{"gene":"DISP1","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2004,"finding":"Disp1 function is required specifically within Shh-producing cells (not receiving cells) for paracrine signaling of cholesterol-modified Hedgehog ligands; non-cholesterol-modified N-Shh rescues early embryonic lethality of Disp1-null mutants, demonstrating Disp1 is exclusively required for secretion of the cholesterol-modified form of Shh.","method":"Conditional knockout using ShhCre knock-in allele, Disp1 conditional allele, and N-Shh rescue allele in mouse","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 — genetic epistasis with cell-type-specific conditional KO plus ligand-form rescue, replicated across multiple developmental contexts","pmids":["15576405"],"is_preprint":false},{"year":2004,"finding":"Disp1 genetically interacts with Patched1 (Ptch1), Shh, and Ihh in a dose-dependent manner: reducing Ptch1 dosage restores ventral neural tube cell identities in Disp1 hypomorphic mutants, and reducing Hh ligand levels worsens Disp1 hypomorphic phenotypes, placing Disp1 upstream of Ptch1 and downstream of Hh ligand production in the signaling pathway.","method":"Genetic epistasis using hypomorphic Disp1 allele combined with null alleles of Ptch1, Shh, and Ihh in mouse; neural tube patterning analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis with multiple allelic combinations and defined cellular phenotype readout","pmids":["15269168"],"is_preprint":false},{"year":2004,"finding":"In vitro studies on Disp1-null mutant fibroblasts indicate that Disp1 is not essential for membrane targeting or release of lipid-modified Shh ligand, suggesting Disp1's in vivo role in paracrine signaling involves a more complex mechanism than simple secretion.","method":"In vitro assay on Disp1-null mutant fibroblasts","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — direct cell-based functional assay, single study","pmids":["15269168"],"is_preprint":false},{"year":2010,"finding":"Disp1 plays a dual role in Shh signaling: (1) promoting secretion of Shh from source cells, and (2) facilitating transport of Shh through intervening tissue to enable long-range signaling. RNAi or dominant-negative Disp1 causes accumulation of Shh in source cells; Disp1-null neuralized embryoid bodies show reduced range of contact-dependent Shh response in co-culture.","method":"RNAi knockdown, dominant-negative constructs, co-culture of Shh-expressing cells with Disp1-null neuralized embryoid bodies derived from ES cells","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (RNAi, dominant-negative, co-culture functional assay) in a single study demonstrating dual secretion and transport roles","pmids":["20023168"],"is_preprint":false},{"year":2008,"finding":"Disp1 is required for the full range of Ihh distribution within the chondrocyte target field in developing long bones; in the absence of functional Disp1, Ihh movement and signaling range is more restricted, shortening the PTHrP-Ihh feedback loop and resulting in shorter bones, demonstrating that Disp1 controls the spatial range of cholesterol-modified Ihh paracrine signaling.","method":"Conditional rescue of Disp1(C829F) lethality with N-Shh; direct Ihh trafficking analysis in target field; skeletal phenotype characterization in mouse","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — direct ligand trafficking analysis with functional consequence (PTHrP-Ihh loop, bone length) in clean genetic background","pmids":["18395198"],"is_preprint":false},{"year":2009,"finding":"Zebrafish disp1 (chameleon/con) is required in cranial neural crest cells for post-migratory patterning and chondrogenic differentiation; loss of disp1 causes failure to maintain sox9a and dlx2a expression in posterior pharyngeal arch neural crest condensations, leading to fibrous connective tissue differentiation instead of chondrogenesis.","method":"Genetic loss-of-function analysis of zebrafish con/disp1 mutants; cyclopamine treatment at defined developmental stages; in situ hybridization for sox9a, dlx2a, bapx1, gdf5","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function with defined downstream transcription factor readouts, single lab","pmids":["19948063"],"is_preprint":false}],"current_model":"DISP1 encodes a 12-transmembrane domain protein that acts within Hedgehog ligand-producing cells to promote the secretion and long-range paracrine transport of cholesterol-modified Hedgehog proteins (Shh and Ihh), functioning upstream of Patched1 and downstream of Hh lipid modification, with its activity specifically required for the cholesterol-modified form of Hh ligands and dispensable when non-lipidated Shh is provided."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that DISP1 acts specifically in Hh-producing cells and is dispensable when Hh lacks its cholesterol modification resolved the question of where and why DISP1 is needed in the pathway.","evidence":"Conditional knockout with ShhCre and rescue with non-cholesterol-modified N-Shh in mouse embryos","pmids":["15576405"],"confidence":"High","gaps":["Biochemical mechanism by which DISP1 recognizes or handles the cholesterol moiety is unknown","Whether DISP1 acts on Hh ligands beyond Shh was not tested in this study"]},{"year":2004,"claim":"Genetic epistasis placed DISP1 upstream of Patched1 and downstream of Hh ligand production, defining its position in the signaling cascade, while in vitro assays indicated its role is more complex than simple membrane release.","evidence":"Combinatorial allelic dosage of Disp1 hypomorph with Ptch1, Shh, and Ihh nulls in mouse; Disp1-null fibroblast secretion assays","pmids":["15269168"],"confidence":"High","gaps":["In vitro fibroblast results could not recapitulate the in vivo paracrine requirement, leaving the exact molecular step unclear","Whether DISP1 physically interacts with Ptch1 or Hh ligands was not addressed"]},{"year":2008,"claim":"Demonstrating restricted Ihh distribution in Disp1-mutant long bones extended DISP1's role to a second Hh ligand and showed it controls the spatial range of paracrine signaling, not merely ligand release.","evidence":"Ihh trafficking analysis and skeletal phenotyping in Disp1(C829F) mutant mice rescued with N-Shh","pmids":["18395198"],"confidence":"High","gaps":["Whether DISP1 acts cell-autonomously in receiving tissue to relay Ihh or solely in Ihh-producing chondrocytes was not resolved","Molecular carriers or co-factors that collaborate with DISP1 for Ihh transport are unidentified"]},{"year":2010,"claim":"Multiple orthogonal approaches established that DISP1 has a dual function—promoting Shh secretion from source cells and facilitating its transport through intervening tissue—resolving whether DISP1's role is limited to release alone.","evidence":"RNAi, dominant-negative DISP1, and co-culture of Shh-expressing cells with Disp1-null neuralized embryoid bodies","pmids":["20023168"],"confidence":"High","gaps":["The biophysical mechanism of DISP1-mediated transport through tissue (e.g., lipoprotein particle loading, direct handoff) is unknown","Structural basis for DISP1 transmembrane domain function has not been determined"]},{"year":null,"claim":"The biochemical mechanism by which DISP1 extracts cholesterol-modified Hh from the membrane and promotes its long-range transport, including direct binding partners and structural basis, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct DISP1–Hh biochemical interaction has been reconstituted in vitro","No high-resolution structure of DISP1 is reported in the timeline","Identity of extracellular carriers or co-factors that collaborate with DISP1 for Hh transport is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["SHH","IHH","PTCH1"],"other_free_text":[]},"mechanistic_narrative":"DISP1 is a 12-transmembrane domain protein that functions within Hedgehog (Hh) ligand-producing cells to promote the secretion and long-range paracrine transport of cholesterol-modified Hedgehog proteins, including Shh and Ihh. Genetic epistasis places DISP1 downstream of Hh ligand production and upstream of the receptor Patched1, and its activity is specifically required for the cholesterol-modified form of Hh—non-cholesterol-modified Shh rescues Disp1-null lethality [PMID:15576405, PMID:15269168]. DISP1 fulfills a dual role: promoting release of Shh from source cells and facilitating its transport through intervening tissue to establish the full signaling range, as demonstrated by Shh accumulation in source cells upon DISP1 loss and restricted Ihh distribution in developing long bones [PMID:20023168, PMID:18395198]."},"prefetch_data":{"uniprot":{"accession":"Q96F81","full_name":"Protein dispatched homolog 1","aliases":[],"length_aa":1524,"mass_kda":170.9,"function":"Functions in hedgehog (Hh) signaling. Regulates the release and extracellular accumulation of cholesterol-modified hedgehog proteins and is hence required for effective production of the Hh signal (By similarity). Synergizes with SCUBE2 to cause an increase in SHH secretion (PubMed:22902404)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q96F81/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DISP1","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/DISP1","total_profiled":1310},"omim":[{"mim_id":"621143","title":"HOLOPROSENCEPHALY 10; HPE10","url":"https://www.omim.org/entry/621143"},{"mim_id":"612530","title":"CHROMOSOME 1q41-q42 DELETION SYNDROME","url":"https://www.omim.org/entry/612530"},{"mim_id":"611251","title":"DISPATCHED RND TRANSPORTER FAMILY, MEMBER 3; DISP3","url":"https://www.omim.org/entry/611251"},{"mim_id":"609637","title":"HOLOPROSENCEPHALY 5; HPE5","url":"https://www.omim.org/entry/609637"},{"mim_id":"607502","title":"DISPATCHED RND TRANSPORTER FAMILY, MEMBER 1; DISP1","url":"https://www.omim.org/entry/607502"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DISP1"},"hgnc":{"alias_symbol":["DISPA","MGC13130","DKFZP434I0428","MGC16796"],"prev_symbol":[]},"alphafold":{"accession":"Q96F81","domains":[{"cath_id":"-","chopping":"230-263_771-971","consensus_level":"medium","plddt":83.3454,"start":230,"end":971},{"cath_id":"-","chopping":"301-490","consensus_level":"high","plddt":84.2115,"start":301,"end":490}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96F81","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96F81-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96F81-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DISP1","jax_strain_url":"https://www.jax.org/strain/search?query=DISP1"},"sequence":{"accession":"Q96F81","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96F81.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96F81/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96F81"}},"corpus_meta":[{"pmid":"15576405","id":"PMC_15576405","title":"Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand.","date":"2004","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15576405","citation_count":77,"is_preprint":false},{"pmid":"19184110","id":"PMC_19184110","title":"Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humans.","date":"2009","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19184110","citation_count":56,"is_preprint":false},{"pmid":"19948063","id":"PMC_19948063","title":"Zebrafish con/disp1 reveals multiple spatiotemporal requirements for Hedgehog-signaling in craniofacial development.","date":"2009","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19948063","citation_count":53,"is_preprint":false},{"pmid":"20023168","id":"PMC_20023168","title":"Evidence for a role of vertebrate Disp1 in long-range Shh signaling.","date":"2010","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20023168","citation_count":51,"is_preprint":false},{"pmid":"20799323","id":"PMC_20799323","title":"Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH.","date":"2010","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/20799323","citation_count":44,"is_preprint":false},{"pmid":"15269168","id":"PMC_15269168","title":"Dose dependency of Disp1 and genetic interaction between Disp1 and other hedgehog signaling components in the mouse.","date":"2004","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15269168","citation_count":25,"is_preprint":false},{"pmid":"36527718","id":"PMC_36527718","title":"Label-Free Quantification from Direct Infusion Shotgun Proteome Analysis (DISPA-LFQ) with CsoDIAq Software.","date":"2022","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36527718","citation_count":16,"is_preprint":false},{"pmid":"35044165","id":"PMC_35044165","title":"Rapid Targeted Quantitation of Protein Overexpression with Direct Infusion Shotgun Proteome Analysis (DISPA-PRM).","date":"2022","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35044165","citation_count":12,"is_preprint":false},{"pmid":"23542665","id":"PMC_23542665","title":"Clinical characterization of DISP1 haploinsufficiency: A case report.","date":"2013","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23542665","citation_count":11,"is_preprint":false},{"pmid":"18395198","id":"PMC_18395198","title":"Disp1 regulates growth of mammalian long bones through the control of Ihh distribution.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18395198","citation_count":9,"is_preprint":false},{"pmid":"29953682","id":"PMC_29953682","title":"Pharmacogenetic evaluation of a DISP1 gene variant in antidepressant treatment of obsessive-compulsive disorder.","date":"2018","source":"Human psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29953682","citation_count":5,"is_preprint":false},{"pmid":"38529886","id":"PMC_38529886","title":"DISP1 deficiency: Monoallelic and biallelic variants cause a spectrum of midline craniofacial malformations.","date":"2024","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38529886","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7021,"output_tokens":1567,"usd":0.022284},"stage2":{"model":"claude-opus-4-6","input_tokens":4802,"output_tokens":1451,"usd":0.090427},"total_usd":0.112711,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Disp1 function is required specifically within Shh-producing cells (not receiving cells) for paracrine signaling of cholesterol-modified Hedgehog ligands; non-cholesterol-modified N-Shh rescues early embryonic lethality of Disp1-null mutants, demonstrating Disp1 is exclusively required for secretion of the cholesterol-modified form of Shh.\",\n      \"method\": \"Conditional knockout using ShhCre knock-in allele, Disp1 conditional allele, and N-Shh rescue allele in mouse\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis with cell-type-specific conditional KO plus ligand-form rescue, replicated across multiple developmental contexts\",\n      \"pmids\": [\"15576405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Disp1 genetically interacts with Patched1 (Ptch1), Shh, and Ihh in a dose-dependent manner: reducing Ptch1 dosage restores ventral neural tube cell identities in Disp1 hypomorphic mutants, and reducing Hh ligand levels worsens Disp1 hypomorphic phenotypes, placing Disp1 upstream of Ptch1 and downstream of Hh ligand production in the signaling pathway.\",\n      \"method\": \"Genetic epistasis using hypomorphic Disp1 allele combined with null alleles of Ptch1, Shh, and Ihh in mouse; neural tube patterning analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis with multiple allelic combinations and defined cellular phenotype readout\",\n      \"pmids\": [\"15269168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In vitro studies on Disp1-null mutant fibroblasts indicate that Disp1 is not essential for membrane targeting or release of lipid-modified Shh ligand, suggesting Disp1's in vivo role in paracrine signaling involves a more complex mechanism than simple secretion.\",\n      \"method\": \"In vitro assay on Disp1-null mutant fibroblasts\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cell-based functional assay, single study\",\n      \"pmids\": [\"15269168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Disp1 plays a dual role in Shh signaling: (1) promoting secretion of Shh from source cells, and (2) facilitating transport of Shh through intervening tissue to enable long-range signaling. RNAi or dominant-negative Disp1 causes accumulation of Shh in source cells; Disp1-null neuralized embryoid bodies show reduced range of contact-dependent Shh response in co-culture.\",\n      \"method\": \"RNAi knockdown, dominant-negative constructs, co-culture of Shh-expressing cells with Disp1-null neuralized embryoid bodies derived from ES cells\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (RNAi, dominant-negative, co-culture functional assay) in a single study demonstrating dual secretion and transport roles\",\n      \"pmids\": [\"20023168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Disp1 is required for the full range of Ihh distribution within the chondrocyte target field in developing long bones; in the absence of functional Disp1, Ihh movement and signaling range is more restricted, shortening the PTHrP-Ihh feedback loop and resulting in shorter bones, demonstrating that Disp1 controls the spatial range of cholesterol-modified Ihh paracrine signaling.\",\n      \"method\": \"Conditional rescue of Disp1(C829F) lethality with N-Shh; direct Ihh trafficking analysis in target field; skeletal phenotype characterization in mouse\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ligand trafficking analysis with functional consequence (PTHrP-Ihh loop, bone length) in clean genetic background\",\n      \"pmids\": [\"18395198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Zebrafish disp1 (chameleon/con) is required in cranial neural crest cells for post-migratory patterning and chondrogenic differentiation; loss of disp1 causes failure to maintain sox9a and dlx2a expression in posterior pharyngeal arch neural crest condensations, leading to fibrous connective tissue differentiation instead of chondrogenesis.\",\n      \"method\": \"Genetic loss-of-function analysis of zebrafish con/disp1 mutants; cyclopamine treatment at defined developmental stages; in situ hybridization for sox9a, dlx2a, bapx1, gdf5\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined downstream transcription factor readouts, single lab\",\n      \"pmids\": [\"19948063\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DISP1 encodes a 12-transmembrane domain protein that acts within Hedgehog ligand-producing cells to promote the secretion and long-range paracrine transport of cholesterol-modified Hedgehog proteins (Shh and Ihh), functioning upstream of Patched1 and downstream of Hh lipid modification, with its activity specifically required for the cholesterol-modified form of Hh ligands and dispensable when non-lipidated Shh is provided.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DISP1 is a 12-transmembrane domain protein that functions within Hedgehog (Hh) ligand-producing cells to promote the secretion and long-range paracrine transport of cholesterol-modified Hedgehog proteins, including Shh and Ihh. Genetic epistasis places DISP1 downstream of Hh ligand production and upstream of the receptor Patched1, and its activity is specifically required for the cholesterol-modified form of Hh—non-cholesterol-modified Shh rescues Disp1-null lethality [PMID:15576405, PMID:15269168]. DISP1 fulfills a dual role: promoting release of Shh from source cells and facilitating its transport through intervening tissue to establish the full signaling range, as demonstrated by Shh accumulation in source cells upon DISP1 loss and restricted Ihh distribution in developing long bones [PMID:20023168, PMID:18395198].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that DISP1 acts specifically in Hh-producing cells and is dispensable when Hh lacks its cholesterol modification resolved the question of where and why DISP1 is needed in the pathway.\",\n      \"evidence\": \"Conditional knockout with ShhCre and rescue with non-cholesterol-modified N-Shh in mouse embryos\",\n      \"pmids\": [\"15576405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical mechanism by which DISP1 recognizes or handles the cholesterol moiety is unknown\",\n        \"Whether DISP1 acts on Hh ligands beyond Shh was not tested in this study\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic epistasis placed DISP1 upstream of Patched1 and downstream of Hh ligand production, defining its position in the signaling cascade, while in vitro assays indicated its role is more complex than simple membrane release.\",\n      \"evidence\": \"Combinatorial allelic dosage of Disp1 hypomorph with Ptch1, Shh, and Ihh nulls in mouse; Disp1-null fibroblast secretion assays\",\n      \"pmids\": [\"15269168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vitro fibroblast results could not recapitulate the in vivo paracrine requirement, leaving the exact molecular step unclear\",\n        \"Whether DISP1 physically interacts with Ptch1 or Hh ligands was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating restricted Ihh distribution in Disp1-mutant long bones extended DISP1's role to a second Hh ligand and showed it controls the spatial range of paracrine signaling, not merely ligand release.\",\n      \"evidence\": \"Ihh trafficking analysis and skeletal phenotyping in Disp1(C829F) mutant mice rescued with N-Shh\",\n      \"pmids\": [\"18395198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DISP1 acts cell-autonomously in receiving tissue to relay Ihh or solely in Ihh-producing chondrocytes was not resolved\",\n        \"Molecular carriers or co-factors that collaborate with DISP1 for Ihh transport are unidentified\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Multiple orthogonal approaches established that DISP1 has a dual function—promoting Shh secretion from source cells and facilitating its transport through intervening tissue—resolving whether DISP1's role is limited to release alone.\",\n      \"evidence\": \"RNAi, dominant-negative DISP1, and co-culture of Shh-expressing cells with Disp1-null neuralized embryoid bodies\",\n      \"pmids\": [\"20023168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The biophysical mechanism of DISP1-mediated transport through tissue (e.g., lipoprotein particle loading, direct handoff) is unknown\",\n        \"Structural basis for DISP1 transmembrane domain function has not been determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which DISP1 extracts cholesterol-modified Hh from the membrane and promotes its long-range transport, including direct binding partners and structural basis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct DISP1–Hh biochemical interaction has been reconstituted in vitro\",\n        \"No high-resolution structure of DISP1 is reported in the timeline\",\n        \"Identity of extracellular carriers or co-factors that collaborate with DISP1 for Hh transport is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SHH\",\n      \"IHH\",\n      \"PTCH1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}