle. We are interested in understanding the mechanisms by which these proteins regulate synaptic function and the synaptic vesicle cycle (Panel a in figure). We also identified a protein kinase C (PKC) orthologe that regulates the secretion of neuropeptides from dense core vesicles. We are interested in using genetic approaches to identify other components of the PKC pathway including downstream targets of this kinase. Finally, we identified a large group of actin associated proteins many of which appear to be localized to specialized sub-synaptic structures called periactive zones (Panel b in figure). We are interested in combining genetic and imaging approaches to learn how these structures are assembled and maintained at synapses.