Proteins in the synapse carry out four major cell biological processes: exocytosis, endocytosis, signal transduction and adhesion. The synaptic proteins involved in endocytosis have been identified by their ability to associate with dynamin, a protein linked genetically to synaptic vesicle recycling. In Drosophila we have identified eight new proteins that are dynamin-associated and have cloned and sequenced two, DAP16O and syndapin. The human form of DAP16O has recently been shown to be overexpressed in Down's Syndrome. Examination of the properties of DAP16O and syndapin have revealed an unexpected link between endocytosis and the actin cytoskeleton. Careful morphological examination of DAP16O's synaptic distribution revealed a novel but logical micro-organization of the nerve terminal plasma membrane into defined zones of exocytosis surrounded by zones of endocytosis. In this grant we propose completing the characterization of the remaining six dynamin-associated proteins and examining the consequences of mutating the new proteins as well as DAP16O and syndapin. This is done, in part, using a novel, directed mutagenesis procedure to generate temperature-sensitive mutations. We explore how the function and the micro-organization of the nerve terminal into endocytotic and exocytotic zones are modified by mutations in the endocytotic machinery. Identifying synapse-specific gene products and establishing their function is essential if we are to use genomic databases, Drosophila or human, to understand the cellular basis of neurological disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Chiu, Arlene Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Marie, Bruno; Sweeney, Sean T; Poskanzer, Kira E et al. (2004) Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth. Neuron 43:207-19
Verstreken, Patrik; Koh, Tong-Wey; Schulze, Karen L et al. (2003) Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating. Neuron 40:733-48
Jarousse, N; Kelly, R B (2001) Endocytotic mechanisms in synapses. Curr Opin Cell Biol 13:461-9
Roos, J; Hummel, T; Ng, N et al. (2000) Drosophila Futsch regulates synaptic microtubule organization and is necessary for synaptic growth. Neuron 26:371-82
Qualmann, B; Kelly, R B (2000) Syndapin isoforms participate in receptor-mediated endocytosis and actin organization. J Cell Biol 148:1047-62
Faundez, V V; Kelly, R B (2000) The AP-3 complex required for endosomal synaptic vesicle biogenesis is associated with a casein kinase Ialpha-like isoform. Mol Biol Cell 11:2591-604
Qualmann, B; Kessels, M M; Kelly, R B (2000) Molecular links between endocytosis and the actin cytoskeleton. J Cell Biol 150:F111-6
Marullo, S; Faundez, V; Kelly, R B (1999) Beta 2-adrenergic receptor endocytic pathway is controlled by a saturable mechanism distinct from that of transferrin receptor. Receptors Channels 6:255-69
Qualmann, B; Roos, J; DiGregorio, P J et al. (1999) Syndapin I, a synaptic dynamin-binding protein that associates with the neural Wiskott-Aldrich syndrome protein. Mol Biol Cell 10:501-13
Roos, J; Kelly, R B (1999) The endocytic machinery in nerve terminals surrounds sites of exocytosis. Curr Biol 9:1411-4

Showing the most recent 10 out of 32 publications