Cartography of neurexins: More than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons

Ullrich, Bernd; Ushkaryov, Yuri A.; Südhof, Thomas C.

doi:10.1016/0896-6273(95)90306-2

Cited by 421 publications

(413 citation statements)

References 8 publications

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“…The alternatively spliced sequences for SS#1-SS#4 are highly homologous among the three neurexins, whereas those of SS#5 differ among neurexins. 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).…”

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confidence: 99%

“…In contrast, the extracellular sequences of β-neurexins comprise a short β-neurexinspecific sequence, and then splice into the sixth LNS domain of α-neurexins, from which point on β-neurexins are identical to α-neurexins (11). All α-neurexins are subject to alternative splicing at five canonical sites [SS#1-SS#5 (14)], of which SS#4 and SS#5 are also found in β-neurexins. The alternatively spliced sequences for SS#1-SS#4 are highly homologous among the three neurexins, whereas those of SS#5 differ among neurexins.…”

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confidence: 99%

“…Six principal neurexins (Nrxn1α-3α and Nrxn1β-3β) are synthesized from three genes (Nrxn1-Nrxn3), each of which expresses larger α-and shorter β-isoforms from independent promoters (11)(12)(13). All neurexin mRNAs are extensively alternatively spliced (8,9,14).…”

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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.

283

262

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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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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.

283

262

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“…Vertebrates express three neurexin genes, each of which includes two promoters that direct the synthesis of the longer ␣-neurexins and the shorter ␤-neurexins (6,7). Neurexins are expressed in all neurons, and are subject to extensive alternative splicing, generating Ͼ1,000 splice variants, some of which exhibit highly regulated developmental and spatial expression patterns (8).…”

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confidence: 99%

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Etherton¹,

Blaiss²,

Powell³

et al. 2009

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

406

369

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Deletions in the neurexin-1␣ gene were identified in large-scale unbiased screens for copy-number variations in patients with autism or schizophrenia. To explore the underlying biology, we studied the electrophysiological and behavioral phenotype of mice lacking neurexin-1␣. Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1␣ deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. This defect was specific for excitatory synaptic transmission, because no change in inhibitory synaptic transmission was observed in the hippocampus. Behavioral studies revealed that, compared with littermate control mice, neurexin-1␣ deficient mice displayed a decrease in prepulse inhibition, an increase in grooming behaviors, an impairment in nestbuilding activity, and an improvement in motor learning. However, neurexin-1␣ deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning. Together, these data indicate that the neurexin-1␣ deficiency induces a discrete neural phenotype whose extent correlates, at least in part, with impairments observed in human patients.autism ͉ neuroligin ͉ schizophrenia ͉ synaptic cell-adhesion ͉ synapse N eurexins are neuronal cell-surface proteins that were identified as receptors for ␣-latrotoxin, a presynaptic toxin that triggers massive neurotransmitter release (1-3). Neurexins are largely presynaptic proteins that form a transsynaptic celladhesion complex with postsynaptic neuroligins (4, 5). Vertebrates express three neurexin genes, each of which includes two promoters that direct the synthesis of the longer ␣-neurexins and the shorter ␤-neurexins (6, 7). Neurexins are expressed in all neurons, and are subject to extensive alternative splicing, generating Ͼ1,000 splice variants, some of which exhibit highly regulated developmental and spatial expression patterns (8).The properties of neurexins suggested that they function as synaptic recognition molecules (1), and mediate transsynaptic interactions via binding to neuroligins (4). In support of this overall concept, ␣-neurexin triple KO mice exhibit major impairments in synaptic transmission that manifest largely, but not exclusively, as presynaptic changes (9-13). Importantly, ␣-neurexin KO mice do not display a major decrease in the number of excitatory synapses, and only a moderate decrease in inhibitory synapses (9, 13). Thus, neurexins appear to be essential components of synaptic function whose roles extend to several different components of synapses.In recent years, enormous progress in human genetics has led to the identification of multiple genes that are linked to autism spectrum disorders (ASDs) and schizophrenia. Interestingly, copy-number variations in the neurexin-1␣ gene (but not the neurexin-1␤ gene) were repeatedly observed in patients with ASDs (14 -21) and schizophrenia (22-25). Because 0.5% of all ASD cases appear to harbor neurexin-1␣ gen...

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“…Great variation is achieved through alternative splice variants. 6 Four members of the neuroligin family have been identified in mice (NLGN1, NLGN2, NLGN3, and NLGN4), while five members of the neuroligin family have been identified in humans: NLGN1, NLGN2, NLGN3, NLGN4, and NLGN4Y. 1,7,8 NLGN3 and NLGN4 are both X-linked, with loci at Xq13 and Xp22.33, respectively.…”

Section: Introductionmentioning

confidence: 99%

Familial deletion within NLGN4 associated with autism and Tourette syndrome

et al. 2008

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Neuroligin 4 (NLGN4) is a member of a cell adhesion protein family that appears to play a role in the maturation and function of neuronal synapses. Mutations in the X-linked NLGN4 gene are a potential cause of autistic spectrum disorders, and mutations have been reported in several patients with autism, Asperger syndrome, and mental retardation. We describe here a family with a wide variation in neuropsychiatric illness associated with a deletion of exons 4, 5, and 6 of NLGN4. The proband is an autistic boy with a motor tic. His brother has Tourette syndrome and attention deficit hyperactivity disorder. Their mother, a carrier, has a learning disorder, anxiety, and depression. This family demonstrates that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions and that carriers may be affected with milder symptoms.

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Cartography of neurexins: More than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons

Cited by 421 publications

References 8 publications

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

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

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Familial deletion within NLGN4 associated with autism and Tourette syndrome

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