{"gene":"NRN1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2023,"finding":"NRN1 (neuritin) provided dendritic spine resilience against amyloid-β (Aβ) and blocked Aβ-induced neuronal hyperexcitability in cultured neurons; exogenous NRN1 altered the neuronal proteome in synapse-related pathways as assessed by TMT-MS.","method":"Microscopy, electrophysiology, and TMT-MS proteomics in cultured neuron cellular model of AD","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cellular experiments with microscopy and physiology, plus proteomics, single lab","pmids":["37024090"],"is_preprint":false},{"year":2021,"finding":"NRN1 suppresses esophageal cancer cell colony formation, proliferation, migration, and invasion, and induces apoptosis and G1/S arrest; NRN1 inhibits PI3K-Akt-mTOR signaling in esophageal cancer cells; NRN1 expression is repressed by promoter methylation.","method":"siRNA knockdown, flow cytometry, colony formation assay, xenograft mouse models, methylation-specific PCR in esophageal cancer cell lines","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple cellular phenotype readouts and in vivo xenograft, single lab","pmids":["33931924"],"is_preprint":false},{"year":2019,"finding":"miR-194 targets NRN1 mRNA, reducing NRN1 protein expression; NRN1 overexpression in Aβ1-42-transduced hippocampal neurons increases p-Akt and Bcl-2, decreases Bax and cleaved Caspase-3, promotes neurite outgrowth and neuronal survival via the PI3K/Akt signaling pathway.","method":"miR-194 mimics transfection, NRN1 overexpression vectors, MTT assay, immunofluorescence, Western blot in Aβ1-42-transduced hippocampal neurons","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple orthogonal readouts (viability, neurite length, protein expression), single lab","pmids":["31010100"],"is_preprint":false},{"year":2020,"finding":"Nrn1 overexpression via AAV2 in retinal ganglion cells following optic nerve crush activates Akt1 and Stat3 signaling pathways and inhibits the mitochondrial apoptotic pathway, reducing RGC apoptosis and promoting axonal regeneration and visual function restoration.","method":"rAAV2-mediated Nrn1 overexpression, intravitreal injection, retinal imaging, histopathology, immunoblot assay in rat optic nerve crush model","journal":"Journal of molecular neuroscience : MN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with defined pathway readouts (Akt1, Stat3, mitochondrial apoptosis markers), single lab","pmids":["32607759"],"is_preprint":false},{"year":2020,"finding":"HIF1α binds functional response elements in the NRN1 promoter and transcriptionally activates NRN1 expression under hypoxia; HIF1α inhibition (siRNA or 2-methoxyestradiol) suppresses NRN1 expression and decreases testicular GCT PDC spheroid growth in vitro and in vivo.","method":"Promoter activity analysis with HIF1α response element identification, siRNA silencing, HIF1α inhibitor treatment, 3D spheroid culture, xenograft models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter assay plus in vitro and in vivo loss-of-function, single lab","pmids":["32544513"],"is_preprint":false},{"year":2021,"finding":"NRN1 promotes clear cell renal cell carcinoma cell viability and upregulates CXCR4 expression; NRN1 silencing by siRNA suppresses xenograft tumor proliferation and represses CXCR4 expression.","method":"Gain- and loss-of-function in RCC patient-derived cell spheroids, siRNA xenograft models, RNA-sequencing dataset correlation","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with in vivo xenograft and defined molecular readout (CXCR4), single lab","pmids":["34804954"],"is_preprint":false},{"year":2024,"finding":"NRN1 directly interacts with the cleaved intracellular domain (NICD) of Notch1 and Notch3, causing potential retention of NICD in the cytoplasm, reducing expression of Notch downstream target Hes1, decreasing JAK/STAT3 sequestration in a Hes1-driven phosphorylation complex, and consequently reducing STAT3 phosphorylation while upregulating oncogenic STAT3 targets (VegfA, Mdr1, cMet) in melanoma cells.","method":"NRN1 overexpression in melanoma cell culture, kinase phosphorylation kit, promoter activity analysis, mRNA and protein analysis, spheroid formation assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction evidence with downstream pathway readouts, multiple molecular methods, single lab","pmids":["38705997"],"is_preprint":false},{"year":2024,"finding":"NEFL regulates NRN1 expression, and this NEFL-NRN1 axis modulates the mitochondrial apoptotic pathway; NEFL overexpression or silencing alters NRN1 levels, mitochondrial membrane potential, ROS accumulation, and apoptosis in diacetylmorphine-treated PC12 cells.","method":"TMT proteomics, lentiviral overexpression/silencing vectors, transmission electron microscopy, mitochondrial membrane potential and ROS assays in PC12 cells","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple orthogonal mechanistic readouts, single lab","pmids":["39557800"],"is_preprint":false},{"year":2025,"finding":"NRN1 reduces tau phosphorylation (p-tau) and neuronal apoptosis in AD cell and mouse models; NRN1 decreases cleaved caspase-3 and elevates Bcl-2/Bax ratio; bioinformatics and PPI analyses implicated PIGU and CASP3 as core regulators of the NRN1-tau phosphorylation axis.","method":"Western blot in AD mouse hippocampus and cell models, bioinformatics/PPI network analysis, GO/KEGG enrichment","journal":"Current Alzheimer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Western blot with limited mechanistic follow-up; PIGU-CASP3 pathway assignment primarily from bioinformatics, single lab","pmids":["40296620"],"is_preprint":false},{"year":2026,"finding":"Western blot analysis reveals that NRN1 protein forms a homodimer, as detected at molecular weights consistent with homodimerization in rodents, humans, and cell models.","method":"Western blot with validated antibody (Abcam ab64186) across multiple species and cell models","journal":"Alzheimer's & dementia : the journal of the Alzheimer's Association","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (Western blot), homodimerization inferred from molecular weight, not confirmed by reconstitution or structural data","pmids":["41645874"],"is_preprint":false}],"current_model":"NRN1 (neuritin-1) is a small extracellular/GPI-anchored neurotrophic protein that promotes neuronal survival, dendritic spine maintenance, axonal/dendritic growth, and synaptic plasticity by activating PI3K/Akt and Stat3 signaling while inhibiting the mitochondrial apoptotic pathway; its transcription is driven by HIF1α binding to promoter response elements; it interacts directly with Notch1/3 intracellular domains to modulate downstream STAT3 target gene expression; NEFL regulates NRN1 levels upstream; and NRN1 reduces tau phosphorylation and counters Aβ-induced synaptic and excitability deficits, collectively positioning it as a synaptic resilience factor in neurodegeneration."},"narrative":{"mechanistic_narrative":"NRN1 (neuritin-1) is a neurotrophic factor that promotes neuronal survival, neurite outgrowth, and synaptic resilience while also acting as a context-dependent modulator of cell proliferation in cancer [PMID:31010100, PMID:32607759]. In neurons, NRN1 engages the PI3K/Akt and Stat3 pathways and suppresses the mitochondrial apoptotic program: overexpression raises p-Akt and Bcl-2 while lowering Bax and cleaved caspase-3, driving neurite outgrowth and survival in Aβ-exposed hippocampal neurons [PMID:31010100], and AAV-delivered Nrn1 activates Akt1/Stat3 and inhibits mitochondrial apoptosis to support retinal ganglion cell axonal regeneration after optic nerve injury [PMID:32607759]. In neurodegenerative contexts NRN1 confers dendritic spine resilience against amyloid-β, blocks Aβ-induced hyperexcitability, and reduces tau phosphorylation alongside apoptosis [PMID:37024090, PMID:40296620]. NRN1 expression is regulated upstream by multiple inputs: HIF1α binds functional response elements in the NRN1 promoter to drive transcription under hypoxia [PMID:32544513], miR-194 targets NRN1 mRNA to lower its protein levels [PMID:31010100], promoter methylation represses it [PMID:33931924], and a NEFL–NRN1 axis tunes NRN1 levels and mitochondrial apoptosis [PMID:39557800]. NRN1 directly binds the cleaved intracellular domain of Notch1 and Notch3, retaining NICD in the cytoplasm, reducing Hes1, and thereby altering STAT3 phosphorylation and downstream oncogenic target expression in melanoma [PMID:38705997]. In cancer the directionality varies: NRN1 suppresses esophageal cancer growth by inhibiting PI3K-Akt-mTOR signaling [PMID:33931924], yet promotes renal cell carcinoma viability via CXCR4 and supports testicular germ-cell and germ-cell-tumor spheroid growth downstream of HIF1α [PMID:32544513, PMID:34804954].","teleology":[{"year":2019,"claim":"Established that NRN1 mediates neuronal survival and neurite outgrowth through a defined PI3K/Akt anti-apoptotic axis and is itself controlled post-transcriptionally by miR-194.","evidence":"miR-194 mimics, NRN1 overexpression, viability/neurite/Western readouts in Aβ1-42-transduced hippocampal neurons","pmids":["31010100"],"confidence":"Medium","gaps":["Does not identify a cell-surface receptor transducing NRN1 signal to Akt","miR-194 regulation shown in one neuronal context only"]},{"year":2020,"claim":"Showed NRN1 drives axonal regeneration and neuronal survival in vivo by co-activating Akt1 and Stat3 and inhibiting mitochondrial apoptosis, extending its survival role beyond culture.","evidence":"rAAV2 Nrn1 overexpression in a rat optic nerve crush model with imaging, histology, immunoblot","pmids":["32607759"],"confidence":"Medium","gaps":["Mechanism linking NRN1 to Akt1/Stat3 activation not resolved","No receptor or direct binding partner identified"]},{"year":2020,"claim":"Defined a transcriptional input to NRN1 by demonstrating HIF1α binds functional promoter response elements to activate NRN1 under hypoxia, coupling NRN1 to a hypoxia-driven proliferative program.","evidence":"Promoter response-element mapping, HIF1α siRNA/inhibitor, 3D spheroid and xenograft assays in testicular germ-cell tumor cells","pmids":["32544513"],"confidence":"Medium","gaps":["Downstream effectors of NRN1 in this proliferative context not mapped","Generality of HIF1α regulation across tissues untested"]},{"year":2021,"claim":"Revealed that NRN1 function is context-dependent in cancer — tumor-suppressive in esophageal cancer via PI3K-Akt-mTOR inhibition, but pro-proliferative in renal cell carcinoma via CXCR4 — and that promoter methylation silences it.","evidence":"siRNA/overexpression, colony formation, flow cytometry, xenografts, methylation-specific PCR in esophageal and RCC models","pmids":["33931924","34804954"],"confidence":"Medium","gaps":["Basis for opposite directionality across tumor types unexplained","Whether CXCR4 is a direct or indirect target unresolved"]},{"year":2023,"claim":"Demonstrated NRN1 acts as a synaptic resilience factor, protecting dendritic spines and blocking Aβ-induced hyperexcitability while remodeling synapse-related proteome pathways.","evidence":"Microscopy, electrophysiology, and TMT-MS proteomics in a cultured-neuron AD model","pmids":["37024090"],"confidence":"Medium","gaps":["Molecular effectors of spine protection not isolated from proteomic changes","No in vivo confirmation in this study"]},{"year":2024,"claim":"Identified a direct molecular partner by showing NRN1 binds Notch1/Notch3 NICD to retain it cytoplasmically, lowering Hes1 and reshaping STAT3 phosphorylation and oncogenic target output.","evidence":"NRN1 overexpression, kinase phosphorylation assays, promoter activity, spheroid assays in melanoma cells","pmids":["38705997"],"confidence":"Medium","gaps":["Direct interaction not confirmed by structural or reciprocal endogenous co-IP","Whether NICD binding operates in neurons not tested"]},{"year":2024,"claim":"Placed NRN1 downstream of NEFL in a regulatory axis controlling the mitochondrial apoptotic pathway, linking cytoskeletal/proteomic signals to NRN1 abundance.","evidence":"TMT proteomics, lentiviral NEFL gain/loss, EM, mitochondrial membrane potential and ROS assays in diacetylmorphine-treated PC12 cells","pmids":["39557800"],"confidence":"Medium","gaps":["Mechanism by which NEFL controls NRN1 levels undefined","Restricted to a single drug-treated cell model"]},{"year":2025,"claim":"Connected NRN1 to tau pathology by showing it reduces tau phosphorylation and neuronal apoptosis, nominating PIGU and CASP3 as candidate axis components.","evidence":"Western blot in AD mouse hippocampus and cell models with bioinformatics/PPI network analysis","pmids":["40296620"],"confidence":"Low","gaps":["PIGU-CASP3 assignment derives primarily from bioinformatics, not direct perturbation","Mechanism of tau dephosphorylation not established"]},{"year":2026,"claim":"Reported that NRN1 protein forms a homodimer, addressing its quaternary state across species.","evidence":"Western blot with a validated antibody across rodent, human, and cell models","pmids":["41645874"],"confidence":"Low","gaps":["Homodimerization inferred from migration weight only, not confirmed by reconstitution or structure","Functional consequence of dimerization untested"]},{"year":null,"claim":"The cell-surface receptor and direct signaling mechanism by which extracellular NRN1 activates PI3K/Akt and Stat3 in neurons remains unidentified.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No NRN1 receptor characterized in the corpus","Reconciliation of tumor-suppressive vs pro-proliferative roles unresolved","Structural basis of NRN1-NICD interaction unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,6]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,7]}],"complexes":[],"partners":["NOTCH1","NOTCH3","NEFL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPD7","full_name":"Neuritin","aliases":[],"length_aa":142,"mass_kda":15.3,"function":"Promotes neurite outgrowth and especially branching of neuritic processes in primary hippocampal and cortical cells","subcellular_location":"Cell membrane; Synapse","url":"https://www.uniprot.org/uniprotkb/Q9NPD7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NRN1","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NRN1","total_profiled":1310},"omim":[{"mim_id":"612582","title":"CHROMOSOME 6pter-p24 DELETION SYNDROME","url":"https://www.omim.org/entry/612582"},{"mim_id":"607409","title":"NEURITIN 1; NRN1","url":"https://www.omim.org/entry/607409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":187.2}],"url":"https://www.proteinatlas.org/search/NRN1"},"hgnc":{"alias_symbol":["NRN"],"prev_symbol":[]},"alphafold":{"accession":"Q9NPD7","domains":[{"cath_id":"-","chopping":"31-115","consensus_level":"high","plddt":82.8138,"start":31,"end":115}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPD7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPD7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPD7-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NRN1","jax_strain_url":"https://www.jax.org/strain/search?query=NRN1"},"sequence":{"accession":"Q9NPD7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPD7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPD7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPD7"}},"corpus_meta":[{"pmid":"37024090","id":"PMC_37024090","title":"Integrated Proteomics to Understand the Role of Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer's Disease.","date":"2023","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/37024090","citation_count":55,"is_preprint":false},{"pmid":"33931924","id":"PMC_33931924","title":"Methylation of NRN1 is a novel synthetic lethal marker of PI3K-Akt-mTOR and ATR inhibitors in esophageal cancer.","date":"2021","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/33931924","citation_count":31,"is_preprint":false},{"pmid":"19569075","id":"PMC_19569075","title":"Impact of Neuritin 1 (NRN1) polymorphisms on fluid intelligence in schizophrenia.","date":"2010","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19569075","citation_count":27,"is_preprint":false},{"pmid":"31176712","id":"PMC_31176712","title":"Association of AEBP1 and NRN1 RNA expression with Alzheimer's disease and neurofibrillary tangle density in middle temporal gyrus.","date":"2019","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/31176712","citation_count":22,"is_preprint":false},{"pmid":"26700405","id":"PMC_26700405","title":"Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning.","date":"2015","source":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/26700405","citation_count":19,"is_preprint":false},{"pmid":"32285140","id":"PMC_32285140","title":"The impact of DNA demethylation on the upregulation of the NRN1 and TNFAIP3 genes associated with advanced gastric cancer.","date":"2020","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/32285140","citation_count":18,"is_preprint":false},{"pmid":"31010100","id":"PMC_31010100","title":"miR-194 Accelerates Apoptosis of Aβ1⁻42-Transduced Hippocampal Neurons by Inhibiting Nrn1 and Decreasing PI3K/Akt Signaling Pathway Activity.","date":"2019","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/31010100","citation_count":15,"is_preprint":false},{"pmid":"32607759","id":"PMC_32607759","title":"Nrn1 Overexpression Attenuates Retinal Ganglion Cell Apoptosis, Promotes Axonal Regeneration, and Improves Visual Function Following Optic Nerve Crush in Rats.","date":"2020","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/32607759","citation_count":14,"is_preprint":false},{"pmid":"36765573","id":"PMC_36765573","title":"A Novel Methylation Marker NRN1 plus TERT and FGFR3 Mutation Using Urine Sediment Enables the Detection of Urothelial Bladder Carcinoma.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36765573","citation_count":11,"is_preprint":false},{"pmid":"28107668","id":"PMC_28107668","title":"Neurotrophins role in depressive symptoms and executive function performance: Association analysis of NRN1 gene and its interaction with BDNF gene in a non-clinical sample.","date":"2016","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/28107668","citation_count":11,"is_preprint":false},{"pmid":"32544513","id":"PMC_32544513","title":"HIF1α inhibitor 2-methoxyestradiol decreases NRN1 expression and represses in vivo and in vitro growth of patient-derived testicular germ cell tumor spheroids.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/32544513","citation_count":8,"is_preprint":false},{"pmid":"38705997","id":"PMC_38705997","title":"NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38705997","citation_count":7,"is_preprint":false},{"pmid":"34530960","id":"PMC_34530960","title":"NRN1 and CAT Gene Polymorphisms, Complex Noise, and Lifestyles interactively Affect the Risk of Noise-induced Hearing Loss.","date":"2021","source":"Biomedical and environmental sciences : BES","url":"https://pubmed.ncbi.nlm.nih.gov/34530960","citation_count":6,"is_preprint":false},{"pmid":"35806464","id":"PMC_35806464","title":"NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35806464","citation_count":4,"is_preprint":false},{"pmid":"38720004","id":"PMC_38720004","title":"NRN1 epistasis with BDNF and CACNA1C: mediation effects on symptom severity through neuroanatomical changes in schizophrenia.","date":"2024","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/38720004","citation_count":3,"is_preprint":false},{"pmid":"34804954","id":"PMC_34804954","title":"Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34804954","citation_count":2,"is_preprint":false},{"pmid":"41645874","id":"PMC_41645874","title":"NRN1 as a therapeutic target for Alzheimer's disease.","date":"2026","source":"Alzheimer's & dementia : the journal of the Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/41645874","citation_count":2,"is_preprint":false},{"pmid":"39557800","id":"PMC_39557800","title":"NEFL Modulates NRN1-Mediated Mitochondrial Pathway to Promote Diacetylmorphine-Induced Neuronal Apoptosis.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39557800","citation_count":1,"is_preprint":false},{"pmid":"39426559","id":"PMC_39426559","title":"NRN1 genetic variability and methylation changes as biomarkers for cognitive remediation therapy response in schizophrenia.","date":"2024","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/39426559","citation_count":1,"is_preprint":false},{"pmid":"40296620","id":"PMC_40296620","title":"NRN1 may Modulate Tau Phosphorylation and Neuronal Apoptosis in AD via the PIGU-CASP3 Axis.","date":"2025","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/40296620","citation_count":0,"is_preprint":false},{"pmid":"36627356","id":"PMC_36627356","title":"NRN-EZ: an application to streamline biophysical modeling of synaptic integration using NEURON.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36627356","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.29.24315982","title":"CLOZAPINE-RELATED BRAIN<i>NRN1</i>EXPRESSION PATTERNS ARE ASSOCIATED WITH METHYLATION AND GENETIC VARIANTS IN SCHIZOPHRENIA","date":"2024-11-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.29.24315982","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.28.651013","title":"SAM-AMP lyases in CRISPR defence and anti-defence","date":"2025-04-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.28.651013","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.10.648218","title":"Inferring non-coding RNA regulatory network from transcriptomic data and curated databases","date":"2025-04-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.10.648218","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.18.623787","title":"<i>In silico</i>  analysis of the evolution of root phenotypes during maize domestication in Neolithic soils of Tehuacán","date":"2024-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.18.623787","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16328,"output_tokens":2524,"usd":0.043422,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9676,"output_tokens":3195,"usd":0.064128,"stage2_stop_reason":"end_turn"},"total_usd":0.10755,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"NRN1 (neuritin) provided dendritic spine resilience against amyloid-β (Aβ) and blocked Aβ-induced neuronal hyperexcitability in cultured neurons; exogenous NRN1 altered the neuronal proteome in synapse-related pathways as assessed by TMT-MS.\",\n      \"method\": \"Microscopy, electrophysiology, and TMT-MS proteomics in cultured neuron cellular model of AD\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cellular experiments with microscopy and physiology, plus proteomics, single lab\",\n      \"pmids\": [\"37024090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NRN1 suppresses esophageal cancer cell colony formation, proliferation, migration, and invasion, and induces apoptosis and G1/S arrest; NRN1 inhibits PI3K-Akt-mTOR signaling in esophageal cancer cells; NRN1 expression is repressed by promoter methylation.\",\n      \"method\": \"siRNA knockdown, flow cytometry, colony formation assay, xenograft mouse models, methylation-specific PCR in esophageal cancer cell lines\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple cellular phenotype readouts and in vivo xenograft, single lab\",\n      \"pmids\": [\"33931924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-194 targets NRN1 mRNA, reducing NRN1 protein expression; NRN1 overexpression in Aβ1-42-transduced hippocampal neurons increases p-Akt and Bcl-2, decreases Bax and cleaved Caspase-3, promotes neurite outgrowth and neuronal survival via the PI3K/Akt signaling pathway.\",\n      \"method\": \"miR-194 mimics transfection, NRN1 overexpression vectors, MTT assay, immunofluorescence, Western blot in Aβ1-42-transduced hippocampal neurons\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple orthogonal readouts (viability, neurite length, protein expression), single lab\",\n      \"pmids\": [\"31010100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nrn1 overexpression via AAV2 in retinal ganglion cells following optic nerve crush activates Akt1 and Stat3 signaling pathways and inhibits the mitochondrial apoptotic pathway, reducing RGC apoptosis and promoting axonal regeneration and visual function restoration.\",\n      \"method\": \"rAAV2-mediated Nrn1 overexpression, intravitreal injection, retinal imaging, histopathology, immunoblot assay in rat optic nerve crush model\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with defined pathway readouts (Akt1, Stat3, mitochondrial apoptosis markers), single lab\",\n      \"pmids\": [\"32607759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HIF1α binds functional response elements in the NRN1 promoter and transcriptionally activates NRN1 expression under hypoxia; HIF1α inhibition (siRNA or 2-methoxyestradiol) suppresses NRN1 expression and decreases testicular GCT PDC spheroid growth in vitro and in vivo.\",\n      \"method\": \"Promoter activity analysis with HIF1α response element identification, siRNA silencing, HIF1α inhibitor treatment, 3D spheroid culture, xenograft models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter assay plus in vitro and in vivo loss-of-function, single lab\",\n      \"pmids\": [\"32544513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NRN1 promotes clear cell renal cell carcinoma cell viability and upregulates CXCR4 expression; NRN1 silencing by siRNA suppresses xenograft tumor proliferation and represses CXCR4 expression.\",\n      \"method\": \"Gain- and loss-of-function in RCC patient-derived cell spheroids, siRNA xenograft models, RNA-sequencing dataset correlation\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with in vivo xenograft and defined molecular readout (CXCR4), single lab\",\n      \"pmids\": [\"34804954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NRN1 directly interacts with the cleaved intracellular domain (NICD) of Notch1 and Notch3, causing potential retention of NICD in the cytoplasm, reducing expression of Notch downstream target Hes1, decreasing JAK/STAT3 sequestration in a Hes1-driven phosphorylation complex, and consequently reducing STAT3 phosphorylation while upregulating oncogenic STAT3 targets (VegfA, Mdr1, cMet) in melanoma cells.\",\n      \"method\": \"NRN1 overexpression in melanoma cell culture, kinase phosphorylation kit, promoter activity analysis, mRNA and protein analysis, spheroid formation assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction evidence with downstream pathway readouts, multiple molecular methods, single lab\",\n      \"pmids\": [\"38705997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NEFL regulates NRN1 expression, and this NEFL-NRN1 axis modulates the mitochondrial apoptotic pathway; NEFL overexpression or silencing alters NRN1 levels, mitochondrial membrane potential, ROS accumulation, and apoptosis in diacetylmorphine-treated PC12 cells.\",\n      \"method\": \"TMT proteomics, lentiviral overexpression/silencing vectors, transmission electron microscopy, mitochondrial membrane potential and ROS assays in PC12 cells\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple orthogonal mechanistic readouts, single lab\",\n      \"pmids\": [\"39557800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NRN1 reduces tau phosphorylation (p-tau) and neuronal apoptosis in AD cell and mouse models; NRN1 decreases cleaved caspase-3 and elevates Bcl-2/Bax ratio; bioinformatics and PPI analyses implicated PIGU and CASP3 as core regulators of the NRN1-tau phosphorylation axis.\",\n      \"method\": \"Western blot in AD mouse hippocampus and cell models, bioinformatics/PPI network analysis, GO/KEGG enrichment\",\n      \"journal\": \"Current Alzheimer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Western blot with limited mechanistic follow-up; PIGU-CASP3 pathway assignment primarily from bioinformatics, single lab\",\n      \"pmids\": [\"40296620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Western blot analysis reveals that NRN1 protein forms a homodimer, as detected at molecular weights consistent with homodimerization in rodents, humans, and cell models.\",\n      \"method\": \"Western blot with validated antibody (Abcam ab64186) across multiple species and cell models\",\n      \"journal\": \"Alzheimer's & dementia : the journal of the Alzheimer's Association\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (Western blot), homodimerization inferred from molecular weight, not confirmed by reconstitution or structural data\",\n      \"pmids\": [\"41645874\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NRN1 (neuritin-1) is a small extracellular/GPI-anchored neurotrophic protein that promotes neuronal survival, dendritic spine maintenance, axonal/dendritic growth, and synaptic plasticity by activating PI3K/Akt and Stat3 signaling while inhibiting the mitochondrial apoptotic pathway; its transcription is driven by HIF1α binding to promoter response elements; it interacts directly with Notch1/3 intracellular domains to modulate downstream STAT3 target gene expression; NEFL regulates NRN1 levels upstream; and NRN1 reduces tau phosphorylation and counters Aβ-induced synaptic and excitability deficits, collectively positioning it as a synaptic resilience factor in neurodegeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NRN1 (neuritin-1) is a neurotrophic factor that promotes neuronal survival, neurite outgrowth, and synaptic resilience while also acting as a context-dependent modulator of cell proliferation in cancer [#2, #3]. In neurons, NRN1 engages the PI3K/Akt and Stat3 pathways and suppresses the mitochondrial apoptotic program: overexpression raises p-Akt and Bcl-2 while lowering Bax and cleaved caspase-3, driving neurite outgrowth and survival in Aβ-exposed hippocampal neurons [#2], and AAV-delivered Nrn1 activates Akt1/Stat3 and inhibits mitochondrial apoptosis to support retinal ganglion cell axonal regeneration after optic nerve injury [#3]. In neurodegenerative contexts NRN1 confers dendritic spine resilience against amyloid-β, blocks Aβ-induced hyperexcitability, and reduces tau phosphorylation alongside apoptosis [#0, #8]. NRN1 expression is regulated upstream by multiple inputs: HIF1α binds functional response elements in the NRN1 promoter to drive transcription under hypoxia [#4], miR-194 targets NRN1 mRNA to lower its protein levels [#2], promoter methylation represses it [#1], and a NEFL–NRN1 axis tunes NRN1 levels and mitochondrial apoptosis [#7]. NRN1 directly binds the cleaved intracellular domain of Notch1 and Notch3, retaining NICD in the cytoplasm, reducing Hes1, and thereby altering STAT3 phosphorylation and downstream oncogenic target expression in melanoma [#6]. In cancer the directionality varies: NRN1 suppresses esophageal cancer growth by inhibiting PI3K-Akt-mTOR signaling [#1], yet promotes renal cell carcinoma viability via CXCR4 and supports testicular germ-cell and germ-cell-tumor spheroid growth downstream of HIF1α [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that NRN1 mediates neuronal survival and neurite outgrowth through a defined PI3K/Akt anti-apoptotic axis and is itself controlled post-transcriptionally by miR-194.\",\n      \"evidence\": \"miR-194 mimics, NRN1 overexpression, viability/neurite/Western readouts in Aβ1-42-transduced hippocampal neurons\",\n      \"pmids\": [\"31010100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify a cell-surface receptor transducing NRN1 signal to Akt\", \"miR-194 regulation shown in one neuronal context only\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed NRN1 drives axonal regeneration and neuronal survival in vivo by co-activating Akt1 and Stat3 and inhibiting mitochondrial apoptosis, extending its survival role beyond culture.\",\n      \"evidence\": \"rAAV2 Nrn1 overexpression in a rat optic nerve crush model with imaging, histology, immunoblot\",\n      \"pmids\": [\"32607759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking NRN1 to Akt1/Stat3 activation not resolved\", \"No receptor or direct binding partner identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a transcriptional input to NRN1 by demonstrating HIF1α binds functional promoter response elements to activate NRN1 under hypoxia, coupling NRN1 to a hypoxia-driven proliferative program.\",\n      \"evidence\": \"Promoter response-element mapping, HIF1α siRNA/inhibitor, 3D spheroid and xenograft assays in testicular germ-cell tumor cells\",\n      \"pmids\": [\"32544513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of NRN1 in this proliferative context not mapped\", \"Generality of HIF1α regulation across tissues untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed that NRN1 function is context-dependent in cancer — tumor-suppressive in esophageal cancer via PI3K-Akt-mTOR inhibition, but pro-proliferative in renal cell carcinoma via CXCR4 — and that promoter methylation silences it.\",\n      \"evidence\": \"siRNA/overexpression, colony formation, flow cytometry, xenografts, methylation-specific PCR in esophageal and RCC models\",\n      \"pmids\": [\"33931924\", \"34804954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for opposite directionality across tumor types unexplained\", \"Whether CXCR4 is a direct or indirect target unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated NRN1 acts as a synaptic resilience factor, protecting dendritic spines and blocking Aβ-induced hyperexcitability while remodeling synapse-related proteome pathways.\",\n      \"evidence\": \"Microscopy, electrophysiology, and TMT-MS proteomics in a cultured-neuron AD model\",\n      \"pmids\": [\"37024090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors of spine protection not isolated from proteomic changes\", \"No in vivo confirmation in this study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a direct molecular partner by showing NRN1 binds Notch1/Notch3 NICD to retain it cytoplasmically, lowering Hes1 and reshaping STAT3 phosphorylation and oncogenic target output.\",\n      \"evidence\": \"NRN1 overexpression, kinase phosphorylation assays, promoter activity, spheroid assays in melanoma cells\",\n      \"pmids\": [\"38705997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction not confirmed by structural or reciprocal endogenous co-IP\", \"Whether NICD binding operates in neurons not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed NRN1 downstream of NEFL in a regulatory axis controlling the mitochondrial apoptotic pathway, linking cytoskeletal/proteomic signals to NRN1 abundance.\",\n      \"evidence\": \"TMT proteomics, lentiviral NEFL gain/loss, EM, mitochondrial membrane potential and ROS assays in diacetylmorphine-treated PC12 cells\",\n      \"pmids\": [\"39557800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NEFL controls NRN1 levels undefined\", \"Restricted to a single drug-treated cell model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected NRN1 to tau pathology by showing it reduces tau phosphorylation and neuronal apoptosis, nominating PIGU and CASP3 as candidate axis components.\",\n      \"evidence\": \"Western blot in AD mouse hippocampus and cell models with bioinformatics/PPI network analysis\",\n      \"pmids\": [\"40296620\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PIGU-CASP3 assignment derives primarily from bioinformatics, not direct perturbation\", \"Mechanism of tau dephosphorylation not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reported that NRN1 protein forms a homodimer, addressing its quaternary state across species.\",\n      \"evidence\": \"Western blot with a validated antibody across rodent, human, and cell models\",\n      \"pmids\": [\"41645874\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Homodimerization inferred from migration weight only, not confirmed by reconstitution or structure\", \"Functional consequence of dimerization untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cell-surface receptor and direct signaling mechanism by which extracellular NRN1 activates PI3K/Akt and Stat3 in neurons remains unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No NRN1 receptor characterized in the corpus\", \"Reconciliation of tumor-suppressive vs pro-proliferative roles unresolved\", \"Structural basis of NRN1-NICD interaction unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NOTCH1\",\n      \"NOTCH3\",\n      \"NEFL\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}