Neurexin-2 (NRXN2) is a neuron-specific, presynaptic single-pass type I membrane protein of the neurexin family that organizes synapses through trans-synaptic adhesion complexes. Like its paralogs NRXN1 and NRXN3, the gene uses two promoters: the upstream promoter produces the long neurexin-2-alpha isoforms described by this entry, with six laminin/neurexin/sex-hormone-binding globulin (LNS) domains interspersed with three EGF-like repeats, and an internal promoter produces short neurexin-2-beta isoforms (separate UniProt entry P58401) that carry only the sixth LNS domain; both share a heparan-sulfate-modified stalk, a transmembrane helix and a short cytoplasmic tail ending in a PDZ-binding motif. NRXN2 lacks the sixth alternatively spliced segment present in NRXN1 and NRXN3, and splice site 4 in LNS6 regulates partner choice. Through Ca2+-dependent binding of LNS6, NRXN2 binds postsynaptic neuroligins, LRRTMs and latrophilin-1, and alpha isoforms bind dystroglycan through LNS2; neurexin-2-alpha is also the selective presynaptic receptor, via LNS1, for the postsynaptic immunoglobulin-superfamily protein IgSF21, which uses it to induce GABAergic presynaptic differentiation at dendritic inhibitory synapses. Presented to dendrites, neurexin-2-alpha clusters glutamatergic and GABAergic postsynaptic components. In vivo its role is circuit-dependent: combined alpha-neurexin deletion impairs Ca2+-triggered release, Nrxn2-alpha loss reduces spontaneous excitatory release in neocortex, whereas neuronal Nrxn2 deletion in hippocampus increases excitatory synapse density and release probability, suggesting that NRXN2 can restrain excitatory synapse assembly; overexpressed neurexin-2-beta suppresses GABAergic transmission without changing synapse numbers. Loss of Nrxn2 in mice causes anxiety-like behaviour, social deficits, behavioural inflexibility and, after cortical/hippocampal deletion, spontaneous seizures. Rare truncating variants and deletions of NRXN2 have been found in individuals with autism and other neurodevelopmental disorders.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004888 transmembrane signaling receptor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the neurexin clade node PTN002227321 (transmembrane signaling receptor activity). Reason: NRXN2 behaves as a presynaptic receptor for postsynaptic organizers: IgSF21, an NRXN2-alpha-selective ligand, recruits axonal neurexin-2-alpha and induces inhibitory presynaptic differentiation only through this interaction. How ligand binding is transduced across the presynaptic membrane is not established, and NRXN2 equally acts as the ligand that induces postsynaptic differentiation, so its core activity is better captured by the adhesion-mediator and trans-synaptic signaling terms. Retained as non-core, as for NRXN1. Supporting Evidence: PMID:28864826 NRX2Ξ± acts as a receptor that mediates presynaptic organization signals induced by postsynaptic organizers such as NLGs19, 22, calsyntenin-335 and IgSF21 but also acts as a ligand that induces postsynaptic organization PMID:28864826 Together, these data indicate that IgSF21 binds and recruits axonal NRX2Ξ± in a trans-interaction manner and that this interaction is essential for the synaptogenic activity of IgSF21. |
| GO:0004888 transmembrane signaling receptor activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn2 (E9Q7X7), whose source is a BHF-UCL IDA from PMID:21424692; that paper shows neurexin-2-alpha acting in trans as a ligand that clusters postsynaptic components. Reason: NRXN2 behaves as a presynaptic receptor for postsynaptic organizers: IgSF21, an NRXN2-alpha-selective ligand, recruits axonal neurexin-2-alpha and induces inhibitory presynaptic differentiation only through this interaction. How ligand binding is transduced across the presynaptic membrane is not established, and NRXN2 equally acts as the ligand that induces postsynaptic differentiation, so its core activity is better captured by the adhesion-mediator and trans-synaptic signaling terms. Retained as non-core, as for NRXN1. Note that the source experiment (coculture clustering) shows NRXN2 acting as the ligand rather than the receptor; the receptor role is better supported by the IgSF21 work. Supporting Evidence: PMID:28864826 NRX2Ξ± acts as a receptor that mediates presynaptic organization signals induced by postsynaptic organizers such as NLGs19, 22, calsyntenin-335 and IgSF21 but also acts as a ligand that induces postsynaptic organization PMID:28864826 Together, these data indicate that IgSF21 binds and recruits axonal NRX2Ξ± in a trans-interaction manner and that this interaction is essential for the synaptogenic activity of IgSF21. PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites |
| GO:0005246 calcium channel regulator activity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from mouse Nrxn2, whose source is an MGI IGI from alpha-neurexin multiple knockouts showing reduced synaptic Ca2+ channel function (PMID:12827191). Reason: As for NRXN1: combined alpha-neurexin deletion reduces synaptic Ca2+ channel function, but cell-surface channel number is normal and alpha-neurexins do not directly alter channel activation or inactivation; they couple channels to release-ready vesicles. For NRXN2 specifically, the Nrxn2-alpha single knockout was used as a control in secretory cells because it was indistinguishable from wild type, so there is no NRXN2-specific evidence for channel regulation. The biology is better represented at the process level. Supporting Evidence: PMID:12827191 Neurotransmitter release is impaired because synaptic Ca2+ channel function is markedly reduced, although the number of cell-surface Ca2+ channels appears normal. PMID:17035546 alpha-neurexins do not affect the activation or inactivation properties of Ca2+ channels directly but may be responsible for coupling them to release-ready vesicles and metabotropic receptors PMID:17035546 both WT and SKO2 genotypes showed virtually identical results in all of the parameters that were examined and are referred to collectively as controls |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA to plasma membrane from the broad neurexin-family node PTN002309037. Reason: Correct: NRXN2 is a single-pass type I membrane protein of the presynaptic plasma membrane that binds neuroligins, LRRTMs and IgSF21 extracellularly. The functionally informative subcompartments (presynaptic membrane, active zone membrane) are also annotated. Supporting Evidence: file:human/NRXN2/NRXN2-uniprot.txt Single-pass type I membrane protein file:human/NRXN2/NRXN2-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:28864826 IgSF21 localizes postsynaptically and recruits axonal neurexin2Ξ± in a trans-interaction manner. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6794346 | ACCEPT | Summary: Reactome TAS placing NRXN2 at the plasma membrane in the neurexin-neuroligin binding reaction. Reason: Correct: NRXN2 is a single-pass type I membrane protein of the presynaptic plasma membrane that binds neuroligins, LRRTMs and IgSF21 extracellularly. The functionally informative subcompartments (presynaptic membrane, active zone membrane) are also annotated. Supporting Evidence: Reactome:R-HSA-6794346 alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes file:human/NRXN2/NRXN2-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6797554 | ACCEPT | Summary: Reactome TAS for plasma membrane from a reaction in the neurexin/neuroligin/SHANK set (DBNL binding SHANK), in which NRXN2 is a participant of the larger complex. Reason: The reaction itself is postsynaptic and says nothing specific about NRXN2, but the location it implies for NRXN2 (plasma membrane) is correct and independently established; treated as for NRXN1. Supporting Evidence: file:human/NRXN2/NRXN2-uniprot.txt Single-pass type I membrane protein file:human/NRXN2/NRXN2-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6797568 | ACCEPT | Summary: Reactome TAS placing NRXN2 at the plasma membrane in the neurexin-CASK-protein 4.1 reaction. Reason: Correct: NRXN2 is a single-pass type I membrane protein of the presynaptic plasma membrane that binds neuroligins, LRRTMs and IgSF21 extracellularly. The functionally informative subcompartments (presynaptic membrane, active zone membrane) are also annotated. Supporting Evidence: Reactome:R-HSA-6797568 Neurexins are recruited together with CASK and protein 4.1 into these actin filaments and thus intercellular junctions initiated by neurexins with neuroligins are at least partially coupled to the actin cytoskeleton file:human/NRXN2/NRXN2-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6797974 | ACCEPT | Summary: Reactome TAS placing NRXN2 at the plasma membrane in the LRRTM-neurexin binding reaction. Reason: Correct: NRXN2 is a single-pass type I membrane protein of the presynaptic plasma membrane that binds neuroligins, LRRTMs and IgSF21 extracellularly. The functionally informative subcompartments (presynaptic membrane, active zone membrane) are also annotated. Supporting Evidence: Reactome:R-HSA-6797974 All four LRRTMs family members are post-synaptic localized and bind specifically to presynaptic alpha and beta-Neurexins (NRXNs) lacking an insert at splice site S4 file:human/NRXN2/NRXN2-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane |
| GO:0007158 neuron cell-cell adhesion | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning IEA for neuron cell-cell adhesion. Reason: Correct in essence: neurexin-2 mediates adhesion between neurons by binding postsynaptic partners across the synaptic cleft (neurexin-2-beta-expressing cells aggregate with latrophilin-1-expressing cells; IgSF21 recruits axonal neurexin-2-alpha in trans). The adhesion is specifically between pre- and postsynaptic membranes, so the precise process is GO:0099560 synaptic membrane adhesion, as chosen for NRXN1. Proposed replacements: synaptic membrane adhesion Supporting Evidence: PMID:22262843 Strikingly, we found that cells expressing either of these two neurexins formed aggregates with CL1-expressing cells, again dependent on a lack of an insert in SS4 in the case of neurexin-2Ξ² PMID:28864826 IgSF21 localizes postsynaptically and recruits axonal neurexin2Ξ± in a trans-interaction manner. PMID:16242404 neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation |
| GO:0007158 neuron cell-cell adhesion | TAS PMID:18923512 Neuroligins and neurexins link synaptic function to cognitiv... | MODIFY | Summary: TAS from a major review describing neurexins and neuroligins as synaptic cell-adhesion molecules connecting pre- and postsynaptic neurons. Reason: The adhesion NRXN2 mediates is between presynaptic and postsynaptic membranes, via trans-synaptic complexes with neuroligins, LRRTMs, latrophilins and the NRXN2-alpha-selective ligand IgSF21. GO:0099560 synaptic membrane adhesion is the precise term and is the process used for neurexins in the neurexin trans-synaptic adhesion module and the NRXN1 review. Proposed replacements: synaptic membrane adhesion Supporting Evidence: PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions PMID:16242404 neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation PMID:22262843 Strikingly, we found that cells expressing either of these two neurexins formed aggregates with CL1-expressing cells, again dependent on a lack of an insert in SS4 in the case of neurexin-2Ξ² PMID:28864826 IgSF21 localizes postsynaptically and recruits axonal neurexin2Ξ± in a trans-interaction manner. |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: IBA to the very general signal transduction, from the broad node PTN002309037 spanning neurexins and related LNS proteins. Reason: Neurexin-2 signalling is trans-synaptic: presented to dendrites, neurexin-2-alpha induces clustering of glutamatergic and GABAergic postsynaptic components, and postsynaptic IgSF21 signals presynaptic inhibitory differentiation through neurexin-2-alpha. GO:0099545 trans-synaptic signaling by trans-synaptic complex describes this; generic signal transduction implies an intracellular cascade that is not established for neurexin. NRXN1 and NRXN3 use the child GO:0099557 (modulating synaptic transmission) because they have cerebellin-GluD1 evidence for receptor tuning without synapse loss; the NRXN2 evidence is synapse organization, so the parent term is kept here. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002309037 SUPPORTS TRANSFER Broad node spanning neurexins and related LNS/neurexin-like proteins; the signalling claim is inherited correctly but at a generic level that hides the trans-synaptic nature of neurexin signalling. Proposed replacements: trans-synaptic signaling by trans-synaptic complex Supporting Evidence: PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites PMID:28864826 Together, these data indicate that IgSF21 binds and recruits axonal NRX2Ξ± in a trans-interaction manner and that this interaction is essential for the synaptogenic activity of IgSF21. PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions |
| GO:0007165 signal transduction | ISS GO_REF:0000024 | MODIFY | Summary: ISS from mouse Nrxn2, whose source is a BHF-UCL IDA from PMID:21424692 (neurexin-2-alpha on COS cells induces postsynaptic clustering in contacting dendrites). Reason: Neurexin-2 signalling is trans-synaptic: presented to dendrites, neurexin-2-alpha induces clustering of glutamatergic and GABAergic postsynaptic components, and postsynaptic IgSF21 signals presynaptic inhibitory differentiation through neurexin-2-alpha. GO:0099545 trans-synaptic signaling by trans-synaptic complex describes this; generic signal transduction implies an intracellular cascade that is not established for neurexin. NRXN1 and NRXN3 use the child GO:0099557 (modulating synaptic transmission) because they have cerebellin-GluD1 evidence for receptor tuning without synapse loss; the NRXN2 evidence is synapse organization, so the parent term is kept here. Proposed replacements: trans-synaptic signaling by trans-synaptic complex Supporting Evidence: PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites PMID:28864826 Together, these data indicate that IgSF21 binds and recruits axonal NRX2Ξ± in a trans-interaction manner and that this interaction is essential for the synaptogenic activity of IgSF21. |
| GO:0007268 chemical synaptic transmission | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn2 (MGI IGI in alpha-neurexin multiple knockouts, PMID:12827191). Nrxn2 deletion alters excitatory transmission in cortex and hippocampus. Reason: True but broad. NRXN2 influences transmission by modulating presynaptic release properties and synapse number and, via trans-synaptic partners, postsynaptic receptor responses. Notably the direction is circuit-dependent: Nrxn2-alpha knockout reduces spontaneous excitatory release in neocortex, whereas neuron-specific Nrxn2 deletion increases CA3-CA1 transmission and release probability. The more specific presynaptic modulation of chemical synaptic transmission (proposed as NEW) is used as the core process; this parent is retained as non-core. Supporting Evidence: PMID:12827191 Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. PMID:25745399 Using patch-clamp recordings in Nrxn2Ξ± knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. PMID:36608123 Unexpectedly, we find that in the hippocampus, the loss of Nrxn2 causes an increase both in the number of excitatory synapses and in the presynaptic release probability, suggesting a function in restricting synapse assembly. |
| GO:0007269 neurotransmitter secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn2 (MGI IGI, PMID:12827191): alpha-neurexins collectively are essential for Ca2+-triggered neurotransmitter release. Reason: Diverges from NRXN1, where this term was accepted as core. The IGI source reflects combined alpha-neurexin deletions, in which NRXN2 contributes to release-site organization with its paralogs. NRXN2 alone, however, is not a required component of the release process: Nrxn2-alpha single knockouts were indistinguishable from wild type in secretory-cell exocytosis, Nrxn2-alpha loss mildly reduces spontaneous excitatory release in neocortex, and neuron-specific Nrxn2 deletion instead increases release probability at CA3-CA1 synapses. NRXN2 therefore modulates release rather than executing it; the modulatory role is captured by the NEW GO:0099171 row, and this term is kept as non-core. Supporting Evidence: PMID:12827191 Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. PMID:12827191 alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery PMID:17035546 both WT and SKO2 genotypes showed virtually identical results in all of the parameters that were examined and are referred to collectively as controls PMID:25745399 Using patch-clamp recordings in Nrxn2Ξ± knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. PMID:36608123 Unexpectedly, we find that in the hippocampus, the loss of Nrxn2 causes an increase both in the number of excitatory synapses and in the presynaptic release probability, suggesting a function in restricting synapse assembly. |
| GO:0007399 nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA to nervous system development from the broad neurexin/neurexin-like node PTN000804946. Reason: Not wrong - NRXN2 is a neuronal synapse organizer - but very general. The specific developmental contribution is synapse organization (captured by the synapse assembly and trans-synaptic signaling terms). Supporting Evidence: PMID:17347997 Therefore, alpha-neurexins are not essential for the formation of the vast majority of synapses in vivo but rather regulate the function of these synapses. PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites |
| GO:0007416 synapse assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn2 (MGI IGI from alpha-neurexin knockouts, PMID:12827191). NRXN2 both promotes and restricts synapse assembly depending on synapse type. Reason: NRXN2 participates in synapse assembly, but its contribution is bidirectional and context-dependent, more so than for NRXN1. It acts as a pro-synaptogenic organizer in gain-of-function assays (neurexin-2-alpha clusters postsynaptic components; IgSF21 induces inhibitory presynaptic differentiation only through neurexin-2-alpha). In vivo, however, neuron-specific Nrxn2 deletion nearly doubles excitatory CA1 synapse density, i.e. NRXN2 restricts excitatory synapse assembly there, while neocortical synapse densities are unchanged in Nrxn2-alpha knockouts and alpha-neurexins as a class are not required for forming most synapses. The source IGI is from combined alpha-neurexin deletions, which showed no requirement for synapse formation. Retained as genuine but non-core. Supporting Evidence: PMID:28864826 Together, these data indicate that IgSF21 binds and recruits axonal NRX2Ξ± in a trans-interaction manner and that this interaction is essential for the synaptogenic activity of IgSF21. PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites PMID:36608123 Here we show that Nrxn2, different from Nrxn1 and Nrxn3, functions to restrict, instead of enabling, synapse assembly in the hippocampus. PMID:25745399 Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. PMID:12827191 Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. file:human/NRXN2/NRXN2-deep-research-falcon.md This restrictive function persists throughout life: hippocampal NRXN2 deletion in mature adult mice also increased synaptic connectivity, demonstrating that NRXN2 continuously controls synaptic circuit dynamics rather than functioning only during development |
| GO:0007612 learning | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the neurexin clade node PTN002227321; NRXN2 itself (Q9P2S2) is among the sources. Reason: Hippocampal Nrxn2 deletion impairs the cognitive flexibility of spatial memory, cortical/hippocampal Nrxn2 deletion impairs reversal learning, and heterozygous Nrxn2-alpha mice lack long-term object discrimination. This is an organism-level consequence of NRXN2's synaptic role rather than an activity it executes, so it is retained as non-core, as for NRXN1. Supporting Evidence: PMID:36608123 hippocampal neurexin-2 deletions also increased synaptic connectivity in the CA1 region when induced in mature mice and impaired the cognitive flexibility of spatial memory PMID:38702381 Emx1-Nrxn2 cKO mice exhibited reversal learning deficits, indicating their inability to adopt new action strategies. PMID:26595880 Nrxn2Ξ± HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. |
| GO:0030534 adult behavior | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA to adult behavior from the neurexin clade node PTN002227321; NRXN2 is among the sources. Reason: Nrxn2 loss alters adult mouse behaviour (anxiety-like behaviour, social deficits, nestlet shredding, behavioural inflexibility). This is a downstream phenotype of synaptic dysfunction; retained as non-core, consistent with NRXN1. Supporting Evidence: PMID:25745399 mice lacking Nrxn2Ξ± exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior PMID:36941261 conditional deletion of Nrxn2 from the hippocampus and cortex (Nrxn2 cKO) results in behavioral abnormalities, including reduced social preference and increased nestlet shredding behavior PMID:38702381 Emx1-Nrxn2 cKO mice exhibited reversal learning deficits, indicating their inability to adopt new action strategies. |
| GO:0030534 adult behavior | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA to adult behavior. Reason: Nrxn2 loss alters adult mouse behaviour (anxiety-like behaviour, social deficits, nestlet shredding, behavioural inflexibility). This is a downstream phenotype of synaptic dysfunction; retained as non-core, consistent with NRXN1. Supporting Evidence: PMID:25745399 mice lacking Nrxn2Ξ± exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior PMID:36941261 conditional deletion of Nrxn2 from the hippocampus and cortex (Nrxn2 cKO) results in behavioral abnormalities, including reduced social preference and increased nestlet shredding behavior |
| GO:0030534 adult behavior | IMP PMID:21424692 Truncating mutations in NRXN2 and NRXN1 in autism spectrum d... | KEEP AS NON CORE | Summary: IMP from a single boy with autism carrying a heterozygous NRXN2 frameshift (c.2733delT) inherited from a father with severe language delay. Reason: One heterozygous family, with an allele also carried by a relatively mildly affected parent, is weak human evidence on its own; the paper's experimental work is on binding and synaptogenic activity of the truncated protein, not behaviour. Mouse Nrxn2-alpha knockouts do show altered adult behaviour (anxiety-like and social phenotypes), so an organism-level involvement is plausible. It is a downstream phenotype of synaptic dysfunction, not a function NRXN2 executes; kept as non-core as for the NRXN1 case-report IMP. Supporting Evidence: PMID:21424692 we discovered a frameshift mutation (c.2733delT; NM_138732.2), located in exon 12 of NRXN2 PMID:21424692 The Autism Diagnostic Observation Schedule-Generic (ADOS-G) score is 21 (autism cutoff = 12). PMID:21424692 This mutation was inherited from the father who had a severe language delay (did not speak until 5 years of age). PMID:25745399 mice lacking Nrxn2Ξ± exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior |
| GO:0035176 social behavior | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA to social behavior. Reason: Unlike Nrxn1-alpha knockouts (normal social behaviour), Nrxn2-alpha knockouts show social deficits in independent studies (sociability and social memory; social interaction), and conditional cortical/hippocampal Nrxn2 deletion reduces social preference, so an organism-level requirement is better supported for NRXN2 than for NRXN1. It is nevertheless a downstream behavioural consequence of synaptic dysfunction; non-core. Supporting Evidence: PMID:25423136 We report that Nrxn2Ξ± KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. PMID:25745399 mice lacking Nrxn2Ξ± exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior PMID:36941261 conditional deletion of Nrxn2 from the hippocampus and cortex (Nrxn2 cKO) results in behavioral abnormalities, including reduced social preference and increased nestlet shredding behavior |
| GO:0035176 social behavior | IMP PMID:21424692 Truncating mutations in NRXN2 and NRXN1 in autism spectrum d... | KEEP AS NON CORE | Summary: IMP from one autistic boy with a heterozygous NRXN2 frameshift that abolishes membrane anchoring and ligand binding. Reason: The single human family is weak evidence by itself, but it is consistent with reproducible social deficits in Nrxn2-alpha and conditional Nrxn2 knockout mice. Unlike Nrxn1-alpha knockouts (normal social behaviour), Nrxn2-alpha knockouts show social deficits in independent studies (sociability and social memory; social interaction), and conditional cortical/hippocampal Nrxn2 deletion reduces social preference, so an organism-level requirement is better supported for NRXN2 than for NRXN1. It is nevertheless a downstream behavioural consequence of synaptic dysfunction; non-core. Supporting Evidence: PMID:21424692 we discovered a frameshift mutation (c.2733delT; NM_138732.2), located in exon 12 of NRXN2 PMID:21424692 The Autism Diagnostic Observation Schedule-Generic (ADOS-G) score is 21 (autism cutoff = 12). PMID:25423136 We report that Nrxn2Ξ± KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. PMID:25423136 Our findings demonstrate a causal role for the loss of Nrxn2Ξ± in the genesis of autism-related behaviors in mice. PMID:36941261 conditional deletion of Nrxn2 from the hippocampus and cortex (Nrxn2 cKO) results in behavioral abnormalities, including reduced social preference and increased nestlet shredding behavior |
| GO:0042297 vocal learning | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA IEA (vocal learning), apparently generalized from the human patient-phenotype annotations. Reason: The only support is that one autistic proband's carrier father had severe language delay. Language delay in an autism/neurodevelopmental context does not show that NRXN2 acts in vocal learning or vocalization per se, and no NRXN2 mouse study reports a specific vocalization phenotype. Over-interpretation of a clinical feature, as for NRXN1. Supporting Evidence: PMID:21424692 This mutation was inherited from the father who had a severe language delay (did not speak until 5 years of age). |
| GO:0042297 vocal learning | IMP PMID:21424692 Truncating mutations in NRXN2 and NRXN1 in autism spectrum d... | MARK AS OVER ANNOTATED | Summary: IMP (vocal learning) based on the language delay of the carrier father of an autistic boy with an NRXN2 frameshift. Reason: The only support is that one autistic proband's carrier father had severe language delay. Language delay in an autism/neurodevelopmental context does not show that NRXN2 acts in vocal learning or vocalization per se, and no NRXN2 mouse study reports a specific vocalization phenotype. Over-interpretation of a clinical feature, as for NRXN1. Supporting Evidence: PMID:21424692 This mutation was inherited from the father who had a severe language delay (did not speak until 5 years of age). PMID:21424692 we discovered a frameshift mutation (c.2733delT; NM_138732.2), located in exon 12 of NRXN2 |
| GO:0042734 presynaptic membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location: presynaptic membrane. Reason: NRXN2 is a presynaptic type I membrane protein; NRXN2-alpha is recruited to presynaptic sites by postsynaptic IgSF21, and SynGO annotates mouse Nrxn2 to glutamatergic synapses. This is its principal site of action. Supporting Evidence: file:human/NRXN2/NRXN2-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:28864826 IgSF21 localizes postsynaptically and recruits axonal neurexin2Ξ± in a trans-interaction manner. |
| GO:0042734 presynaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Nrxn1 (Q9CS84): presynaptic membrane. Reason: NRXN2 is a presynaptic type I membrane protein; NRXN2-alpha is recruited to presynaptic sites by postsynaptic IgSF21, and SynGO annotates mouse Nrxn2 to glutamatergic synapses. This is its principal site of action. Supporting Evidence: file:human/NRXN2/NRXN2-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:28864826 IgSF21 localizes postsynaptically and recruits axonal neurexin2Ξ± in a trans-interaction manner. |
| GO:0048787 presynaptic active zone membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the neurexin clade node PTN002227321: presynaptic active zone membrane. Reason: Consistent with neurexin function: alpha-neurexins organize the release site by coupling Ca2+ channels to the release machinery and bind presynaptic PDZ scaffolds, and neuronal Nrxn2 deletion changes release probability, placing NRXN2 function at the active zone. Supporting Evidence: PMID:12827191 alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins PMID:36608123 Unexpectedly, we find that in the hippocampus, the loss of Nrxn2 causes an increase both in the number of excitatory synapses and in the presynaptic release probability, suggesting a function in restricting synapse assembly. |
| GO:0050839 cell adhesion molecule binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Nrxn2, whose source is a BHF-UCL IPI (PMID:21424692) showing neurexin-2-alpha binding LRRTM2 and NLGN2 ectodomains. Reason: NRXN2 binds several postsynaptic adhesion molecules: neuroligins and LRRTM2 via LNS6, latrophilin-1 (SS4-regulated), dystroglycan via LNS2, and IgSF21, an NRXN2-alpha-selective ligand that binds LNS1. The source experiment is directly on neurexin-2-alpha. Supporting Evidence: PMID:21424692 unlike the high affinity binding of wild-type neurexin2Ξ±-CFP, the delA mutant expressed in COS cells was unable to bind either LRRTM2-AP or NLGN2-Fc PMID:21424692 removes nearly half of the neurexin2Ξ± protein, including the binding sites for NLGNs and LRRTMs in LNS6, the transmembrane domain, and the intracellular domain PMID:28864826 Interestingly, IgSF21-Fc interacted only with NRX2Ξ± and not with any other NRX isoforms PMID:22262843 Strikingly, we found that cells expressing either of these two neurexins formed aggregates with CL1-expressing cells, again dependent on a lack of an insert in SS4 in the case of neurexin-2Ξ² PMID:11470830 The second LNS domain of all three Ξ±-neurexins (neurexin 1Ξ±, 2Ξ±, and 3Ξ±) formed tight Ca2+-dependent complexes with dystroglycan, suggesting that all Ξ±-neurexins bind to dystroglycan |
| GO:0071625 vocalization behavior | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA IEA (vocalization behavior), apparently generalized from the human patient-phenotype annotations. Reason: The only support is that one autistic proband's carrier father had severe language delay. Language delay in an autism/neurodevelopmental context does not show that NRXN2 acts in vocal learning or vocalization per se, and no NRXN2 mouse study reports a specific vocalization phenotype. Over-interpretation of a clinical feature, as for NRXN1. Supporting Evidence: PMID:21424692 This mutation was inherited from the father who had a severe language delay (did not speak until 5 years of age). |
| GO:0071625 vocalization behavior | IMP PMID:21424692 Truncating mutations in NRXN2 and NRXN1 in autism spectrum d... | MARK AS OVER ANNOTATED | Summary: IMP (vocalization behavior) based on the same single NRXN2 frameshift family. Reason: The only support is that one autistic proband's carrier father had severe language delay. Language delay in an autism/neurodevelopmental context does not show that NRXN2 acts in vocal learning or vocalization per se, and no NRXN2 mouse study reports a specific vocalization phenotype. Over-interpretation of a clinical feature, as for NRXN1. Supporting Evidence: PMID:21424692 This mutation was inherited from the father who had a severe language delay (did not speak until 5 years of age). PMID:21424692 we discovered a frameshift mutation (c.2733delT; NM_138732.2), located in exon 12 of NRXN2 |
| GO:0097104 postsynaptic membrane assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn2 (BHF-UCL IDA, PMID:21424692): postsynaptic membrane assembly. Reason: Neurexin-2-alpha presented on COS cells induces clustering of glutamatergic (LRRTM2, PSD-95) and GABAergic (NLGN2, gephyrin) postsynaptic components in contacting dendrites, and this activity is lost with the ASD-associated truncation that removes LNS6. NRXN2 acts in trans as the organizing ligand; the clustering itself is executed by the postsynaptic machinery. A gain-of-function coculture readout of the trans-synaptic organizer role; non-core, as for NRXN1. Supporting Evidence: PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites |
| GO:0097109 neuroligin family protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: neuroligin family protein binding. Reason: Neuroligin binding is conserved for neurexin-2: the NLGN2 ectodomain binds neurexin-2-alpha with high affinity through LNS6 (lost in the LNS6-deleting ASD truncation), and neurexin-2-beta Ca2+-site mutation abolishes neuroligin-1-mediated adhesion. The IBA node PTN002227321 is well placed. Supporting Evidence: PMID:21424692 unlike the high affinity binding of wild-type neurexin2Ξ±-CFP, the delA mutant expressed in COS cells was unable to bind either LRRTM2-AP or NLGN2-Fc PMID:21424692 removes nearly half of the neurexin2Ξ± protein, including the binding sites for NLGNs and LRRTMs in LNS6, the transmembrane domain, and the intracellular domain PMID:20064387 was blocked by a single amino-acid substitution in neurexin-2Ξ² that abolishes Ca2+-binding to the neurexin LNS domain, and that also abolishes neuroligin-1 mediated cell adhesion Reactome:R-HSA-6794346 alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes |
| GO:0097109 neuroligin family protein binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Nrxn2 (BHF-UCL IPI with NLGN2, PMID:21424692). Reason: Neuroligin binding is conserved for neurexin-2: the NLGN2 ectodomain binds neurexin-2-alpha with high affinity through LNS6 (lost in the LNS6-deleting ASD truncation), and neurexin-2-beta Ca2+-site mutation abolishes neuroligin-1-mediated adhesion. The IBA node PTN002227321 is well placed. Supporting Evidence: PMID:21424692 unlike the high affinity binding of wild-type neurexin2Ξ±-CFP, the delA mutant expressed in COS cells was unable to bind either LRRTM2-AP or NLGN2-Fc PMID:21424692 removes nearly half of the neurexin2Ξ± protein, including the binding sites for NLGNs and LRRTMs in LNS6, the transmembrane domain, and the intracellular domain Reactome:R-HSA-6794346 alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes |
| GO:0097116 gephyrin clustering involved in postsynaptic density assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: gephyrin clustering involved in postsynaptic density assembly. Reason: Neurexin-2-alpha presented on COS cells induces clustering of glutamatergic (LRRTM2, PSD-95) and GABAergic (NLGN2, gephyrin) postsynaptic components in contacting dendrites, and this activity is lost with the ASD-associated truncation that removes LNS6. NRXN2 acts in trans as the organizing ligand; the clustering itself is executed by the postsynaptic machinery. A gain-of-function coculture readout of the trans-synaptic organizer role; non-core, as for NRXN1. Supporting Evidence: PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites |
| GO:0097116 gephyrin clustering involved in postsynaptic density assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn2 (BHF-UCL IDA, PMID:21424692): gephyrin clustering. Reason: Neurexin-2-alpha presented on COS cells induces clustering of glutamatergic (LRRTM2, PSD-95) and GABAergic (NLGN2, gephyrin) postsynaptic components in contacting dendrites, and this activity is lost with the ASD-associated truncation that removes LNS6. NRXN2 acts in trans as the organizing ligand; the clustering itself is executed by the postsynaptic machinery. A gain-of-function coculture readout of the trans-synaptic organizer role; non-core, as for NRXN1. Supporting Evidence: PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites |
| GO:0097118 neuroligin clustering involved in postsynaptic membrane assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn2 (BHF-UCL IDA, PMID:21424692): neuroligin clustering. Reason: Direct: neurexin-2-alpha binds NLGN2 and clusters it at contact sites. Neurexin-2-alpha presented on COS cells induces clustering of glutamatergic (LRRTM2, PSD-95) and GABAergic (NLGN2, gephyrin) postsynaptic components in contacting dendrites, and this activity is lost with the ASD-associated truncation that removes LNS6. NRXN2 acts in trans as the organizing ligand; the clustering itself is executed by the postsynaptic machinery. A gain-of-function coculture readout of the trans-synaptic organizer role; non-core, as for NRXN1. Supporting Evidence: PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites PMID:21424692 unlike the high affinity binding of wild-type neurexin2Ξ±-CFP, the delA mutant expressed in COS cells was unable to bind either LRRTM2-AP or NLGN2-Fc |
| GO:0097119 postsynaptic density protein 95 clustering | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn2 (BHF-UCL IDA, PMID:21424692): PSD-95 clustering. Reason: Neurexin-2-alpha presented on COS cells induces clustering of glutamatergic (LRRTM2, PSD-95) and GABAergic (NLGN2, gephyrin) postsynaptic components in contacting dendrites, and this activity is lost with the ASD-associated truncation that removes LNS6. NRXN2 acts in trans as the organizing ligand; the clustering itself is executed by the postsynaptic machinery. A gain-of-function coculture readout of the trans-synaptic organizer role; non-core, as for NRXN1. Supporting Evidence: PMID:21424692 Whereas wild-type neurexin2Ξ±-CFP induced robust clustering of glutamatergic components YFP-LRRTM2 and PSD-95, and GABAergic components NLGN2 and gephyrin at dendrite contact sites |
| GO:0098820 trans-synaptic protein complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the neurexin clade node PTN002227321: trans-synaptic protein complex. Reason: Core: NRXN2 forms cleft-spanning complexes with postsynaptic neuroligins, LRRTMs and IgSF21; the IgSF21-neurexin-2-alpha complex is a trans-synaptic adhesion complex at inhibitory synapses. This is the complex through which NRXN2 mediates adhesion and trans-synaptic signalling. Supporting Evidence: PMID:28864826 IgSF21 localizes postsynaptically and recruits axonal neurexin2Ξ± in a trans-interaction manner. PMID:21424692 unlike the high affinity binding of wild-type neurexin2Ξ±-CFP, the delA mutant expressed in COS cells was unable to bind either LRRTM2-AP or NLGN2-Fc PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions |
| GO:0098632 cell-cell adhesion mediator activity | ISS PMID:22262843 High affinity neurexin binding to cell adhesion G-protein-co... | NEW | Summary: Neurexin-2 on one cell binds latrophilin-1, neuroligins or IgSF21 on an apposed cell and holds the two together; NRXN2 is the presynaptic half of these trans-synaptic adhesion bridges. Reason: Same activity and reasoning as the NEW row in the NRXN1 review, here with neurexin-2-specific data. Participation: NRXN2 is itself one half of the adhesive bond - neurexin-2-beta-expressing cells form aggregates with latrophilin-1-expressing cells in an SS4-dependent manner, a neurexin-2-beta Ca2+-site mutant abolishes neuroligin-1-mediated cell adhesion, and postsynaptic IgSF21 recruits axonal neurexin-2-alpha in trans. Comparator check: other synaptic adhesion molecules in the same role (CLSTN1, contactins, CD200) carry this term, and the neurexin trans-synaptic adhesion module uses it for the neurexin hub. The existing cell adhesion molecule binding and neuroligin family protein binding rows describe the partner, not the adhesive activity. Evidence is from rodent neurexin-2 (ISS). Supporting Evidence: PMID:22262843 Strikingly, we found that cells expressing either of these two neurexins formed aggregates with CL1-expressing cells, again dependent on a lack of an insert in SS4 in the case of neurexin-2Ξ² PMID:20064387 was blocked by a single amino-acid substitution in neurexin-2Ξ² that abolishes Ca2+-binding to the neurexin LNS domain, and that also abolishes neuroligin-1 mediated cell adhesion PMID:28864826 IgSF21 localizes postsynaptically and recruits axonal neurexin2Ξ± in a trans-interaction manner. PMID:16242404 neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation |
| GO:0099171 presynaptic modulation of chemical synaptic transmission | ISS PMID:36608123 Neurexin-2: An inhibitory neurexin that restricts excitatory... | NEW | Summary: Loss of neurexin-2 changes presynaptic release properties at excitatory synapses: neuron-specific Nrxn2 deletion increases release probability at hippocampal CA3-CA1 synapses, and Nrxn2-alpha knockout reduces spontaneous excitatory release in neocortex. Reason: NRXN2-specific biology that the existing rows do not capture. NRXN2 acts in the presynaptic membrane to set release properties (participation: the protein itself resides in and organizes the presynaptic release site, as the alpha-neurexin Ca2+ channel-coupling work shows), but for NRXN2 the sign of the effect depends on the circuit - it restrains release probability and synapse number at hippocampal CA3-CA1 synapses yet supports spontaneous release in neocortex. A direction-neutral modulation term fits better than the neurotransmitter secretion row. Comparator check: SynGO annotates mouse Nrxn2 (from this study) and mouse Nrxn3 to GO:0099171, so the term is used for neurexins in their presynaptic role. Evidence is from mouse (ISS). Caveat recorded in the notes: the source paper's 2025 expression of concern was lifted in 2026, but a companion PNAS paper from the same group was retracted, and the paper disputes the Nrxn2 mouse line used by Born et al. Supporting Evidence: PMID:36608123 Unexpectedly, we find that in the hippocampus, the loss of Nrxn2 causes an increase both in the number of excitatory synapses and in the presynaptic release probability, suggesting a function in restricting synapse assembly. PMID:36608123 Parallel measurements of inhibitory postsynaptic currents (IPSCs) did not uncover any change in the synaptic strength or the presynaptic release probability of inhibitory synapses PMID:25745399 Using patch-clamp recordings in Nrxn2Ξ± knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. PMID:12827191 alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery |
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Download this section (compressed HTML)Q: How does NRXN2, which binds the same neuroligins and LRRTMs as NRXN1 and NRXN3, restrict excitatory synapse assembly in hippocampus while supporting release in neocortex? Does the anti-synaptogenic effect depend on a specific ligand, splice isoform, or glial NRXN2 expression?
Q: The hippocampal restriction phenotype comes from one laboratory, whose companion PNAS paper was retracted and which disputes the Nrxn2 line used in an earlier study; has it been independently replicated with separately generated Nrxn2 alleles?
Q: NRXN2 uses GO:0099545 trans-synaptic signaling by trans-synaptic complex, whereas NRXN1 and NRXN3 use its child GO:0099557 on cerebellin-GluD1 evidence. Does NRXN2 also tune postsynaptic receptor responses trans-synaptically, and should the postsynaptic partners (NLGNs, LRRTMs, IGSF21) follow the same split?
Q: Behaviour annotations (vocal learning, vocalization) for NRXN2 derive from language delay in one carrier parent; is there a curation convention for when family phenotypes justify behaviour-process IMP annotations for a synaptic organizer?
Experiment: Cell aggregation and surface-binding assays with human NRXN2-alpha (SS4+ and SS4-), LNS1 interface mutants and LNS6 Ca2+-site mutants against cells expressing human IGSF21, NLGN1 and LRRTM2.
Hypothesis: Human NRXN2-alpha binds human IGSF21 through LNS1 and mediates cell-cell adhesion with IGSF21-, NLGN1- and LRRTM2-expressing cells.
Type: cell aggregation assay
Experiment: Isogenic human iPSC-derived cortical and hippocampal-like neurons with NRXN2 deletion versus NRXN1 deletion; quantify excitatory and inhibitory synapse density, release probability and mEPSC frequency.
Hypothesis: NRXN2 restricts excitatory synapse number in human neurons as it does in mouse hippocampus.
Type: electrophysiology in iPSC-derived neurons
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