{"gene":"CHODL","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2002,"finding":"CHODL encodes a type I transmembrane protein with a single C-type lectin carbohydrate recognition domain (CRD) in its extracellular portion; it is N-glycosylated (~36 kDa) and shows predominantly perinuclear localization in transiently transfected COS1 cells; no specific interaction with hyaluronan was detected.","method":"Molecular cloning, Northern blot, RT-PCR, immunohistochemistry, Western blot, transient transfection with immunofluorescence","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and biochemical characterization in single study with multiple methods","pmids":["12079284"],"is_preprint":false},{"year":2003,"finding":"Mouse Chodl protein is a type I transmembrane C-type lectin expressed in muscle cells; fluorescent immunostaining on newborn mouse limbs localized Chodl protein to striated muscle cells, and Western blot confirmed expression during both proliferation and differentiation phases of C2C12 myoblasts.","method":"RT-PCR, in situ hybridization, fluorescent immunostaining, Western blot in C2C12 cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization linked to cell type and differentiation stage with multiple orthogonal methods","pmids":["12711387"],"is_preprint":false},{"year":2003,"finding":"An alternatively spliced CHODL isoform lacking the transmembrane domain (CHODLfΔE/CHODLΔe) is expressed exclusively in the T lymphocyte lineage and is regulated during T lymphopoiesis; the transmembrane-containing isoform CHODLf colocalizes with rBet1 to the endoplasmic reticulum–Golgi apparatus.","method":"RT-PCR, double-label immunofluorescence, expression profiling in thymocytes and lymphocytes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct subcellular localization with functional isoform context, single lab","pmids":["12621022"],"is_preprint":false},{"year":2007,"finding":"The soluble CHODL isoform CHODLΔe/CHODLfΔe, which terminates in the ER-retention signal QDEL, localizes to the late endoplasmic reticulum and is differentially expressed in thymocytes versus peripheral lymphocytes, suggesting a role in T cell development.","method":"Immunofluorescence localization, expression analysis in spleen and tonsil lymphocytes, thymocyte/lymphocyte comparison","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method for localization, no functional perturbation","pmids":["17606388"],"is_preprint":false},{"year":2008,"finding":"The cytoplasmic domain of mouse chondrolectin (Chodl) interacts with the β-subunit of Rab geranylgeranyl transferase (Rabggtb), identified by a Sos recruitment system (SRS) yeast screen and confirmed by in vitro transcription/translation and co-immunoprecipitation.","method":"Sos recruitment system (SRS) screen, in vitro transcription/translation, co-immunoprecipitation","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus in vitro binding, single lab","pmids":["18161010"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, knockdown of chodl causes stalling of motor axon growth cones at the horizontal myoseptum (an intermediate target/navigational choice point) and reduced muscle innervation; overexpression rescues this phenotype, demonstrating that correct chodl expression levels are required for growth cone interactions with this intermediate target.","method":"Morpholino knockdown, mRNA overexpression, in vivo motor axon imaging in zebrafish embryos","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function + gain-of-function rescue with defined cellular phenotype, replicated in same study","pmids":["22457492"],"is_preprint":false},{"year":2013,"finding":"Chodl is alternatively spliced in SMA mouse spinal cord before symptom onset; functional studies show Chodl has distinct effects on cell survival and neurite outgrowth in vitro, and increasing chodl expression rescues motor neuron outgrowth defects in Smn-depleted zebrafish.","method":"Exon-level splicing analysis, in vitro cell survival/neurite outgrowth assays, zebrafish Smn knockdown rescue by chodl overexpression","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vitro assay + in vivo rescue), loss-of-function context in SMA model","pmids":["24067532"],"is_preprint":false},{"year":2025,"finding":"CHODL is identified as a candidate substrate for S-palmitoylation at juxtamembrane cysteine residues, predicted by a machine-learning topology model (TopoPalmTree) and experimentally assessed as a Type I transmembrane protein candidate for this lipid modification.","method":"Machine learning prediction (TopoPalmTree) with experimental assessment of S-palmitoylation candidates","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 4/3 — ML prediction with limited experimental validation specific to CHODL","pmids":["39909380"],"is_preprint":false},{"year":2025,"finding":"Chodl is highly enriched in quiescent skeletal muscle satellite cells (SCs) but downregulated in proliferating myoblasts; conditional knockout of Chodl in embryonic myoblasts or adult SCs does not affect muscle development but markedly impairs regeneration. Chodl-deficient SCs show reduced self-renewal, proliferation, and differentiation; a significant fraction of Chodl-null SCs localize outside the basal lamina and undergo precocious activation, implicating CHODL in ECM niche interactions and Notch signaling maintenance.","method":"Single-cell RNA-seq, conditional knockout (Cre-lox), muscle regeneration assays, immunofluorescence for SC localization relative to basal lamina, in silico network perturbation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined cellular and molecular phenotype, multiple readouts; preprint not yet peer-reviewed","pmids":["40964242"],"is_preprint":true},{"year":2024,"finding":"Sst-Chodl neurons (somatostatin and chondrolectin co-expressing GABAergic interneurons) are selectively active during low-arousal states; selective activation of Sst-Chodl cells via long-range axons is sufficient to promote multi-region cortical synchronization and induce sleep, establishing their role as long-range inhibitory neurons coordinating cortical state.","method":"In vivo electrophysiology, optogenetic activation (cell-type selective), chemogenetic manipulation, behavioral sleep assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — optogenetic gain-of-function with defined circuit phenotype; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.06.20.599756"],"is_preprint":true},{"year":2025,"finding":"In a 15q13.3 microdeletion mouse model, the Sst_Chodl subtype (long-range GABAergic projecting neurons) shows the largest gene expression alterations; patch-clamp recordings reveal increased activity specifically in Sst_Chodl neurons at late maturation; chemogenetic inhibition of Sst_Chodl neurons rescues sleep disturbances in microdeletion mice.","method":"Single-nucleus RNA-seq, calcium imaging, patch-clamp electrophysiology, Patch-seq, chemogenetic inhibition (DREADD)","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal electrophysiology methods plus chemogenetic rescue in defined circuit, single study","pmids":["40997796"],"is_preprint":false},{"year":2016,"finding":"CHODL protein expression is restricted to β-cells (not α-cells) in human pancreatic islets, as confirmed by immunoreactivity in sorted cell populations, identifying it as a β-cell signature protein.","method":"ATAC-seq + RNA-seq with protein-level immunoreactivity confirmation in sorted human α- and β-cells","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein-level confirmation in sorted cell populations","pmids":["26977395"],"is_preprint":false}],"current_model":"CHODL encodes a type I transmembrane C-type lectin that functions in motor axon growth cone navigation at intermediate targets, skeletal muscle satellite cell niche localization and regeneration (via ECM and Notch interactions), and as a marker/functional component of long-range GABAergic Sst-Chodl inhibitory neurons that promote cortical synchrony and sleep; its cytoplasmic domain interacts with the β-subunit of Rab geranylgeranyl transferase, and it undergoes alternative splicing to produce soluble isoforms with distinct subcellular localizations and expression patterns in T lymphocytes."},"narrative":{"teleology":[{"year":2002,"claim":"Initial cloning established CHODL as a novel type I transmembrane C-type lectin with a single CRD, N-glycosylation, and perinuclear localization, defining the basic molecular architecture of the protein.","evidence":"Molecular cloning, Northern blot, immunofluorescence, and Western blot in COS1 cells","pmids":["12079284"],"confidence":"Medium","gaps":["No carbohydrate ligand identified","Perinuclear localization may reflect overexpression artifact","Endogenous expression pattern in human tissues not characterized"]},{"year":2003,"claim":"Two studies revealed that Chodl is expressed in muscle cells during both proliferation and differentiation and that alternative splicing produces a soluble isoform (CHODLΔe) selectively expressed in T lymphocytes, establishing tissue-specific isoform regulation.","evidence":"RT-PCR, in situ hybridization, immunostaining on mouse limbs, C2C12 Western blots, and double-label immunofluorescence showing ER-Golgi colocalization of the transmembrane isoform","pmids":["12711387","12621022"],"confidence":"Medium","gaps":["Function of the soluble T-cell isoform unknown","No loss-of-function data in muscle or T cells","Lectin ligand still unidentified"]},{"year":2008,"claim":"Identification of Rab geranylgeranyl transferase β-subunit (Rabggtb) as a cytoplasmic domain interactor suggested a link between CHODL and vesicular trafficking machinery.","evidence":"SRS yeast two-hybrid screen, in vitro transcription/translation binding, and co-immunoprecipitation","pmids":["18161010"],"confidence":"Medium","gaps":["Functional consequence of Chodl–Rabggtb interaction not tested","No in vivo validation","Whether interaction occurs in neurons or muscle not examined"]},{"year":2012,"claim":"Loss-of-function and rescue experiments in zebrafish demonstrated that Chodl is required for motor axon growth cone navigation past an intermediate target, establishing the first in vivo function.","evidence":"Morpholino knockdown and mRNA overexpression rescue with in vivo motor axon imaging in zebrafish embryos","pmids":["22457492"],"confidence":"High","gaps":["Mechanism of growth cone–intermediate target interaction unknown","Mammalian motor axon phenotype not tested","Relevant extracellular ligand not identified"]},{"year":2013,"claim":"Chodl was linked to spinal muscular atrophy pathogenesis: its splicing is altered in SMA mouse spinal cord before symptoms, and Chodl overexpression rescues motor neuron outgrowth in Smn-depleted zebrafish, positioning it as a downstream effector of SMN.","evidence":"Exon-level splicing analysis in SMA mice, neurite outgrowth assays in vitro, and zebrafish Smn knockdown rescue","pmids":["24067532"],"confidence":"High","gaps":["Direct transcriptional or splicing regulation by SMN not demonstrated","Whether Chodl restoration is sufficient to ameliorate SMA disease progression in mammals unknown"]},{"year":2016,"claim":"CHODL protein was found to be restricted to β-cells in human pancreatic islets, expanding its known expression profile beyond muscle and neurons.","evidence":"ATAC-seq, RNA-seq, and immunoreactivity confirmation in sorted human α- and β-cells","pmids":["26977395"],"confidence":"Medium","gaps":["Function in β-cells completely unknown","Whether CHODL contributes to insulin secretion or β-cell identity not tested"]},{"year":2024,"claim":"Optogenetic and chemogenetic manipulation of Sst-Chodl long-range GABAergic interneurons showed they are sufficient to drive multi-region cortical synchronization and sleep, establishing CHODL as a marker of a functionally distinct inhibitory circuit element.","evidence":"In vivo electrophysiology, cell-type-selective optogenetics and chemogenetics, behavioral sleep assays (preprint)","pmids":["bio_10.1101_2024.06.20.599756"],"confidence":"Medium","gaps":["Whether Chodl protein itself contributes to Sst-Chodl neuron function or is merely a marker is unknown","Preprint not yet peer-reviewed","Molecular mechanism of long-range axon targeting not addressed"]},{"year":2025,"claim":"Conditional knockout in satellite cells demonstrated that Chodl maintains quiescent satellite cells within the basal lamina niche and supports Notch signaling; loss impairs muscle regeneration by causing precocious activation and niche displacement.","evidence":"Conditional Cre-lox knockout, muscle regeneration assays, immunofluorescence for SC position relative to basal lamina, single-cell RNA-seq (preprint)","pmids":["40964242"],"confidence":"Medium","gaps":["ECM binding partner mediating niche retention not identified","Preprint not yet peer-reviewed","Whether lectin domain is required for the niche function not tested"]},{"year":2025,"claim":"In a 15q13.3 microdeletion model, Sst_Chodl neurons showed the largest transcriptomic changes and increased electrophysiological activity, and chemogenetic inhibition of these neurons rescued sleep disturbances, causally linking Sst-Chodl neuron hyperactivity to sleep pathology in a neurodevelopmental disorder model.","evidence":"snRNA-seq, patch-clamp, Patch-seq, DREADD chemogenetic inhibition in 15q13.3 microdeletion mice","pmids":["40997796"],"confidence":"Medium","gaps":["Which gene(s) within 15q13.3 drive Sst_Chodl dysregulation not resolved","Whether Chodl protein itself is functionally altered in these neurons unknown"]},{"year":null,"claim":"The extracellular carbohydrate ligand of the CHODL C-type lectin domain, the structural basis for its interactions at intermediate targets and the satellite cell niche, and whether CHODL protein is functionally required (versus serving as a marker) in Sst-Chodl interneurons remain unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No carbohydrate or ECM ligand identified for the CRD","No crystal or cryo-EM structure","Cell-autonomous neuronal function of CHODL protein in Sst-Chodl cells untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[9,10]}],"complexes":[],"partners":["RABGGTB"],"other_free_text":[]},"mechanistic_narrative":"CHODL encodes a type I transmembrane C-type lectin with a single carbohydrate recognition domain that functions in cell–extracellular matrix interactions critical for axon navigation, muscle stem cell niche maintenance, and long-range inhibitory circuit coordination. In zebrafish, Chodl is required for motor axon growth cone navigation past the horizontal myoseptum intermediate target, and its overexpression rescues motor neuron outgrowth defects caused by Smn depletion in a spinal muscular atrophy model [PMID:22457492, PMID:24067532]. Chodl is enriched in quiescent skeletal muscle satellite cells, where conditional knockout impairs regeneration by disrupting satellite cell retention within the basal lamina niche and Notch signaling maintenance [PMID:40964242]. The cytoplasmic domain interacts with the β-subunit of Rab geranylgeranyl transferase, and alternative splicing produces a soluble isoform with an ER-retention signal that is selectively expressed in T lymphocytes [PMID:18161010, PMID:12621022]."},"prefetch_data":{"uniprot":{"accession":"Q9H9P2","full_name":"Chondrolectin","aliases":["Transmembrane protein MT75"],"length_aa":273,"mass_kda":30.4,"function":"May play a role in the development of the nervous system such as in neurite outgrowth and elongation. May be involved in motor axon growth and guidance","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H9P2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHODL","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/CHODL","total_profiled":1310},"omim":[{"mim_id":"607247","title":"CHONDROLECTIN; CHODL","url":"https://www.omim.org/entry/607247"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":13.3},{"tissue":"testis","ntpm":29.0}],"url":"https://www.proteinatlas.org/search/CHODL"},"hgnc":{"alias_symbol":["FLJ12627","PRED12","MT75"],"prev_symbol":["C21orf68"]},"alphafold":{"accession":"Q9H9P2","domains":[{"cath_id":"3.10.100.10","chopping":"41-87_95-106_117-179","consensus_level":"high","plddt":95.2978,"start":41,"end":179}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9P2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9P2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9P2-F1-predicted_aligned_error_v6.png","plddt_mean":75.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHODL","jax_strain_url":"https://www.jax.org/strain/search?query=CHODL"},"sequence":{"accession":"Q9H9P2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H9P2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H9P2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9P2"}},"corpus_meta":[{"pmid":"26977395","id":"PMC_26977395","title":"Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes.","date":"2016","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26977395","citation_count":212,"is_preprint":false},{"pmid":"20437528","id":"PMC_20437528","title":"Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells.","date":"2010","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20437528","citation_count":98,"is_preprint":false},{"pmid":"24067532","id":"PMC_24067532","title":"Chondrolectin affects cell survival and neuronal outgrowth in in vitro and in vivo models of spinal muscular atrophy.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24067532","citation_count":60,"is_preprint":false},{"pmid":"11707072","id":"PMC_11707072","title":"From PREDs and open reading frames to cDNA isolation: revisiting the human 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Research","url":"https://pubmed.ncbi.nlm.nih.gov/22016508","citation_count":22,"is_preprint":false},{"pmid":"22457492","id":"PMC_22457492","title":"Chondrolectin mediates growth cone interactions of motor axons with an intermediate target.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22457492","citation_count":21,"is_preprint":false},{"pmid":"12711387","id":"PMC_12711387","title":"Isolation and characterization of chondrolectin (Chodl), a novel C-type lectin predominantly expressed in muscle cells.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12711387","citation_count":18,"is_preprint":false},{"pmid":"29941967","id":"PMC_29941967","title":"Accumulation of poly(A) RNA in nuclear granules enriched in Sam68 in motor neurons from the SMNΔ7 mouse model of SMA.","date":"2018","source":"Scientific 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/39386678","citation_count":10,"is_preprint":false},{"pmid":"28356950","id":"PMC_28356950","title":"Expression of CHODL in hepatocellular carcinoma affects invasion and migration of liver cancer cells.","date":"2016","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28356950","citation_count":8,"is_preprint":false},{"pmid":"38975339","id":"PMC_38975339","title":"Integrating single-cell and spatial transcriptomic analysis to unveil heterogeneity in high-grade serous ovarian cancer.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38975339","citation_count":8,"is_preprint":false},{"pmid":"18161010","id":"PMC_18161010","title":"The cytoplasmic domain of chondrolectin interacts with the beta-subunit of Rab geranylgeranyl transferase.","date":"2008","source":"Cellular & molecular biology 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sleep","date":"2024-06-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.20.599756","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12966,"output_tokens":2750,"usd":0.040074},"stage2":{"model":"claude-opus-4-6","input_tokens":6132,"output_tokens":2347,"usd":0.134002},"total_usd":0.174076,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"CHODL encodes a type I transmembrane protein with a single C-type lectin carbohydrate recognition domain (CRD) in its extracellular portion; it is N-glycosylated (~36 kDa) and shows predominantly perinuclear localization in transiently transfected COS1 cells; no specific interaction with hyaluronan was detected.\",\n      \"method\": \"Molecular cloning, Northern blot, RT-PCR, immunohistochemistry, Western blot, transient transfection with immunofluorescence\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and biochemical characterization in single study with multiple methods\",\n      \"pmids\": [\"12079284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse Chodl protein is a type I transmembrane C-type lectin expressed in muscle cells; fluorescent immunostaining on newborn mouse limbs localized Chodl protein to striated muscle cells, and Western blot confirmed expression during both proliferation and differentiation phases of C2C12 myoblasts.\",\n      \"method\": \"RT-PCR, in situ hybridization, fluorescent immunostaining, Western blot in C2C12 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization linked to cell type and differentiation stage with multiple orthogonal methods\",\n      \"pmids\": [\"12711387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"An alternatively spliced CHODL isoform lacking the transmembrane domain (CHODLfΔE/CHODLΔe) is expressed exclusively in the T lymphocyte lineage and is regulated during T lymphopoiesis; the transmembrane-containing isoform CHODLf colocalizes with rBet1 to the endoplasmic reticulum–Golgi apparatus.\",\n      \"method\": \"RT-PCR, double-label immunofluorescence, expression profiling in thymocytes and lymphocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization with functional isoform context, single lab\",\n      \"pmids\": [\"12621022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The soluble CHODL isoform CHODLΔe/CHODLfΔe, which terminates in the ER-retention signal QDEL, localizes to the late endoplasmic reticulum and is differentially expressed in thymocytes versus peripheral lymphocytes, suggesting a role in T cell development.\",\n      \"method\": \"Immunofluorescence localization, expression analysis in spleen and tonsil lymphocytes, thymocyte/lymphocyte comparison\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method for localization, no functional perturbation\",\n      \"pmids\": [\"17606388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The cytoplasmic domain of mouse chondrolectin (Chodl) interacts with the β-subunit of Rab geranylgeranyl transferase (Rabggtb), identified by a Sos recruitment system (SRS) yeast screen and confirmed by in vitro transcription/translation and co-immunoprecipitation.\",\n      \"method\": \"Sos recruitment system (SRS) screen, in vitro transcription/translation, co-immunoprecipitation\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus in vitro binding, single lab\",\n      \"pmids\": [\"18161010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, knockdown of chodl causes stalling of motor axon growth cones at the horizontal myoseptum (an intermediate target/navigational choice point) and reduced muscle innervation; overexpression rescues this phenotype, demonstrating that correct chodl expression levels are required for growth cone interactions with this intermediate target.\",\n      \"method\": \"Morpholino knockdown, mRNA overexpression, in vivo motor axon imaging in zebrafish embryos\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function + gain-of-function rescue with defined cellular phenotype, replicated in same study\",\n      \"pmids\": [\"22457492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Chodl is alternatively spliced in SMA mouse spinal cord before symptom onset; functional studies show Chodl has distinct effects on cell survival and neurite outgrowth in vitro, and increasing chodl expression rescues motor neuron outgrowth defects in Smn-depleted zebrafish.\",\n      \"method\": \"Exon-level splicing analysis, in vitro cell survival/neurite outgrowth assays, zebrafish Smn knockdown rescue by chodl overexpression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vitro assay + in vivo rescue), loss-of-function context in SMA model\",\n      \"pmids\": [\"24067532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHODL is identified as a candidate substrate for S-palmitoylation at juxtamembrane cysteine residues, predicted by a machine-learning topology model (TopoPalmTree) and experimentally assessed as a Type I transmembrane protein candidate for this lipid modification.\",\n      \"method\": \"Machine learning prediction (TopoPalmTree) with experimental assessment of S-palmitoylation candidates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4/3 — ML prediction with limited experimental validation specific to CHODL\",\n      \"pmids\": [\"39909380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Chodl is highly enriched in quiescent skeletal muscle satellite cells (SCs) but downregulated in proliferating myoblasts; conditional knockout of Chodl in embryonic myoblasts or adult SCs does not affect muscle development but markedly impairs regeneration. Chodl-deficient SCs show reduced self-renewal, proliferation, and differentiation; a significant fraction of Chodl-null SCs localize outside the basal lamina and undergo precocious activation, implicating CHODL in ECM niche interactions and Notch signaling maintenance.\",\n      \"method\": \"Single-cell RNA-seq, conditional knockout (Cre-lox), muscle regeneration assays, immunofluorescence for SC localization relative to basal lamina, in silico network perturbation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular and molecular phenotype, multiple readouts; preprint not yet peer-reviewed\",\n      \"pmids\": [\"40964242\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sst-Chodl neurons (somatostatin and chondrolectin co-expressing GABAergic interneurons) are selectively active during low-arousal states; selective activation of Sst-Chodl cells via long-range axons is sufficient to promote multi-region cortical synchronization and induce sleep, establishing their role as long-range inhibitory neurons coordinating cortical state.\",\n      \"method\": \"In vivo electrophysiology, optogenetic activation (cell-type selective), chemogenetic manipulation, behavioral sleep assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — optogenetic gain-of-function with defined circuit phenotype; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.06.20.599756\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a 15q13.3 microdeletion mouse model, the Sst_Chodl subtype (long-range GABAergic projecting neurons) shows the largest gene expression alterations; patch-clamp recordings reveal increased activity specifically in Sst_Chodl neurons at late maturation; chemogenetic inhibition of Sst_Chodl neurons rescues sleep disturbances in microdeletion mice.\",\n      \"method\": \"Single-nucleus RNA-seq, calcium imaging, patch-clamp electrophysiology, Patch-seq, chemogenetic inhibition (DREADD)\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal electrophysiology methods plus chemogenetic rescue in defined circuit, single study\",\n      \"pmids\": [\"40997796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHODL protein expression is restricted to β-cells (not α-cells) in human pancreatic islets, as confirmed by immunoreactivity in sorted cell populations, identifying it as a β-cell signature protein.\",\n      \"method\": \"ATAC-seq + RNA-seq with protein-level immunoreactivity confirmation in sorted human α- and β-cells\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein-level confirmation in sorted cell populations\",\n      \"pmids\": [\"26977395\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHODL encodes a type I transmembrane C-type lectin that functions in motor axon growth cone navigation at intermediate targets, skeletal muscle satellite cell niche localization and regeneration (via ECM and Notch interactions), and as a marker/functional component of long-range GABAergic Sst-Chodl inhibitory neurons that promote cortical synchrony and sleep; its cytoplasmic domain interacts with the β-subunit of Rab geranylgeranyl transferase, and it undergoes alternative splicing to produce soluble isoforms with distinct subcellular localizations and expression patterns in T lymphocytes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CHODL encodes a type I transmembrane C-type lectin with a single carbohydrate recognition domain that functions in cell–extracellular matrix interactions critical for axon navigation, muscle stem cell niche maintenance, and long-range inhibitory circuit coordination. In zebrafish, Chodl is required for motor axon growth cone navigation past the horizontal myoseptum intermediate target, and its overexpression rescues motor neuron outgrowth defects caused by Smn depletion in a spinal muscular atrophy model [PMID:22457492, PMID:24067532]. Chodl is enriched in quiescent skeletal muscle satellite cells, where conditional knockout impairs regeneration by disrupting satellite cell retention within the basal lamina niche and Notch signaling maintenance [PMID:40964242]. The cytoplasmic domain interacts with the β-subunit of Rab geranylgeranyl transferase, and alternative splicing produces a soluble isoform with an ER-retention signal that is selectively expressed in T lymphocytes [PMID:18161010, PMID:12621022].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Initial cloning established CHODL as a novel type I transmembrane C-type lectin with a single CRD, N-glycosylation, and perinuclear localization, defining the basic molecular architecture of the protein.\",\n      \"evidence\": \"Molecular cloning, Northern blot, immunofluorescence, and Western blot in COS1 cells\",\n      \"pmids\": [\"12079284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No carbohydrate ligand identified\", \"Perinuclear localization may reflect overexpression artifact\", \"Endogenous expression pattern in human tissues not characterized\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Two studies revealed that Chodl is expressed in muscle cells during both proliferation and differentiation and that alternative splicing produces a soluble isoform (CHODLΔe) selectively expressed in T lymphocytes, establishing tissue-specific isoform regulation.\",\n      \"evidence\": \"RT-PCR, in situ hybridization, immunostaining on mouse limbs, C2C12 Western blots, and double-label immunofluorescence showing ER-Golgi colocalization of the transmembrane isoform\",\n      \"pmids\": [\"12711387\", \"12621022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the soluble T-cell isoform unknown\", \"No loss-of-function data in muscle or T cells\", \"Lectin ligand still unidentified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of Rab geranylgeranyl transferase β-subunit (Rabggtb) as a cytoplasmic domain interactor suggested a link between CHODL and vesicular trafficking machinery.\",\n      \"evidence\": \"SRS yeast two-hybrid screen, in vitro transcription/translation binding, and co-immunoprecipitation\",\n      \"pmids\": [\"18161010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Chodl–Rabggtb interaction not tested\", \"No in vivo validation\", \"Whether interaction occurs in neurons or muscle not examined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Loss-of-function and rescue experiments in zebrafish demonstrated that Chodl is required for motor axon growth cone navigation past an intermediate target, establishing the first in vivo function.\",\n      \"evidence\": \"Morpholino knockdown and mRNA overexpression rescue with in vivo motor axon imaging in zebrafish embryos\",\n      \"pmids\": [\"22457492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of growth cone–intermediate target interaction unknown\", \"Mammalian motor axon phenotype not tested\", \"Relevant extracellular ligand not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Chodl was linked to spinal muscular atrophy pathogenesis: its splicing is altered in SMA mouse spinal cord before symptoms, and Chodl overexpression rescues motor neuron outgrowth in Smn-depleted zebrafish, positioning it as a downstream effector of SMN.\",\n      \"evidence\": \"Exon-level splicing analysis in SMA mice, neurite outgrowth assays in vitro, and zebrafish Smn knockdown rescue\",\n      \"pmids\": [\"24067532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional or splicing regulation by SMN not demonstrated\", \"Whether Chodl restoration is sufficient to ameliorate SMA disease progression in mammals unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CHODL protein was found to be restricted to β-cells in human pancreatic islets, expanding its known expression profile beyond muscle and neurons.\",\n      \"evidence\": \"ATAC-seq, RNA-seq, and immunoreactivity confirmation in sorted human α- and β-cells\",\n      \"pmids\": [\"26977395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function in β-cells completely unknown\", \"Whether CHODL contributes to insulin secretion or β-cell identity not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Optogenetic and chemogenetic manipulation of Sst-Chodl long-range GABAergic interneurons showed they are sufficient to drive multi-region cortical synchronization and sleep, establishing CHODL as a marker of a functionally distinct inhibitory circuit element.\",\n      \"evidence\": \"In vivo electrophysiology, cell-type-selective optogenetics and chemogenetics, behavioral sleep assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.06.20.599756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Chodl protein itself contributes to Sst-Chodl neuron function or is merely a marker is unknown\", \"Preprint not yet peer-reviewed\", \"Molecular mechanism of long-range axon targeting not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conditional knockout in satellite cells demonstrated that Chodl maintains quiescent satellite cells within the basal lamina niche and supports Notch signaling; loss impairs muscle regeneration by causing precocious activation and niche displacement.\",\n      \"evidence\": \"Conditional Cre-lox knockout, muscle regeneration assays, immunofluorescence for SC position relative to basal lamina, single-cell RNA-seq (preprint)\",\n      \"pmids\": [\"40964242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ECM binding partner mediating niche retention not identified\", \"Preprint not yet peer-reviewed\", \"Whether lectin domain is required for the niche function not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In a 15q13.3 microdeletion model, Sst_Chodl neurons showed the largest transcriptomic changes and increased electrophysiological activity, and chemogenetic inhibition of these neurons rescued sleep disturbances, causally linking Sst-Chodl neuron hyperactivity to sleep pathology in a neurodevelopmental disorder model.\",\n      \"evidence\": \"snRNA-seq, patch-clamp, Patch-seq, DREADD chemogenetic inhibition in 15q13.3 microdeletion mice\",\n      \"pmids\": [\"40997796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which gene(s) within 15q13.3 drive Sst_Chodl dysregulation not resolved\", \"Whether Chodl protein itself is functionally altered in these neurons unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The extracellular carbohydrate ligand of the CHODL C-type lectin domain, the structural basis for its interactions at intermediate targets and the satellite cell niche, and whether CHODL protein is functionally required (versus serving as a marker) in Sst-Chodl interneurons remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No carbohydrate or ECM ligand identified for the CRD\", \"No crystal or cryo-EM structure\", \"Cell-autonomous neuronal function of CHODL protein in Sst-Chodl cells untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RABGGTB\"],\n    \"other_free_text\": []\n  }\n}\n```"}