| 1 | J. Neurosci. 2010 Jun 30: 7495-506 |
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| PMID | 20519524 |
| Title | LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development. |
| Abstract | Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) were recently found to instruct presynaptic and mediate postsynaptic glutamatergic differentiation. In a candidate screen, here we identify neurexin-1beta lacking an insert at splice site 4 (-S4) as a ligand for LRRTM2. Neurexins bind LRRTM2 with a similar affinity but distinct code from the code for binding neuroligin-1 (the predominant form of neuroligin-1 at glutamate synapses, containing the B splice site insert). Whereas neuroligin-1 binds to neurexins 1, 2, and 3 beta but not alpha variants, regardless of insert at splice site 4, LRRTM2 binds to neurexins 1, 2, and 3 alpha and beta variants specifically lacking an insert at splice site 4. We further show that this binding code is conserved in LRRTM1, the family member linked to schizophrenia and handedness, and that the code is functional in a coculture hemisynapse formation assay. Mutagenesis of LRRTM2 to prevent binding to neurexins abolishes presynaptic inducing activity of LRRTM2. Remarkably, mutagenesis of neurexins shows that the binding face on neurexin-1beta (-S4) is highly overlapping for the structurally distinct LRRTM2 and neuroligin-1 partners. Finally, we explore here the interplay of neuroligin-1 and LRRTM2 in synapse regulation. In neuron cultures, LRRTM2 is more potent than neuroligin-1 in promoting synaptic differentiation, and, most importantly, these two families of neurexin-binding partners cooperate in an additive or synergistic manner. Thus, we propose a synaptic code hypothesis suggesting that neurexins are master regulators of the cooperative activities of LRRTMs and neuroligins. |
| SCZ Keywords | schizophrenia |
| 2 | Biochem. Biophys. Res. Commun. 2011 Jul 411: 56-61 |
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| PMID | 21708131 |
| Title | Bidirectional transcription from human LRRTM2/CTNNA1 and LRRTM1/CTNNA2 gene loci leads to expression of N-terminally truncated CTNNA1 and CTNNA2 isoforms. |
| Abstract | ?-Catenins (CTNNAs) are essential for the regulation of cell-cell and cell-matrix interactions in tissues. All human CTNNA genes contain antisense oriented leucine rich repeat transmembrane (LRRTM) genes within their seventh introns. Recently, a haplotype upstream of one of the human LRRTM genes, LRRTM1 that resides in CTNNA2, was shown to be associated with handedness and schizophrenia. Here, we show that both CTNNA1 and CTNNA2 contain alternative 5' exons linked to bidirectional promoters that are shared with the antisense oriented LRRTM2 and LRRTM1 genes, respectively. We demonstrate that bidirectional activity of these promoters results in alternative CTNNA1 and CTNNA2 transcripts that are expressed at high levels in the nervous system and show that N-terminally truncated CTNNA1 and CTNNA2 proteins lacking the ?-catenin interaction domain are produced from these alternative CTNNA mRNAs. In addition, our results indicate that the haplotype that affects LRRTM1 expression and is associated with schizophrenia and handedness, could also influence the expression of brain-enriched alternative transcripts of CTNNA2. |
| SCZ Keywords | schizophrenia |
| 3 | Hum. Genet. 2011 Oct 130: 563-73 |
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| PMID | 21424692 |
| Title | Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. |
| Abstract | Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders. |
| SCZ Keywords | schizophrenia |
| 4 | J. Neurochem. 2011 Jun 117: 765-78 |
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| PMID | 21155806 |
| Title | Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy. |
| Abstract | Recent studies have identified the leucine rich repeat protein LRRTM2 as a post-synaptic ligand of Neurexins. Neurexins also bind the post-synaptic adhesion molecules, Neuroligins. All three families of genes have been implicated in the etiologies of neurodevelopmental disorders, specifically autism spectrum disorders and schizophrenia. Does the binding promiscuity of Neurexins now suggest complex cooperativity or redundancy at the synapse? While recent studies in primary neuronal cultures and also systematic extracellular protein interaction screens suggest summative effects of these systems, we propose that studying these interactions in the developing zebrafish embryo or larvae may shed more light on their functions during synaptogenesis in vivo. These gene families have recently been extensively characterized in zebrafish, demonstrating high sequence conservation with the human genes. The simpler circuitry of the zebrafish, together with the characterization of the expression patterns down to single, identifiable neurons and the ability to knock-down or over-express multiple genes in a rapid way lend themselves to dissecting complex interaction pathways. Furthermore, the capability of performing high-throughput drug screens suggests that these small vertebrates may prove extremely useful in identifying pharmacological approaches to treating autism spectrum disorders. |
| SCZ Keywords | schizophrenia |
| 5 | PLoS ONE 2014 -1 9: e89910 |
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| PMID | 24587117 |
| Title | Origin and loss of nested LRRTM/?-catenin genes during vertebrate evolution. |
| Abstract | Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) form in mammals a family of four postsynaptic adhesion proteins, which have been shown to bind neurexins and heparan sulphate proteoglycan (HSPG) glypican on the presynaptic side. Mutations in the genes encoding LRRTMs and neurexins are implicated in human cognitive disorders such as schizophrenia and autism. Our analysis shows that in most jawed vertebrates, lrrtm1, LRRTM2, and lrrtm3 genes are nested on opposite strands of large conserved intron of ?-catenin genes ctnna2, ctnna1, and ctnna3, respectively. No lrrtm genes could be found in tunicates or lancelets, while two lrrtm genes are found in the lamprey genome, one of which is adjacent to a single ctnna homolog. Based on similar highly positive net charge of lamprey LRRTMs and the HSPG-binding LRRTM3 and LRRTM4 proteins, we speculate that the ancestral LRRTM might have bound HSPG before acquiring neurexins as binding partners. Our model suggests that lrrtm gene translocated into the large ctnna intron in early vertebrates, and that subsequent duplications resulted in three lrrtm/ctnna gene pairs present in most jawed vertebrates. However, we detected three prominent exceptions: (1) the lrrtm3/ctnna3 gene structure is absent in the ray-finned fish genomes, (2) the genomes of clawed frogs contain ctnna1 but lack the corresponding nested (LRRTM2) gene, and (3) contain lrrtm3 gene in the syntenic position but lack the corresponding host (ctnna3) gene. We identified several other protein-coding nested gene structures of which either the host or the nested gene has presumably been lost in the frog or chicken lineages. Interestingly, majority of these nested genes comprise LRR domains. |
| SCZ Keywords | schizophrenia |