SAM68 Regulates Neuronal Activity-Dependent Alternative Splicing of Neurexin-1

Iijima, Takahiro; Wu, Karen; Witte, Harald; Hanno-Iijima, Yoko; Glatter, Timo; Richard, Stéphane; Scheiffele, Peter

doi:10.1016/j.cell.2011.11.028

Cited by 253 publications

(334 citation statements)

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“…In contrast to the mostly splice-codedependent trans-synaptic interactions of Nrxn (13,14,18,68,70,71), binding of Nxph1 is splice-site independent (23) and has a high degree of local specificity due to its restricted expression in subpopulations of GABAergic interneurons (19). This is an important aspect because the preferred neuroligin variant of α-Nrxn at GABAergic contacts, neuroligin2 (7,72), has been shown to similarly regulate defined subsets of inhibitory connections (73).…”

Section: Discussionmentioning

confidence: 99%

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Born

Breuer

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like α-neurexins (α-Nrxn) and their extracellular binding partners determine synapse function. Although α-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an α-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABA B receptor (GABA B R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABA B R, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABA B R. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABA B R with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABA A R with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABA B R and postsynaptic GABA A R. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA A R and GABA B R subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors. synaptic transmission | thalamus | autism | neuroligin | ultrastructure

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Section: Discussionmentioning

confidence: 99%

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Born

Breuer

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In the case of neurexins, which are highly polymorphic owing to extensive alternative splicing 18 , the alternative splicing events are frequently modulated by synaptic activity 19 . To examine the temporal regulation of alternative splicing in PTPs and PTPd during neuronal development, we used quantitative reverse transcription-PCR (qRT-PCR) to monitor the expression levels of the PTPs/d messenger RNA in cultured rat hippocampal neurons.…”

Section: Minimal Domain Identification For Binding and Synaptogenesismentioning

confidence: 99%

Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

et al. 2014

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Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate synapse development by interacting with postsynaptic Slit-and Trk-like family proteins (Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1-3 and Slitrks LRR1, for their interaction and synaptogenic function. Subsequent crystallographic and structureguided functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular determinants for Slitrk binding and synapse formation. Moreover, structural comparison of the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1 render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.

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“…Here the variable sequence in Nrxn1 encompasses only 3 residues, whereas in Nrxn2 it is composed of 194 residues, and in Nrxn3 a variety of alternatively spliced sequences are observed that include inserts of 247 residues and sequences with in-frame stop codons, effectively producing secreted Nrxn3 isoforms (9,14). Alternative splicing of neurexins is differentially regulated in different brain regions (10,14,16), exhibits a diurnal cycle (17), and is modulated by development, neurotrophins, and neuronal activity (18)(19)(20)(21).Neurexins are known to bind to a large number of ligands, of which neuroligins, leucine-rich repeat transmembrane proteins, and cerebellins are best-characterized (22-28). All of these ligands Significance Neurexins are presynaptic cell-adhesion molecules that are essential for synapse formation and synaptic transmission.…”

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confidence: 99%

Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing

Treutlein¹,

Gökçe

Quake

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

298

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Neurexins are evolutionarily conserved presynaptic cell-adhesion molecules that are essential for normal synapse formation and synaptic transmission. Indirect evidence has indicated that extensive alternative splicing of neurexin mRNAs may produce hundreds if not thousands of neurexin isoforms, but no direct evidence for such diversity has been available. Here we use unbiased long-read sequencing of full-length neurexin (Nrxn)1α, Nrxn1β, Nrxn2β, Nrxn3α, and Nrxn3β mRNAs to systematically assess how many sites of alternative splicing are used in neurexins with a significant frequency, and whether alternative splicing events at these sites are independent of each other. In sequencing more than 25,000 full-length mRNAs, we identified a novel, abundantly used alternatively spliced exon of Nrxn1α and Nrxn3α (referred to as alternatively spliced sequence 6) that encodes a 9-residue insertion in the flexible hinge region between the fifth LNS (laminin-α, neurexin, sex hormone-binding globulin) domain and the third EGF-like sequence. In addition, we observed several larger-scale events of alternative splicing that deleted multiple domains and were much less frequent than the canonical six sites of alternative splicing in neurexins. All of the six canonical events of alternative splicing appear to be independent of each other, suggesting that neurexins may exhibit an even larger isoform diversity than previously envisioned and comprise thousands of variants. Our data are consistent with the notion that α-neurexins represent extracellular protein-interaction scaffolds in which different LNS and EGF domains mediate distinct interactions that affect diverse functions and are independently regulated by independent events of alternative splicing.N eurons form highly specific and complex patterns of synaptic connections that underlie all brain function (1-5). Such specific connections require trillions of chemically differentiated synapses whose identity may be shaped by interactions of specific pre-and postsynaptic signaling molecules, especially cell-adhesion molecules. The genome size is insufficient to encode such diversity, but a mixture of combinatorial expression patterns that pair different synaptic cell-adhesion molecules with each other and of distinct alternative splicing patterns that amplify the number of cell-adhesion molecules into a large number of isoforms may generate the number of transsynaptic interactions needed to account for the enormous diversity of synaptic connections. In Drosophila melanogaster, alternative splicing of the mRNAs encoding the Down syndrome cell-adhesion molecule can generate nearly 20,000 protein isoforms whose structures specify axon bundling but not synapse formation (6). In mammals, alternative splicing of neurexin and some protocadherin mRNAs can also produce thousands of isoforms, which may at least in the case of neurexins be involved in synapse formation (7-10).Neurexins are type I membrane proteins that were discovered as presynaptic receptors for α-latrotoxin (8, 9). Six prin...

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SAM68 Regulates Neuronal Activity-Dependent Alternative Splicing of Neurexin-1

Cited by 253 publications

References 78 publications

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing

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