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First published online October 24, 2007
doi: 10.1242/10.1242/jcs.03491

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LAR, liprin and the regulation of active zone morphogenesis

Department of Biology and Program in Neuroscience, Pomona College, 175 West 6th Street, Claremont, CA 91711, USA

View larger version (28K): [in this window] [in a new window]   Fig. 1. The structure of the active zone. An electron micrograph of a Drosophila NMJ [adapted from Atwood (Atwood, 2006)] shows electron-dense active zones, synaptic vesicles and mitochondria (m). The schematized active zone on the right shows the cycling of synaptic vesicles (white circles) at the active zone. Synaptic vesicle endocytosis occurs peripheral to the active zone, and synaptic vesicle exocytosis and neurotransmitter release occur within the active zone.

View larger version (17K): [in this window] [in a new window]   Fig. 2. Key molecular interactions of LAR and liprin at the synapse. The extracellular domains of LAR have three identified ligands, which regulate the function and/or localization of LAR at the synapse. Nidogen genetically interacts with PTP-3 in C. elegans and may regulate active zone morphogenesis through its ability to localize PTP-3 to the synapse. Dallylike and syndecan both bind to the extracellular domains of LAR in Drosophila and have distinct effects on synapse formation; syndecan positively regulates LAR to promote synapse growth, whereas Dallylike inhibits its ability to limit active zone size. Inside the presynaptic terminus, liprin binds the MALS/Veli-Cask-Mint1 complex, ERC2, and RIM. Through these interactions, liprin is able to promote the formation of an electron-dense, tightly clustered, robust active zone.

View larger version (17K): [in this window] [in a new window]   Fig. 3. Modeling the function of liprin and LAR during active zone assembly. Active zone formation can be divided into five steps: (1) the synthesis of dense core vesicles (dark circles) in the Golgi complex; (2) the transport of dense core vesicles to the presynaptic terminus; (3) the targeting of dense core vesicles to appropriate sites on the membrane; (4) the fusion of dense core vesicles with the plasma membrane; and (5) the stabilization of active zone proteins. The LAR and liprin mutant phenotypes suggest that these proteins are essential for stabilizing numerous proteins in a condensed and functional active zone. In addition, proper neurotransmitter release at the active zone depends on the proper transport (6) of synaptic vesicles (white circles) to the presynaptic terminus. In Drosophila, liprin mutants have severe defects in synaptic vesicle transport, in which synaptic vesicles accumulate in axons.