The C2H2 zinc-finger protein SYD-9 is a putative posttranscriptional regulator for synaptic transmission

Abstract

Communication between neurons is largely achieved through chemical synapses, where neurotransmitters are released from synaptic vesicles at presynaptic terminals to activate postsynaptic cells. Exo-and endocytosis are coordinated to replenish the synaptic vesicle pool for sustained neuronal activity. We identified syd-9 (syd, synapse defective), a gene that encodes multiple C2H2 zinc-finger domain-containing proteins specifically required for synaptic function in Caenorhabditis elegans. syd-9 loss-of-function mutants exhibit locomotory defects, a diffuse distribution of synaptic proteins, and decreased synaptic transmission with unaffected neurodevelopment. syd-9 mutants share phenotypic and ultrastructural characteristics with mutants that lack synaptic proteins that are required for endocytosis. syd-9 mutants also display genetic interactions with these endocytotic mutants, suggesting that SYD-9 regulates endocytosis. SYD-9 proteins are enriched in the nuclei of both neuron and muscle cells, but their neuronal expression plays a major role in locomotion. SYD-9 isoforms display a speckle-like expression pattern that is typical of RNAbinding proteins that regulate premRNA splicing. Furthermore, syd-9 functions in parallel with unc-75 (unc, uncoordinated), the C. elegans homologue of the CELF͞BrunoL family protein that regulates mRNA alternative splicing and processing, and is also required specifically for synaptic transmission. We propose that neuronal SYD-9 proteins are previously uncharacterized and specific posttranscriptional regulators of synaptic vesicle endocytosis.BrunoL͞UNC-75 ͉ Caenorhabditis elegans ͉ endocytosis ͉ synaptic function C hemical synapses mediate neuronal communication through the regulated release of neurotransmitters from synaptic vesicles. Extensive studies have focused on the molecular machinery that mediates and regulates exocytosis, the process in which membrane fusion between synaptic vesicles and the plasma membrane leads to neurotransmitter release and endocytosis, the process that recovers synaptic vesicles from the plasma membrane (1, 2).The release of neurotransmitters is stimulated by the influx of Ca 2ϩ at the presynaptic active zones. Protein components of the vesicle membranes (synaptobrevin, SNB) and plasma membranes [syntaxin and SNAP-25 (synaptosome-associated protein of 25 kDa)] form a SNARE complex that functions as a minimal fusion machine to drive vesicle fusion (3-5). The formation and conformational change of the SNARE complex requires modulation by other proteins (6-9). Synaptotagmin (SNT) is a vesicle membrane protein that binds to Ca 2ϩ and forms complexes with phospholipids and SNARE complexes. It is a proposed Ca 2ϩ sensor for Ca 2ϩ -dependent exocytosis (10-12). SNT-1 knockout mice display selective loss of Ca 2ϩ -triggered fast exocytosis, and loss of SNT function in Caenorhabditis elegans and Drosophila leads to a large reduction of exocytosis (13,14). Disrupting the function of UNC13͞mUNC13 and UNC-18͞mUNC18 (UNC, uncoordinated) also leads to a reduction...

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“…Recent studies in C. elegans have identified multiple nuclear RNA-binding proteins that localize to subnuclear speckles in neurons, including the CELF/BrunoL ortholog UNC-75, the ELAVlike protein EXC-7, and the putative RNA-binding protein SYD-9 (Loria et al, 2003;Wang et al, 2006). Interestingly, these RNAbinding proteins show specific synergistic genetic interactions with mutations that affect synaptic transmission but not synaptic development.…”