ERIK M. JORGENSEN
Erik M. Jorgensen
email: jorgensen@biology.utah.edu		 Professor of Biology
Investigator of the Howard Hughes Institute

The Jorgensen Lab Home Page
Molecular Neuroscience
Cellular Neuroscience

B.A. 1979, University of California, Berkeley; Ph.D. 1989; University of Washington; Postdoctoral Fellow, 1989-1994, Massachusetts Institute of Technology.

Fig 1. The nematode C. elegans. This animal is expressing the Green Fluorescent Protein in the GABA neurons. Fig 2. Schematic of synaptic vesicle cycling. Synaptic vesicles fuse with the plasma membrane to release neurotransmitters. Membrane and protein components are recycled via endocytosis. Fig 3. UNC-13 function. UNC-13 is activated by modulatory pathways and then primes vesicles by converting the SNARE protein syntaxin to the open state.

RESEARCH:

Mechanisms of synaptic function

What is the molecular nature of memory? It seems that memory is encoded by changes in the strength of synapses. It is our goal to identify the molecules that function at the synapse and to understand how the activities of these molecules are changed to strengthen or weaken a synapse. To identify such molecules we have undertaken a genetic analysis of neurotransmission in the nematode Caenorhabditis elegans (Fig. 1). C. elegans is particularly advantageous for genetic studies of the nervous system for several reasons: First, mutants with defective synapses are viable and can be studied as adults. Second, we can select for mutants with defective neurotransmission using drug resistance screens. Third, we can characterize mutant synapses at the ultrastructural and electrophysiological level. Fourth, the entire genomic sequence of the nematode has been completed; and knockouts of many genes have been generated; this greatly expedites the characterization of genes.

Our goal is to identify the genes required for synaptic function. Such genes are likely to regulate synaptic vesicle dynamics (Fig. 2). When a neuron fires an action potential, calcium ions flow into the axonal terminus of the presynaptic cell. Calcium influx causes synaptic vesicles to fuse with the plasma membrane and to release neurotransmitter to the surface of the neighboring cell.

What is the molecular mechanism of calcium sensing and vesicle fusion? In our screens we have identified synaptotagmin and the SNARE proteins, the proteins thought to mediate these steps. In addition, we have identified other proteins such as UNC-13 and UNC-18. Our electrophysiological and ultrastructural analysis indicates that these proteins are required for vesicle fusion. One model is that these proteins are required to convert the SNARE protein syntaxin into the open configuration (Fig. 3). We tested this model and determined that UNC-13 was required to open syntaxin but UNC-18 was not.

What is the molecular mechanism of synaptic vesicle retrieval? Once synaptic vesicles have fused with the plasma membrane, the components must be retrieved from the plasma membrane via endocytosis to regenerate a reserve pool of vesicles. We are studying clathrin-mediated endocytosis and lipid modifying proteins that are essential for endocytosis.

What are the mechanisms for synaptic plasticity? We are currently studying the role of GTPases in potentiating or weakening synaptic strength. Our data indicate that Gq subunits of trimeric G proteins have novel targets beyond the lipid modifying enzymes of the canonical pathway.

What neurotransmitters function at synapses? GABA is the primary inhibitory neurotransmitter in vertebrate and invertebrate nervous systems. Our analysis of GABA has demonstrated that GABA is an excitatory neurotransmitter at both neurons and muscles in the nematode. Moreover, we have discovered that protons can act as a transmitter at some synapses. These studies suggest that there is an unforeseen richness to the molecular complexity of the nervous system - and hence the brain.

Selected Publications

Hammarlund, M., Nix, P., Hauth, L., Jorgensen, E.M., and Bastiani, M.J. (2009) Axon regeneration requires a conserved MAP kinase pathway. Science, 323:802-806, NIHMSID: NIHMS107622.

Sato, K., Ernstrom, G., Watanabe, S., Weimer, R., Chen, C.H., Sato, M., Siddiqui, A., Jorgensen, E.M., and Grant, B. (2009) Differential requirements for clathrin in receptor-mediated endocytosis and maintenance of synaptic vesicle pools. Proc Natl Acad Sci USA, 106:1139-1144, PMCID: PMC2633560.

Gu, M, Schuske, K., Watanabe, S., Baum, P., Garriga, G., and Jorgensen, E.M. (2008) m2 adaptin is not essential for synaptic vesicle recycling in C. elegans. Journal of Cell Biology, 183:881-892, PMCID: PMC2592831.

Frøkjær-Jensen, C., Davis, M.W., Hopkins, C.E., Newmann, B., Thummel, J.M., Olesen, S-P., Grunnet, M., and Jorgensen, E.M. (2008) Single copy insertion of transgenes in C. elegans. Nature Genetics, 40:1375-1383, PMCID: PMC2749959.

Hammarlund, M., Watanabe, S., Schuske, K., and Jorgensen, E.M. (2008) CAPS and syntaxin dock dense core vesicles to the plasma membrane in neurons. Journal of Cell Biology, 180:483-491.

Beg, A., Ernstrom, G., Nix, P., Davis, M.W., and Jorgensen, E.M. (2008) Protons act as a transmitter for muscle contraction in C. elegans. Cell, 132:149-160.

White, J.Q., Nicholas, T. J., Gritton, J., Truong, L., Davidson, E.R., and Jorgensen, E.M. (2007) The sensory circuitry for sexual attraction in C. elegans males. Current Biology, 17:1847-1857.

Peters, M., Teramoto, T., White, J.Q., Iwasaki, K., and Jorgensen, E.M. (2007) A calcium wave mediated by gap junctions coordinates a rhythmic behavior in C. elegans. Current Biology, 17:1601-1608.

Jospin, M., Watanabe, S., Joshi, D., Young, S., Hamming, K., Thacker, C., Snutch, T., Jorgensen, E.M., and Schuske, K. (2007) UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants. Current Biology, 17:1595-1600.

Hammarlund, M., Palfreyman, M., Watanabe, S., Olsen, S., and Jorgensen, E.M. (2007) Open syntaxin docks synaptic vesicles. PLoS Biology, 5(8):e198, 1695-1711.

Schuske, K., Palfreyman, M.T., Watanabe, S., and Jorgensen, E.M. (2007) UNC-46, a novel protein required for trafficking of the vesicular GABA transporter. Nature Neuroscience, 10:846-853.

Bednarek, E., Schaheen, L., Gaubatz, J., Jorgensen, E.M., and Fares, H. (2007) The plasma membrane calcium-ATPase is required for clathrin-mediated endocytosis. Traffic, 8:543-553.

Hammarlund, M., Jorgensen, E.M., and Bastiani, M.J. (2007) Axons break in animals lacking beta-spectrin. J Cell Biol, 176:269-275.

Williams, D.C., Boulin, T., Ruaud, A.F., Jorgensen, E.M., and Bessereau, J.L. (2005) Characterization of Mos1-Mediated Mutagenesis in Caenorhabditis elegans: A Method for the Rapid Identification of Mutated Genes. Genetics, 169:1779-1785.

Bamber, B.A., Richmond, J.E., Otto, J.F., and Jorgensen, E.M. (2005) The composition of the GABA receptor at the Caenorhabditis elegans neuromuscular junction. Br. J. Pharm., 144:502-509.

Davis, M.W., Birnie, A.J., Chan, A.C., Page, A.P., and Jorgensen, E.M. (2004) A conserved metalloprotease mediates ecdysis in C. elegans. Development, 131:6001-6008.

Schuske, K.R., Richmond, J.E., Matthies, D.S., Davis, W.S., Runz, S., Rube, D.A., van der Bliek, A.M., and Jorgensen, E.M. (2003) Endophilin is required for synaptic vesicle endocytosis by localizing synaptojanin. Neuron, 40:749-762.

Beg, A., and Jorgensen, E.M. (2003) An excitatory GABA receptor. Nature Neuroscience, 6:1145-1152.

Weimer, R., Richmond, J.E., Davis, W.S., Gritton, J., Hadwiger, G., Nonet, M., and Jorgensen, E.M. (2003) Defects in synaptic vesicle docking in unc-18 mutants. Nature Neuroscience, 6:1023-1030.

Knobel, K., Davis. W., Jorgensen, E.M., and Bastiani, M. (2001) UNC-119 suppresses axon branching in C. elegans. Development, 128:4079-4092.

Bessereau, J.L., Wright, A., Williams, D.C., Schuske, K., Davis, M.W., and Jorgensen, E.M. (2001) Mobilization of a Drosophila transposon in the Caenorhabditis elegans germ line. Nature, 413:70-74.

Richmond, J.E., Weimer, R.M., and Jorgensen, E.M. (2001) An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature, 412:338-341.

Harris, T.W., Hartwieg, E., Horvitz, H.R., and Jorgensen, E.M. (2000) Mutations in synaptojanin disrupt vesicle recycling. J Cell Biol, 150:589-600.

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