LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation

Wit, Joris de; Sylwestrak, Emily L.; O’Sullivan, Matthew L.; Otto, Stefanie; Tiglio, Katie; Savas, Jeffrey N.; Yates, John R.; Comoletti, Davide; Taylor, Palmer; Ghosh, Anirvan

doi:10.1016/j.neuron.2009.12.019

Cited by 334 publications

(412 citation statements)

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“…All four LRRTM family members display synaptogenic activities in these assays, although the induction strength of LRRTM2 is the strongest (de Wit et al, 2009;Ko et al, 2009;Linhoff et al, 2009). LRRTM2 specifically localizes in excitatory synapses, and not in inhibitory synapses (Linhoff et al, 2009).…”

Section: Lrr Synaptic Adhesion Moleculesmentioning

confidence: 92%

“…A systematic bioinformatics study has shown that extracellular LRR domain-containing proteins have greatly expanded in mammals (135 in mouse, 139 in human) compared with worms (29 extracellular LRR proteins) and flies (66 extracellular LRR proteins) (Dolan et al, 2007). The ligands of these extracellular LRR proteins remain largely unknown, although the process of ligand identification has recently accelerated (de Wit et al, 2009;Ko et al, 2009;Siddiqui et al, 2010;Takahashi et al, 2011;Woo et al, 2009). Mounting evidence from invertebrate systems shows that extracellular LRR proteins control key phases of neuron development and neural circuit formation including axon guidance, target-cell recognition, and synapse formation.…”

Section: Leucine-rich Repeats (Lrrs)mentioning

confidence: 99%

“…Four LRRTM genes are found only in vertebrates and share similar domain structures comprising 10 LRRs, a single transmembrane segment and a short cytoplasmic stretch, which ends in a type I PDZ-binding motif; this latter motif has been shown to mediate direct interactions with the postsynaptic scaffolding protein, PSD-95 (postsynaptic density 95), in heterologous cells (de Wit et al, 2009;Lauren et al, 2003;Linhoff et al, 2009). All four LRRTM mRNAs, determined by reverse transcription-polymerase chain reaction, are highly expressed in the brain and show overlapping distributions in various brain regions (Lauren et al, 2003).…”

Section: Lrr Synaptic Adhesion Moleculesmentioning

confidence: 99%

“…The localizations of the other LRRTMs have not yet been determined due to a lack of reliable antibodies suitable for immunohistochemical analyses. Overexpression of LRRTM1 or -2 specifically increases the number of excitatory synapses (de Wit et al, 2009;Ko et al, 2009;Linhoff et al, 2009). In addition, LRRTMs interact with neurexins, a well-known family of presynaptic adhesion molecules whose members bind to neuroligins (de Wit et al, 2009;Ko et al, 2009;Siddiqui et al, 2010).…”

Section: Lrr Synaptic Adhesion Moleculesmentioning

confidence: 99%

“…Among the factors that regulate the development of neural circuits, proteins containing extracellular leucine-rich repeat (LRR) domains have recently emerged as key organizers of connectivity (de Wit et al, 2011;Ko and Kim, 2007). Artificial synapse formation assays have shown that a host of LRR-containing proteins, which are widely and highly expressed in the brain, are capable of recruiting various synaptic scaffolds and inducing synaptic differentiation in heterologous cells in which these LRR-containing proteins are exogenously expressed (de Wit et al, 2009;Kim et al, 2006;Ko et al, 2006;Linhoff et al, 2009;Mah et al, 2010;Takahashi et al, 2011;Woo et al, 2009). Selected LRR proteins that function at synapses are shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

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The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

2012

Molecules and Cells

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Section: Lrr Synaptic Adhesion Moleculesmentioning

confidence: 92%

Section: Leucine-rich Repeats (Lrrs)mentioning

confidence: 99%

Section: Lrr Synaptic Adhesion Moleculesmentioning

confidence: 99%

Section: Lrr Synaptic Adhesion Moleculesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

2012

Molecules and Cells

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Investigation ofNRXN1deletions: Clinical and molecular characterization

Dabell

Rosenfeld

Bader

et al. 2013

American J of Med Genetics Pt A

106

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Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.

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Hypomethylation of the paternally inherited LRRTM1 promoter linked to schizophrenia

Brucato

DeLisi

Fisher

et al. 2014

American J of Med Genetics Pt B

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Epigenetic effects on psychiatric traits remain relatively understudied, and it remains unclear what the sizes of individual epigenetic effects may be, or how they vary between different clinical populations. The gene LRRTM1 (chromosome 2p12) has previously been linked and associated with schizophrenia in a parent-of-origin manner in a set of affected siblings (LOD ¼ 4.72), indirectly suggesting a disruption of paternal imprinting at this locus in these families. From the same set of siblings that originally showed strong linkage at this locus, we analyzed 99 individuals using 454-bisulfite sequencing, from whole blood DNA, to measure the level of DNA methylation in the promoter region of LRRTM1. We also assessed seven additional loci that would be informative to compare. Paternal identity-by-descent sharing at LRRTM1, within sibling pairs, was linked to their similarity of methylation at the gene's promoter. Reduced methylation at the promoter showed a significant association with schizophrenia. Sibling pairs concordant for schizophrenia showed more similar methylation levels at the LRRTM1 promoter than diagnostically discordant pairs. The alleles of common SNPs spanning the locus did not explain this epigenetic linkage, which can therefore be considered as largely independent of DNA sequence variation and would not be detected in standard genetic association analysis. Our data suggest that hypomethylation at the LRRTM1 promoter, particularly of the paternally inherited allele, was a risk factor for the development of schizophrenia in this set of siblings affected with familial schizophrenia, and that had previously showed linkage at this locus in an affected-sib-pair context. Ó 2014 Wiley Periodicals, Inc.Key words: epigenetics; parental imprint; sibling pair; psychosis INTRODUCTIONThe complex etiology of schizophrenia involves multiple environmental and genetic factors [Insel, 2010]. Epigenetic variation may also be involved, including DNA methylation [Nishioka et al., 2012], which has long been of interest in psychiatric diseases due to a role in gene regulation, and its potential to transduce environmental and genetic effects at the molecular level [Bernstein et al., 2007;Feil and Fraga, 2011]. Mainly located on cytosine bases of DNA [Bernstein et al., 2007], the role of methylation has been particularly studied in the context of gene promoters, where it can interfere with transcription [Jones, 2012;Zhang et al., 2013]. Recent technological developments now permit the precise quantification of methylation on a locus-specific level, or on a genome-wide scale. However, DNA methylation is subject to variation according to factors such as cell and tissue type, genotype, gender, age, stress, alcohol, and drug consumption [Morris et al., 2011;Bleich et al., 2006;Christensen et al., 2009;Cordero et al., 2013;Horvath, 2013;Lim and Song, 2012; Liu et al., 2010a; Liu et al., 2010b;Philibert et al., 2008;Kerkel et al., 2008]. Distinguishing cause from effect is therefore challenging in studies that find links between...

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LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation

Cited by 334 publications

References 35 publications

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

Investigation ofNRXN1deletions: Clinical and molecular characterization

Hypomethylation of the paternally inherited LRRTM1 promoter linked to schizophrenia

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