{"gene":"SLITRK5","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2010,"finding":"Loss of Slitrk5 in mice leads to selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology, and alterations in glutamate receptor composition, contributing to deficient corticostriatal neurotransmission; Slitrk5 knockout mice show OCD-like behaviors (excessive self-grooming, increased anxiety) alleviated by fluoxetine, establishing Slitrk5 as an essential molecule at corticostriatal synapses.","method":"Slitrk5 knockout mouse model; behavioral assays; neuroanatomical analysis; electrophysiology; glutamate receptor composition analysis; fluoxetine rescue","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal phenotypic and molecular readouts (behavior, anatomy, receptor composition, pharmacological rescue), replicated across multiple analyses in one rigorous study","pmids":["20418887"],"is_preprint":false},{"year":2015,"finding":"Slitrk5 directly interacts with TrkB receptors and, upon BDNF stimulation, shifts from a transsynaptic interaction with PTPδ to cis-interaction with TrkB; Slitrk5 mediates optimal targeting of TrkB to Rab11-positive recycling endosomes through recruitment of the Rab11 effector protein Rab11-FIP3, and loss of Slitrk5 reduces the rate of ligand-dependent TrkB recycling and alters responsiveness to BDNF.","method":"Co-immunoprecipitation; structured illumination microscopy; TrkB trafficking assays in Slitrk5-deficient neurons; Rab11-FIP3 recruitment assay; BDNF stimulation experiments","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, structured illumination microscopy, functional trafficking assays in KO neurons, multiple orthogonal methods in a single rigorous study","pmids":["26004511"],"is_preprint":false},{"year":2015,"finding":"Under basal conditions, Slitrk5 interacts primarily with the transsynaptic binding partner protein tyrosine phosphatase δ (PTPδ); upon BDNF stimulation this interaction shifts to TrkB, indicating a stimulus-dependent switch in binding partners.","method":"Co-immunoprecipitation under basal vs. BDNF-stimulated conditions","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP under two distinct conditions, part of a multi-method study","pmids":["26004511"],"is_preprint":false},{"year":2017,"finding":"Rare non-synonymous mutations in SLITRK5 identified in OCD subjects impaired synaptogenic activity in vitro, whereas pseudo-matched mutations from controls had no significant effect, demonstrating that specific human SLITRK5 variants functionally disrupt synaptogenesis.","method":"Resequencing of SLITRK5 coding sequence in OCD subjects; in vitro synaptogenesis assays with recombinant mutant SLITRK5 proteins; comparison to 1000 Genomes controls","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional synaptogenesis assay with recombinant proteins, single lab, multiple mutations tested with Fisher's exact comparison to controls","pmids":["28085938"],"is_preprint":false},{"year":2021,"finding":"SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain; SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation, establishing SLITRK5 as a negative regulator of hedgehog signaling in osteoblasts that inhibits downstream hedgehog target gene expression.","method":"Co-immunoprecipitation (extracellular domain binding to hedgehog ligands; intracellular domain interaction with PTCH1); primary cilium localization by immunofluorescence; SMO ciliary enrichment assay; overexpression and loss-of-function in osteoblasts; hedgehog target gene expression assays in vitro and in vivo","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP of two distinct interactions, ciliary localization, gain- and loss-of-function in vitro and in vivo, target gene readouts) in a single rigorous study","pmids":["34326333"],"is_preprint":false},{"year":2022,"finding":"MUC21 overexpression suppresses SLITRK5 expression, leading to activation of the hedgehog pathway and sustained melanoma cell proliferation and invasion; this places SLITRK5 downstream of MUC21 as a negative regulator of hedgehog signaling in melanoma cells.","method":"Overexpression of MUC21 in melanoma cell lines (A375, A875); cell proliferation (CCK-8) and invasion (transwell) assays; measurement of SLITRK5 and hedgehog pathway activity; xenograft model with hedgehog inhibitor cyclopamine","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional cell-based assays and in vivo xenograft with pathway readout, single lab, mechanistic link to SLITRK5 inferred from expression suppression rather than direct molecular interaction","pmids":["35579188"],"is_preprint":false},{"year":2003,"finding":"SLITRK5 (and other SLITRK family members) are integral membrane proteins characterized by two N-terminal leucine-rich repeat (LRR) domains (similar to SLIT) and a C-terminal domain partially similar to TRK neurotrophin receptors; they are expressed predominantly in neural tissue and have neurite-modulating activity in cultured neuronal cells.","method":"cDNA cloning; domain/homology analysis; expression profiling; neurite outgrowth assays in cultured neuronal cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain characterization and neurite outgrowth functional assay across family members, replicated in multiple family members but SLITRK5-specific data not distinguished from family-level findings","pmids":["14557068"],"is_preprint":false},{"year":2022,"finding":"Gintonin treatment ameliorated the reduction in dendritic formation caused by Slitrk5 deficiency in striatal neurons, acting through LPA receptor (LPAR1/3)-mediated Akt/CREB activation, placing Slitrk5 upstream of dendritic development in striatal neurons.","method":"Primary striatal neuron culture from Slitrk5-deficient mice; gintonin treatment; Akt/CREB phosphorylation assays; dendritic morphology analysis; pharmacological inhibition with Ki16425","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function neuronal culture with pharmacological rescue and signaling readouts, single lab, Slitrk5 role inferred from rescue experiment","pmids":["36385759"],"is_preprint":false}],"current_model":"SLITRK5 is a single-pass transmembrane protein with extracellular LRR domains and an intracellular TRK-like domain that functions at corticostriatal synapses by: (1) interacting with PTPδ under basal conditions and shifting to cis-interaction with TrkB upon BDNF stimulation, thereby mediating TrkB recycling to Rab11/Rab11-FIP3-positive endosomes and BDNF-dependent signaling; (2) acting as a negative regulator of hedgehog signaling in osteoblasts by binding hedgehog ligands extracellularly and PTCH1 intracellularly, localizing to the primary cilium, and restricting SMO ciliary enrichment; and (3) being required for normal corticostriatal neurotransmission, glutamate receptor composition, and dendritic development in striatal neurons, with loss-of-function producing OCD-like behaviors in mice."},"narrative":{"mechanistic_narrative":"SLITRK5 is a single-pass transmembrane protein with extracellular leucine-rich repeat (LRR) domains and a C-terminal TRK-like domain that operates as an adhesion and signaling regulator at corticostriatal synapses [PMID:14557068, PMID:20418887]. Loss of Slitrk5 in mice produces deficient corticostriatal neurotransmission, altered striatal anatomy and glutamate receptor composition, and OCD-like behaviors that are alleviated by fluoxetine, establishing it as an essential synaptic molecule [PMID:20418887]; rare human OCD-associated SLITRK5 variants disrupt its synaptogenic activity in vitro [PMID:28085938]. Mechanistically, SLITRK5 engages in a stimulus-dependent switch of binding partners: under basal conditions it binds the transsynaptic phosphatase PTPδ, and upon BDNF stimulation it shifts to a cis-interaction with TrkB, recruiting the Rab11 effector Rab11-FIP3 to target TrkB to Rab11-positive recycling endosomes and thereby tuning BDNF-dependent signaling [PMID:26004511]. Independently of its synaptic role, SLITRK5 acts as a negative regulator of hedgehog signaling: it binds hedgehog ligands through its extracellular domain and PTCH1 through its intracellular domain, localizes to the primary cilium, and restricts SHH-induced SMO ciliary enrichment and downstream target gene expression in osteoblasts [PMID:34326333].","teleology":[{"year":2003,"claim":"Established the basic molecular identity of SLITRK5 as a neural-enriched integral membrane protein combining SLIT-like LRR domains with a TRK-like cytoplasmic region capable of modulating neurite outgrowth, framing it as a candidate synaptic/neuronal adhesion molecule.","evidence":"cDNA cloning, domain/homology analysis, and neurite outgrowth assays in cultured neurons across SLITRK family members","pmids":["14557068"],"confidence":"Medium","gaps":["SLITRK5-specific function not distinguished from family-level findings","No binding partners or signaling mechanism identified","No in vivo role established"]},{"year":2010,"claim":"Defined SLITRK5 as physiologically essential at corticostriatal synapses by showing that its loss disrupts neurotransmission, striatal morphology, and glutamate receptor composition and produces fluoxetine-reversible OCD-like behavior, linking the molecule to a defined circuit and disease phenotype.","evidence":"Slitrk5 knockout mouse with behavioral, neuroanatomical, electrophysiological, and receptor composition analyses plus pharmacological rescue","pmids":["20418887"],"confidence":"High","gaps":["Molecular binding partners mediating synaptic function not yet identified","Direct molecular cause of altered glutamate receptor composition unresolved","Cell-autonomous vs circuit-level contributions not dissected"]},{"year":2015,"claim":"Resolved a molecular mechanism by demonstrating a BDNF-triggered partner switch (PTPδ to TrkB) and a role in TrkB recycling, explaining how SLITRK5 couples transsynaptic adhesion to neurotrophin signaling and endosomal trafficking.","evidence":"Reciprocal co-immunoprecipitation under basal vs BDNF conditions, structured illumination microscopy, and TrkB trafficking/Rab11-FIP3 recruitment assays in Slitrk5-deficient neurons","pmids":["26004511"],"confidence":"High","gaps":["Structural basis of the cis-TrkB versus trans-PTPδ switch unknown","How the partner switch connects to the glutamate receptor and behavioral phenotypes not established","Stoichiometry and dynamics of Rab11-FIP3 recruitment not quantified"]},{"year":2017,"claim":"Connected human genetic variation to mechanism by showing OCD-associated SLITRK5 coding variants impair synaptogenic activity while control variants do not, providing functional support for SLITRK5 as a disease-relevant synaptogenic protein.","evidence":"Resequencing of SLITRK5 in OCD subjects with in vitro synaptogenesis assays using recombinant mutant proteins versus matched controls","pmids":["28085938"],"confidence":"Medium","gaps":["In vitro synaptogenesis defect not validated in vivo","Variant effects on PTPδ/TrkB binding not tested","Causal link between specific variants and human OCD remains correlational"]},{"year":2021,"claim":"Revealed a second, non-neuronal function by showing SLITRK5 binds hedgehog ligands extracellularly and PTCH1 intracellularly, localizes to the primary cilium, and restrains SMO ciliary enrichment, defining it as a ciliary negative regulator of hedgehog signaling in osteoblasts.","evidence":"Co-IP of distinct extracellular and intracellular interactions, ciliary immunofluorescence, SMO enrichment assays, and gain/loss-of-function with target gene readouts in vitro and in vivo","pmids":["34326333"],"confidence":"High","gaps":["Relationship between the synaptic and hedgehog functions unclear","Mechanism by which PTCH1 binding restricts SMO not defined","Whether ciliary localization occurs in neurons not addressed"]},{"year":2022,"claim":"Extended the hedgehog-regulatory role to disease by placing SLITRK5 downstream of MUC21 as a suppressed negative regulator whose loss activates hedgehog signaling and drives melanoma proliferation and invasion.","evidence":"MUC21 overexpression in melanoma cell lines with proliferation/invasion assays, pathway readouts, and cyclopamine-treated xenografts","pmids":["35579188"],"confidence":"Medium","gaps":["Link to SLITRK5 inferred from expression suppression rather than direct interaction","How MUC21 suppresses SLITRK5 expression unknown","Endogenous relevance in primary melanoma not established"]},{"year":2022,"claim":"Placed SLITRK5 upstream of dendritic development by showing that gintonin rescues the dendritic deficit of Slitrk5-deficient striatal neurons via LPAR-mediated Akt/CREB activation, implicating a tractable signaling axis downstream of SLITRK5 loss.","evidence":"Slitrk5-deficient primary striatal neuron cultures with gintonin treatment, Akt/CREB phosphorylation assays, dendritic morphology analysis, and LPAR inhibition","pmids":["36385759"],"confidence":"Medium","gaps":["SLITRK5 role inferred from pharmacological rescue rather than direct mechanism","Whether Akt/CREB signaling is normally controlled by SLITRK5 unresolved","In vivo relevance of the rescue not demonstrated"]},{"year":null,"claim":"How SLITRK5's synaptic adhesion/neurotrophin functions and its ciliary hedgehog-regulatory functions are mechanistically and developmentally integrated within and across cell types remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SLITRK5 in complex with PTPδ, TrkB, or PTCH1","Whether the same protein performs both roles in the same cells is untested","Mechanistic basis linking variant-level synaptogenic defects to circuit and behavioral phenotypes unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1]}],"complexes":[],"partners":["PTPRD","NTRK2","RAB11FIP3","PTCH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94991","full_name":"SLIT and NTRK-like protein 5","aliases":["Leucine-rich repeat-containing protein 11"],"length_aa":958,"mass_kda":107.5,"function":"Suppresses neurite outgrowth","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/O94991/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLITRK5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLITRK5","total_profiled":1310},"omim":[{"mim_id":"609681","title":"SLIT- AND NTRK-LIKE FAMILY, MEMBER 6; SLITRK6","url":"https://www.omim.org/entry/609681"},{"mim_id":"609680","title":"SLIT- AND NTRK-LIKE FAMILY, MEMBER 5; SLITRK5","url":"https://www.omim.org/entry/609680"},{"mim_id":"609678","title":"SLIT- AND NTRK-LIKE FAMILY, MEMBER 1; SLITRK1","url":"https://www.omim.org/entry/609678"},{"mim_id":"164230","title":"OBSESSIVE-COMPULSIVE DISORDER; OCD","url":"https://www.omim.org/entry/164230"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":9.2},{"tissue":"fallopian tube","ntpm":9.6},{"tissue":"salivary gland","ntpm":9.2}],"url":"https://www.proteinatlas.org/search/SLITRK5"},"hgnc":{"alias_symbol":["bA364G4.2","KIAA0918"],"prev_symbol":["LRRC11"]},"alphafold":{"accession":"O94991","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94991","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94991-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94991-F1-predicted_aligned_error_v6.png","plddt_mean":65.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLITRK5","jax_strain_url":"https://www.jax.org/strain/search?query=SLITRK5"},"sequence":{"accession":"O94991","fasta_url":"https://rest.uniprot.org/uniprotkb/O94991.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94991/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94991"}},"corpus_meta":[{"pmid":"20418887","id":"PMC_20418887","title":"Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice.","date":"2010","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20418887","citation_count":272,"is_preprint":false},{"pmid":"10048485","id":"PMC_10048485","title":"Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.","date":"1998","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/10048485","citation_count":190,"is_preprint":false},{"pmid":"14557068","id":"PMC_14557068","title":"Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/14557068","citation_count":119,"is_preprint":false},{"pmid":"26004511","id":"PMC_26004511","title":"Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling.","date":"2015","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/26004511","citation_count":77,"is_preprint":false},{"pmid":"34183866","id":"PMC_34183866","title":"Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants.","date":"2021","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34183866","citation_count":73,"is_preprint":false},{"pmid":"28948967","id":"PMC_28948967","title":"Corticostriatal circuit defects in Hoxb8 mutant mice.","date":"2017","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/28948967","citation_count":69,"is_preprint":false},{"pmid":"24211371","id":"PMC_24211371","title":"Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism.","date":"2013","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/24211371","citation_count":53,"is_preprint":false},{"pmid":"34326333","id":"PMC_34326333","title":"SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34326333","citation_count":31,"is_preprint":false},{"pmid":"35685361","id":"PMC_35685361","title":"Integrative RNA profiling of TBEV-infected neurons and astrocytes reveals potential pathogenic effectors.","date":"2022","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/35685361","citation_count":31,"is_preprint":false},{"pmid":"28085938","id":"PMC_28085938","title":"Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28085938","citation_count":29,"is_preprint":false},{"pmid":"30834271","id":"PMC_30834271","title":"New Gene Markers of Angiogenesis and Blood Vessels Development in Porcine Ovarian Granulosa Cells during Short-Term Primary Culture In Vitro.","date":"2019","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/30834271","citation_count":27,"is_preprint":false},{"pmid":"27671336","id":"PMC_27671336","title":"Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors.","date":"2016","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/27671336","citation_count":21,"is_preprint":false},{"pmid":"26634513","id":"PMC_26634513","title":"Quantitative candidate gene association studies of metabolic traits in Han Chinese type 2 diabetes patients.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26634513","citation_count":21,"is_preprint":false},{"pmid":"22454401","id":"PMC_22454401","title":"Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice.","date":"2012","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22454401","citation_count":19,"is_preprint":false},{"pmid":"24987507","id":"PMC_24987507","title":"Highly Expressed Genes within Hippocampal Sector CA1: Implications for the Physiology of Memory.","date":"2014","source":"Neurology international","url":"https://pubmed.ncbi.nlm.nih.gov/24987507","citation_count":17,"is_preprint":false},{"pmid":"35872846","id":"PMC_35872846","title":"The Role of SliTrk5 in Central Nervous System.","date":"2022","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/35872846","citation_count":14,"is_preprint":false},{"pmid":"30558461","id":"PMC_30558461","title":"Precision medicine validation: identifying the MYBPC3 A31P variant with whole-genome sequencing in two Maine Coon cats with hypertrophic cardiomyopathy.","date":"2018","source":"Journal of feline medicine and surgery","url":"https://pubmed.ncbi.nlm.nih.gov/30558461","citation_count":8,"is_preprint":false},{"pmid":"31217515","id":"PMC_31217515","title":"Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31217515","citation_count":8,"is_preprint":false},{"pmid":"25426764","id":"PMC_25426764","title":"Association study of the SLITRK5 gene and Tourette syndrome.","date":"2015","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25426764","citation_count":7,"is_preprint":false},{"pmid":"36811190","id":"PMC_36811190","title":"Upregulation of SLITRK5 in patients with epilepsy and in a rat model.","date":"2023","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36811190","citation_count":7,"is_preprint":false},{"pmid":"38369117","id":"PMC_38369117","title":"Archetypal clustering reveals physiological mechanisms linking milk yield and fertility in dairy cattle.","date":"2024","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/38369117","citation_count":7,"is_preprint":false},{"pmid":"35579188","id":"PMC_35579188","title":"MUC21 controls melanoma progression via regulating SLITRK5 and hedgehog signaling pathway.","date":"2022","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/35579188","citation_count":6,"is_preprint":false},{"pmid":"36385759","id":"PMC_36385759","title":"Gintonin stimulates dendritic growth in striatal neurons by activating Akt and CREB.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36385759","citation_count":4,"is_preprint":false},{"pmid":"36102151","id":"PMC_36102151","title":"Identification of 4 New Loci Associated With Primary Hyperparathyroidism (PHPT) and a Polygenic Risk Score for PHPT.","date":"2022","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36102151","citation_count":4,"is_preprint":false},{"pmid":"35089926","id":"PMC_35089926","title":"The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/35089926","citation_count":4,"is_preprint":false},{"pmid":"30156382","id":"PMC_30156382","title":"Born This Way: Using Intrinsic Disorder to Map the Connections between SLITRKs, TSHR, and Male Sexual Orientation.","date":"2018","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/30156382","citation_count":3,"is_preprint":false},{"pmid":"40033250","id":"PMC_40033250","title":"Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses.","date":"2025","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40033250","citation_count":2,"is_preprint":false},{"pmid":"40054571","id":"PMC_40054571","title":"Pharmacogenetics of obsessive-compulsive disorder: Investigations of intragenic and regulatory region genetic variations.","date":"2025","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/40054571","citation_count":1,"is_preprint":false},{"pmid":"39792217","id":"PMC_39792217","title":"Oligogenic risk score for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders.","date":"2025","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39792217","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.23.25328231","title":"Neonatal methylation-based predictors of childhood cognition","date":"2025-05-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.23.25328231","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17487,"output_tokens":2336,"usd":0.04375,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9431,"output_tokens":3248,"usd":0.064177,"stage2_stop_reason":"end_turn"},"total_usd":0.107927,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of Slitrk5 in mice leads to selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology, and alterations in glutamate receptor composition, contributing to deficient corticostriatal neurotransmission; Slitrk5 knockout mice show OCD-like behaviors (excessive self-grooming, increased anxiety) alleviated by fluoxetine, establishing Slitrk5 as an essential molecule at corticostriatal synapses.\",\n      \"method\": \"Slitrk5 knockout mouse model; behavioral assays; neuroanatomical analysis; electrophysiology; glutamate receptor composition analysis; fluoxetine rescue\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal phenotypic and molecular readouts (behavior, anatomy, receptor composition, pharmacological rescue), replicated across multiple analyses in one rigorous study\",\n      \"pmids\": [\"20418887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Slitrk5 directly interacts with TrkB receptors and, upon BDNF stimulation, shifts from a transsynaptic interaction with PTPδ to cis-interaction with TrkB; Slitrk5 mediates optimal targeting of TrkB to Rab11-positive recycling endosomes through recruitment of the Rab11 effector protein Rab11-FIP3, and loss of Slitrk5 reduces the rate of ligand-dependent TrkB recycling and alters responsiveness to BDNF.\",\n      \"method\": \"Co-immunoprecipitation; structured illumination microscopy; TrkB trafficking assays in Slitrk5-deficient neurons; Rab11-FIP3 recruitment assay; BDNF stimulation experiments\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, structured illumination microscopy, functional trafficking assays in KO neurons, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"26004511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Under basal conditions, Slitrk5 interacts primarily with the transsynaptic binding partner protein tyrosine phosphatase δ (PTPδ); upon BDNF stimulation this interaction shifts to TrkB, indicating a stimulus-dependent switch in binding partners.\",\n      \"method\": \"Co-immunoprecipitation under basal vs. BDNF-stimulated conditions\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP under two distinct conditions, part of a multi-method study\",\n      \"pmids\": [\"26004511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rare non-synonymous mutations in SLITRK5 identified in OCD subjects impaired synaptogenic activity in vitro, whereas pseudo-matched mutations from controls had no significant effect, demonstrating that specific human SLITRK5 variants functionally disrupt synaptogenesis.\",\n      \"method\": \"Resequencing of SLITRK5 coding sequence in OCD subjects; in vitro synaptogenesis assays with recombinant mutant SLITRK5 proteins; comparison to 1000 Genomes controls\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional synaptogenesis assay with recombinant proteins, single lab, multiple mutations tested with Fisher's exact comparison to controls\",\n      \"pmids\": [\"28085938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain; SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation, establishing SLITRK5 as a negative regulator of hedgehog signaling in osteoblasts that inhibits downstream hedgehog target gene expression.\",\n      \"method\": \"Co-immunoprecipitation (extracellular domain binding to hedgehog ligands; intracellular domain interaction with PTCH1); primary cilium localization by immunofluorescence; SMO ciliary enrichment assay; overexpression and loss-of-function in osteoblasts; hedgehog target gene expression assays in vitro and in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP of two distinct interactions, ciliary localization, gain- and loss-of-function in vitro and in vivo, target gene readouts) in a single rigorous study\",\n      \"pmids\": [\"34326333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MUC21 overexpression suppresses SLITRK5 expression, leading to activation of the hedgehog pathway and sustained melanoma cell proliferation and invasion; this places SLITRK5 downstream of MUC21 as a negative regulator of hedgehog signaling in melanoma cells.\",\n      \"method\": \"Overexpression of MUC21 in melanoma cell lines (A375, A875); cell proliferation (CCK-8) and invasion (transwell) assays; measurement of SLITRK5 and hedgehog pathway activity; xenograft model with hedgehog inhibitor cyclopamine\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional cell-based assays and in vivo xenograft with pathway readout, single lab, mechanistic link to SLITRK5 inferred from expression suppression rather than direct molecular interaction\",\n      \"pmids\": [\"35579188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SLITRK5 (and other SLITRK family members) are integral membrane proteins characterized by two N-terminal leucine-rich repeat (LRR) domains (similar to SLIT) and a C-terminal domain partially similar to TRK neurotrophin receptors; they are expressed predominantly in neural tissue and have neurite-modulating activity in cultured neuronal cells.\",\n      \"method\": \"cDNA cloning; domain/homology analysis; expression profiling; neurite outgrowth assays in cultured neuronal cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain characterization and neurite outgrowth functional assay across family members, replicated in multiple family members but SLITRK5-specific data not distinguished from family-level findings\",\n      \"pmids\": [\"14557068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Gintonin treatment ameliorated the reduction in dendritic formation caused by Slitrk5 deficiency in striatal neurons, acting through LPA receptor (LPAR1/3)-mediated Akt/CREB activation, placing Slitrk5 upstream of dendritic development in striatal neurons.\",\n      \"method\": \"Primary striatal neuron culture from Slitrk5-deficient mice; gintonin treatment; Akt/CREB phosphorylation assays; dendritic morphology analysis; pharmacological inhibition with Ki16425\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function neuronal culture with pharmacological rescue and signaling readouts, single lab, Slitrk5 role inferred from rescue experiment\",\n      \"pmids\": [\"36385759\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLITRK5 is a single-pass transmembrane protein with extracellular LRR domains and an intracellular TRK-like domain that functions at corticostriatal synapses by: (1) interacting with PTPδ under basal conditions and shifting to cis-interaction with TrkB upon BDNF stimulation, thereby mediating TrkB recycling to Rab11/Rab11-FIP3-positive endosomes and BDNF-dependent signaling; (2) acting as a negative regulator of hedgehog signaling in osteoblasts by binding hedgehog ligands extracellularly and PTCH1 intracellularly, localizing to the primary cilium, and restricting SMO ciliary enrichment; and (3) being required for normal corticostriatal neurotransmission, glutamate receptor composition, and dendritic development in striatal neurons, with loss-of-function producing OCD-like behaviors in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLITRK5 is a single-pass transmembrane protein with extracellular leucine-rich repeat (LRR) domains and a C-terminal TRK-like domain that operates as an adhesion and signaling regulator at corticostriatal synapses [#6, #0]. Loss of Slitrk5 in mice produces deficient corticostriatal neurotransmission, altered striatal anatomy and glutamate receptor composition, and OCD-like behaviors that are alleviated by fluoxetine, establishing it as an essential synaptic molecule [#0]; rare human OCD-associated SLITRK5 variants disrupt its synaptogenic activity in vitro [#3]. Mechanistically, SLITRK5 engages in a stimulus-dependent switch of binding partners: under basal conditions it binds the transsynaptic phosphatase PTPδ, and upon BDNF stimulation it shifts to a cis-interaction with TrkB, recruiting the Rab11 effector Rab11-FIP3 to target TrkB to Rab11-positive recycling endosomes and thereby tuning BDNF-dependent signaling [#1, #2]. Independently of its synaptic role, SLITRK5 acts as a negative regulator of hedgehog signaling: it binds hedgehog ligands through its extracellular domain and PTCH1 through its intracellular domain, localizes to the primary cilium, and restricts SHH-induced SMO ciliary enrichment and downstream target gene expression in osteoblasts [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the basic molecular identity of SLITRK5 as a neural-enriched integral membrane protein combining SLIT-like LRR domains with a TRK-like cytoplasmic region capable of modulating neurite outgrowth, framing it as a candidate synaptic/neuronal adhesion molecule.\",\n      \"evidence\": \"cDNA cloning, domain/homology analysis, and neurite outgrowth assays in cultured neurons across SLITRK family members\",\n      \"pmids\": [\"14557068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SLITRK5-specific function not distinguished from family-level findings\", \"No binding partners or signaling mechanism identified\", \"No in vivo role established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined SLITRK5 as physiologically essential at corticostriatal synapses by showing that its loss disrupts neurotransmission, striatal morphology, and glutamate receptor composition and produces fluoxetine-reversible OCD-like behavior, linking the molecule to a defined circuit and disease phenotype.\",\n      \"evidence\": \"Slitrk5 knockout mouse with behavioral, neuroanatomical, electrophysiological, and receptor composition analyses plus pharmacological rescue\",\n      \"pmids\": [\"20418887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular binding partners mediating synaptic function not yet identified\", \"Direct molecular cause of altered glutamate receptor composition unresolved\", \"Cell-autonomous vs circuit-level contributions not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved a molecular mechanism by demonstrating a BDNF-triggered partner switch (PTPδ to TrkB) and a role in TrkB recycling, explaining how SLITRK5 couples transsynaptic adhesion to neurotrophin signaling and endosomal trafficking.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation under basal vs BDNF conditions, structured illumination microscopy, and TrkB trafficking/Rab11-FIP3 recruitment assays in Slitrk5-deficient neurons\",\n      \"pmids\": [\"26004511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the cis-TrkB versus trans-PTPδ switch unknown\", \"How the partner switch connects to the glutamate receptor and behavioral phenotypes not established\", \"Stoichiometry and dynamics of Rab11-FIP3 recruitment not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected human genetic variation to mechanism by showing OCD-associated SLITRK5 coding variants impair synaptogenic activity while control variants do not, providing functional support for SLITRK5 as a disease-relevant synaptogenic protein.\",\n      \"evidence\": \"Resequencing of SLITRK5 in OCD subjects with in vitro synaptogenesis assays using recombinant mutant proteins versus matched controls\",\n      \"pmids\": [\"28085938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro synaptogenesis defect not validated in vivo\", \"Variant effects on PTPδ/TrkB binding not tested\", \"Causal link between specific variants and human OCD remains correlational\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a second, non-neuronal function by showing SLITRK5 binds hedgehog ligands extracellularly and PTCH1 intracellularly, localizes to the primary cilium, and restrains SMO ciliary enrichment, defining it as a ciliary negative regulator of hedgehog signaling in osteoblasts.\",\n      \"evidence\": \"Co-IP of distinct extracellular and intracellular interactions, ciliary immunofluorescence, SMO enrichment assays, and gain/loss-of-function with target gene readouts in vitro and in vivo\",\n      \"pmids\": [\"34326333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between the synaptic and hedgehog functions unclear\", \"Mechanism by which PTCH1 binding restricts SMO not defined\", \"Whether ciliary localization occurs in neurons not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the hedgehog-regulatory role to disease by placing SLITRK5 downstream of MUC21 as a suppressed negative regulator whose loss activates hedgehog signaling and drives melanoma proliferation and invasion.\",\n      \"evidence\": \"MUC21 overexpression in melanoma cell lines with proliferation/invasion assays, pathway readouts, and cyclopamine-treated xenografts\",\n      \"pmids\": [\"35579188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link to SLITRK5 inferred from expression suppression rather than direct interaction\", \"How MUC21 suppresses SLITRK5 expression unknown\", \"Endogenous relevance in primary melanoma not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SLITRK5 upstream of dendritic development by showing that gintonin rescues the dendritic deficit of Slitrk5-deficient striatal neurons via LPAR-mediated Akt/CREB activation, implicating a tractable signaling axis downstream of SLITRK5 loss.\",\n      \"evidence\": \"Slitrk5-deficient primary striatal neuron cultures with gintonin treatment, Akt/CREB phosphorylation assays, dendritic morphology analysis, and LPAR inhibition\",\n      \"pmids\": [\"36385759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SLITRK5 role inferred from pharmacological rescue rather than direct mechanism\", \"Whether Akt/CREB signaling is normally controlled by SLITRK5 unresolved\", \"In vivo relevance of the rescue not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLITRK5's synaptic adhesion/neurotrophin functions and its ciliary hedgehog-regulatory functions are mechanistically and developmentally integrated within and across cell types remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SLITRK5 in complex with PTPδ, TrkB, or PTCH1\", \"Whether the same protein performs both roles in the same cells is untested\", \"Mechanistic basis linking variant-level synaptogenic defects to circuit and behavioral phenotypes unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PTPRD\", \"NTRK2\", \"RAB11FIP3\", \"PTCH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}