SYD-2 Liprin-α organizes presynaptic active zone formation through ELKS

Dai, Ya; Taru, Hidenori; Deken, Scott L.; Grill, Brock; Ackley, Brian D.; Nonet, Michael L.; Jin, Yishi

doi:10.1038/nn1808

Cited by 211 publications

(312 citation statements)

References 38 publications

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“…1a) and Liprin-α (Syd-2) promote presynaptic assembly 5,[15][16][17][18] . When we expressed Nlg1∆Cyto in a Liprin-α mutant background, NMJ terminals still showed severe under-growth compared to those in the Liprin-α mutant background alone (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, identifying proteins coupling Nrx-Nlg to the assembly process itself and defining where in the sequence of events Nrx-Nlg acts is critical for a deeper understanding of synapse formation and remodeling. Independent work in model organisms has identified and characterized proteins guiding active zone assembly, with Syd-1 proteins functioning upstream of Syd-2 (Liprin-α) 5,15,16 . In vivo imaging demonstrated that both Syd-1 and Liprin-α accumulate very early during synapse assembly (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

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Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

et al. 2012

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Understanding the process of synapse assembly in molecular and cell-biological detail is a prerequisite for understanding neural circuit development and activity-mediated remodeling, and thus is important for unraveling learning and memory processes (structural plasticity) [1][2][3] . Functional chemical synapses are characterized by two apposed compartments that must be coestablished with high spatiotemporal precision: the presynaptic active zone, where regulated and rapid fusion of neurotransmitter-filled synaptic vesicles takes place, and the postsynaptic density (PSD), which embeds neurotransmitter receptors.Glutamatergic neuromuscular junction (NMJ) terminals of Drosophila larvae grow to meet the requirements of the growing muscle fibers, a process in which new synapses are continuously added 4 (where a synapse is defined as a single active zone opposed by a single PSD 1 ). In vivo imaging has shown that presynaptic Syd-1 and Liprin-α clusters initiate active zone formation 5 . On the postsynaptic side, initial PSD growth depends on incorporation of a glutamate receptor (GluR) containing the GluRIIA subunit. Later PSD maturation is marked by the incorporation of GluRIIB-containing receptor complexes 6 . Synapse assembly is concluded at presynaptic active zones by the incorporation of the active zone scaffold component Bruchpilot (BRP) 5 .Coordinating synapse assembly requires signaling across the synaptic cleft, which separates pre-from postsynaptic membranes. Transsynaptic cell adhesion molecules are obvious candidates for coupling active zone and PSD assembly. In vitro, the Neurexin-Neuroligin (Nrx-Nlg) complex can mediate the trans-synaptic signaling required for synapse assembly 7,8 . How this signaling axis integrates with the additional assembly machinery, however, has remained largely unclear.Here, we provide evidence of a dual role for Syd-1 in early assembly of NMJ synapses. It retains Liprin-α clusters at active zones and is important for clustering of presynaptic Nrx-1, likely through a direct and PDZ-domain-dependent interaction. Consequently, Syd-1 is also needed for clustering of postsynaptic Nlg1, which organizes postsynaptic assembly. Coincident action of Syd-1 with Nrx-1-Nlg1 appears to allow active zone scaffolds to pass through an initial, still fragile assembly phase. We suggest that binding between Syd-1 and Nrx-1-Nlg1 is a means to coordinate pre-with postsynaptic assembly. Our study shows an example of how coincident action of a presynaptic active zone scaffold protein and a trans-synaptic cell adhesion protein module can spatiotemporally orchestrate synapse assembly. RESULTSInitially described in cell culture systems (for a review, see ref. 9), interaction between mammalian presynaptic Nrx proteins and postsynaptic Nlg molecules was proposed to be important for proper synapse assembly. However, genetic ablation of three Nlg (Nlgn) genes in mice 10 does not result in a substantial structural phenotype, potentially reflecting a strong capacity for compensatory processes in vivo.Nonethe...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

et al. 2012

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“…Recent evidence suggests that the molecules involved in early formation of active zones, such as liprins and CAST/ELKS/ERC proteins, also contribute to or correlate with changes in active zone size in mature synapses (Zhen and Jin, 1999;Kaufmann et al, 2002, p 2;Olsen et al, 2005;Dai et al, 2006;Astigarraga et al, 2010;Lazarevic et al, 2011). Active zone size can change over different timescales from minutes (Matz et al, 2010) to hours (SpiwoksBecker et al, 2004;Hull et al, 2006) to days (Lazarevic et al, 2011), accompanying changes of synaptic activity and the circadian cycle.…”

Section: Reduced Active Zone Size But Preserved Molecular Synapse Anamentioning

confidence: 99%

“…We hypothesize that CAST, as a molecular scaffold with multiple binding sites for other cytomatrix proteins, contributes to the proper lateral assembly of the ribbon and the arciform density to establish and/or stabilize a full-length active zone. Other candidates mediating stabilization might be liprin-␣s (Dai et al, 2006) and in particular liprin-␣4, because it shows an overlapping expression pattern with other CAZ proteins at rod photoreceptor synapses. It seems, however, not to be confined to the active zone (Zürner et al, 2011).…”

Section: Reduced Active Zone Size But Preserved Molecular Synapse Anamentioning

confidence: 99%

Deletion of the Presynaptic Scaffold CAST Reduces Active Zone Size in Rod Photoreceptors and Impairs Visual Processing

Dieck

Specht

Strenzke³

et al. 2012

J. Neurosci.

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How size and shape of presynaptic active zones are regulated at the molecular level has remained elusive. Here we provide insight from studying rod photoreceptor ribbon-type active zones after disruption of CAST/ERC2, one of the cytomatrix of the active zone (CAZ) proteins. Rod photoreceptors were present in normal numbers, and the a-wave of the electroretinogram (ERG)-reflecting their physiological population response-was unchanged in CAST knock-out (CAST Ϫ/Ϫ ) mice. Using immunofluorescence and electron microscopy, we found that the size of the rod presynaptic active zones, their Ca 2ϩ channel complement, and the extension of the outer plexiform layer were diminished. Moreover, we observed sprouting of horizontal and bipolar cells toward the outer nuclear layer indicating impaired rod transmitter release. However, rod synapses of CAST Ϫ/Ϫ mice, unlike in mouse mutants for the CAZ protein Bassoon, displayed anchored ribbons, normal vesicle densities, clustered Ca 2ϩ channels, and essentially normal molecular organization. The reduction of the rod active zone size went along with diminished amplitudes of the b-wave in scotopic ERGs. Assuming, based on the otherwise intact synaptic structure, an unaltered function of the remaining release apparatus, we take our finding to suggest a scaling of release rate with the size of the active zone. Multielectrode-array recordings of retinal ganglion cells showed decreased contrast sensitivity. This was also observed by optometry, which, moreover, revealed reduced visual acuity. We conclude that CAST supports large active zone size and high rates of transmission at rod ribbon synapses, which are required for normal vision.

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“…Morphological elucidation of the active zone suggests that a protein scaffold organizes the active zones and links it physically to presynaptic vesicles [6] . To date, mainly three active zone proteins have been identified in Caenorhabditis elegans as the synaptic scaffolds: UNC-10/ RIMs are putative Rab3A-effectors in regulating synaptic vesicle exocytosis and neurotransmitter release [7] , Unc-13/ Munc-13s are required for priming synaptic vesicles for exocytosis and synaptic transmission [8] , and α-liprins/SYD-2 bind to and recruit tyrosine phosphatases (receptor type) to defined areas for active zones development and normal active zone function [9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

HLB-1 functions as a new regulator for the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans

Wang

2009

Neurosci. Bull.

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Rescue and mosaic analysis experiments suggested that HLB-1 regulated synaptic functions in a cell nonautonomously way.Moreover, HLB-1 expression was not required for the presynaptic active zone morphology. Genetic evidence further demonstrated that hlb-1 acted in a parallel pathway with syd-2 to regulate the synaptic functions. Conclusion HLB-1 appeared as a new regulator for the organization and function of neuromuscular junctions in C. elegans.

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SYD-2 Liprin-α organizes presynaptic active zone formation through ELKS

Cited by 211 publications

References 38 publications

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

Deletion of the Presynaptic Scaffold CAST Reduces Active Zone Size in Rod Photoreceptors and Impairs Visual Processing

HLB-1 functions as a new regulator for the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans

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