{"gene":"IFT80","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2007,"finding":"IFT80 is a component of the intraflagellar transport (IFT) machinery required for cilia formation; morpholino knockdown of ift80 in zebrafish caused cystic kidneys, and knockdown in Tetrahymena produced shortened or absent cilia, establishing IFT80 as essential for ciliogenesis in vivo.","method":"Morpholino knockdown in zebrafish and Tetrahymena; loss-of-function phenotypic analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function in two model organisms with defined cellular phenotypes; foundational paper with 237 citations","pmids":["17468754"],"is_preprint":false},{"year":2010,"finding":"Loss of ift80 in zebrafish disrupts photoreceptor outer segment formation, causes opsin mislocalization in rods and cones, and shortens kinocilia of the ear and motile cilia in the kidney; Western blot analysis revealed a slight increase in the stability of other IFT proteins upon ift80 loss, suggesting Ift80 functions as a maintenance factor for the IFT particle.","method":"Morpholino knockdown, transmission electron microscopy, immunohistochemistry, Western blot","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (TEM, IHC, Western blot) in zebrafish model with defined cellular phenotypes","pmids":["20207966"],"is_preprint":false},{"year":2011,"finding":"Hypomorphic Ift80 mouse embryonic fibroblasts show significant reduction in Hedgehog pathway activation in response to Hedgehog agonist treatment without loss or malformation of cilia, demonstrating that IFT80 has an absolute requirement in Hh signaling that is separable from its role in ciliogenesis.","method":"Gene-trap hypomorphic mouse model; Hedgehog pathway activation assay in mouse embryonic fibroblasts; phenotypic analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with defined signaling readout; replicated concept across multiple downstream papers","pmids":["21227999"],"is_preprint":false},{"year":2012,"finding":"Silencing IFT80 in murine mesenchymal progenitor cells causes shortening or loss of cilia, decreases Arl13b expression, inhibits osteoblast marker expression and ALP activity, and downregulates Gli2; Gli2 overexpression rescues the osteoblast differentiation defect, placing IFT80 upstream of Gli2 in the Hedgehog/Gli signaling pathway during osteogenesis.","method":"Lentivirus-mediated RNAi in C3H10T1/2 and bone marrow stromal cells; ALP assay; mineralization assay; rescue by Gli2 overexpression","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established by rescue experiment; single lab","pmids":["22771375"],"is_preprint":false},{"year":2013,"finding":"Silencing IFT80 in mouse bone marrow stromal cells impairs cilia formation, downregulates Hh signaling (Gli2), and upregulates Wnt signaling, inhibiting chondrogenic differentiation; Gli2 overexpression in IFT80-silenced cells promotes chondrogenesis, placing IFT80 as a regulator of both Hh and Wnt pathways in chondrocyte differentiation.","method":"RNAi knockdown; chondrogenic differentiation assay; pathway activation assays; rescue by Gli2 overexpression","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via rescue; single lab with two orthogonal signaling readouts","pmids":["23333501"],"is_preprint":false},{"year":2019,"finding":"Conditional deletion of IFT80 in chondrocytes (Col2α1-CreER mice) reduces cilia formation, chondrocyte proliferation, and downregulates TGF-β signaling (TGF-βI, TGF-βR, and phospho-Smad2/3) in fracture callus, establishing IFT80 as required for fracture healing through the TGF-β/Smad2/3 pathway in chondrocytes.","method":"Conditional knockout mice; microCT; immunohistochemistry; in vitro primary chondrocyte culture; Western blot for Smad2/3 phosphorylation","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — conditional in vivo KO with defined molecular pathway readout and in vitro corroboration","pmids":["31643106"],"is_preprint":false},{"year":2019,"finding":"Deletion of IFT80 in odontoblast lineage disrupts dental pulp stem cell (DPSC) proliferation via impaired FGF2-FGFR1-PI3K-AKT signaling, and disrupts odontoblast differentiation via Hedgehog signaling; IFT80-deficient DPSCs show reduced FGFR1 expression, establishing IFT80 as an upstream regulator of both FGF/AKT and Hh pathways in tooth development.","method":"Conditional knockout mice; DPSC culture; Western blot; pathway inhibition/rescue assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO combined with in vitro pathway analysis; single lab","pmids":["30683845"],"is_preprint":false},{"year":2019,"finding":"In IFT80-deficient dental pulp stem cells, reduced FGFR1 expression disrupts FGF2-FGFR1 signaling, which normally induces stress fiber rearrangement to promote cilia elongation and stimulates PI3K-AKT signaling to activate Hh/BMP2 signaling for odontogenic differentiation; loss of IFT80 uncouples these cooperative signaling mechanisms.","method":"IFT80 knockdown/KO in DPSCs; FGFR1 rescue; Western blot; actin cytoskeleton imaging; cilia length measurement","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic coupling established with rescue experiments; single lab","pmids":["31592124"],"is_preprint":false},{"year":2020,"finding":"Conditional deletion of IFT80 in type II collagen-positive cells causes cilia loss in growth plate and cartilage endplate, disorganizes intervertebral disc structure, increases cell apoptosis, and decreases expression of Hh signaling components Gli1 and Patched1; deletion in type I collagen-positive cells disorganizes outer annulus fibrosus, and Smoothened agonist rescues OAF cell proliferation, placing IFT80 upstream of Hh signaling in intervertebral disc maintenance.","method":"Conditional knockout mice (Col2-creERT and Col1-creERT); histology; immunohistochemistry; Smo agonist (SAG) rescue","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — dual conditional KO lines with pharmacological rescue; single lab","pmids":["32227389"],"is_preprint":false},{"year":2022,"finding":"IFT80 (an IFT complex B protein) negatively regulates osteoclast differentiation by physically associating with the E3 ubiquitin ligase Cbl-b to promote proteasomal degradation of TRAF6; IFT80 knockdown increases Cbl-b ubiquitination and elevates TRAF6 levels, thereby hyperactivating RANKL/NF-κB signaling and enhancing osteoclast formation; IFT80 overexpression rescues osteolysis in a calvarial model.","method":"Myeloid-specific conditional KO mice; co-immunoprecipitation (IFT80-Cbl-b association); ubiquitination assay; TRAF6 protein level analysis; calvarial rescue model by IFT80 overexpression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — Co-IP for binding partner, ubiquitination mechanistic assay, in vivo rescue; multiple orthogonal methods","pmids":["35733270"],"is_preprint":false},{"year":2025,"finding":"IFT80 deficiency in mesenchymal stem cells (Prx1Cre; IFT80f/f mice) downregulates transient receptor potential ankyrin 1 (TRPA1) expression and TRPA1-mediated Ca2+ influx, which inhibits mechanical stimulation-induced osteoblastic differentiation via AKT and ERK signaling pathways; TRPA1 overexpression reverses the impaired bone formation.","method":"MSC-specific conditional KO mice; exercise/mechanical stimulation; Ca2+ influx measurement; TRPA1 overexpression rescue; Western blot for AKT and ERK","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with rescue by TRPA1 overexpression and defined signaling readout; single lab","pmids":["39954781"],"is_preprint":false},{"year":2024,"finding":"Deletion of IFT80 in Prx1 mesenchymal lineage cells reduces osteogenic markers and impairs migration/proliferation of alveolar bone-derived MSCs; TAZ overexpression rescues these defects and upregulates RUNX2 and OSX, placing IFT80 upstream of the TAZ/RUNX2 pathway in osteogenesis.","method":"Prx1Cre conditional KO mice; tooth extraction socket model; lentivirus-mediated TAZ overexpression rescue; immunofluorescence; ALP/TRAP staining","journal":"Oral diseases","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with pathway rescue; single lab","pmids":["38287672"],"is_preprint":false},{"year":2008,"finding":"A long isoform of human IFT80 (IFT80-L) was identified; sequence analysis indicates it is an evolutionarily merged product of IFT80 and TRIM59 genes, sharing the C-terminal protein sequence with IFT80; IFT80-L is ubiquitously expressed and is highly expressed in rapidly proliferating cells but not in NGF-differentiated (cell cycle-withdrawn) cells.","method":"Sequence analysis; expression analysis by RT-PCR; NGF-induced differentiation assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — expression-based characterization of isoform; no direct functional/mechanistic assay","pmids":["18601909"],"is_preprint":false}],"current_model":"IFT80 is a component of IFT complex B that is essential for cilia assembly and bidirectional intraflagellar transport; within cilia it transduces Hedgehog signaling (acting upstream of Gli2/Gli1) to regulate skeletal, chondrocyte, and dental cell differentiation, while in osteoclasts it operates independently of cilia by physically associating with the E3 ligase Cbl-b to promote TRAF6 proteasomal degradation and thereby suppress RANKL/NF-κB-driven osteoclastogenesis, and it additionally couples cilia-based mechanosensing to TRPA1-Ca2+-AKT/ERK signaling during mechanical stimulation-induced bone formation."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing IFT80 as an essential ciliogenesis factor resolved the question of whether this WD-repeat protein functions within the intraflagellar transport machinery, as knockdown in two divergent organisms produced cilia loss and associated tissue phenotypes.","evidence":"Morpholino knockdown in zebrafish (cystic kidneys) and Tetrahymena (shortened/absent cilia)","pmids":["17468754"],"confidence":"High","gaps":["Precise position within IFT-B subcomplex not defined","Mechanism of IFT80 contribution to IFT particle assembly unknown"]},{"year":2010,"claim":"Demonstrating that IFT80 loss disrupts photoreceptor outer segment formation and causes opsin mislocalization extended its role from general ciliogenesis to specialized ciliary cargo transport, while altered IFT protein stability suggested a particle-maintenance function.","evidence":"Morpholino knockdown in zebrafish; TEM, immunohistochemistry, and Western blot","pmids":["20207966"],"confidence":"High","gaps":["Whether IFT80 directly stabilizes other IFT-B subunits or acts indirectly is unresolved","Cargo specificity for outer segment transport not identified"]},{"year":2011,"claim":"Showing that hypomorphic IFT80 cells retain cilia but lose Hedgehog responsiveness separated IFT80's signaling role from its structural ciliogenesis function, establishing a dual requirement.","evidence":"Gene-trap hypomorphic mouse model; Hedgehog agonist stimulation of MEFs","pmids":["21227999"],"confidence":"High","gaps":["Molecular mechanism by which IFT80 enables Hh signal transduction within cilia not determined","Whether IFT80 directly affects Smoothened trafficking is unknown"]},{"year":2012,"claim":"Epistasis experiments placing IFT80 upstream of Gli2 in osteoblast and chondrocyte differentiation defined the signaling hierarchy through which IFT80 controls mesenchymal cell fate via Hedgehog signaling.","evidence":"RNAi knockdown in mesenchymal progenitors; Gli2 overexpression rescue of osteoblast and chondrocyte differentiation","pmids":["22771375","23333501"],"confidence":"Medium","gaps":["Whether IFT80 acts on Gli2 transcription, processing, or trafficking is undefined","Wnt pathway upregulation upon IFT80 loss lacks mechanistic explanation","Single-lab findings"]},{"year":2019,"claim":"Conditional knockout studies in chondrocytes and dental cells broadened IFT80's signaling repertoire beyond Hedgehog to TGF-β/Smad2/3 and FGF2/FGFR1/PI3K-AKT, showing tissue-specific pathway coupling through cilia.","evidence":"Col2α1-CreER and odontoblast-lineage conditional KO mice; Western blot for Smad2/3 phosphorylation; FGFR1 rescue in DPSCs","pmids":["31643106","30683845","31592124"],"confidence":"Medium","gaps":["Whether IFT80 directly regulates FGFR1 expression or acts indirectly through cilia structure is unclear","Whether TGF-β pathway effects are cilia-dependent was not directly tested"]},{"year":2022,"claim":"Identifying a cilia-independent, cytoplasmic function of IFT80 — physical association with Cbl-b to promote TRAF6 proteasomal degradation — resolved how IFT80 suppresses osteoclastogenesis through the RANKL/NF-κB axis.","evidence":"Myeloid-specific conditional KO mice; co-immunoprecipitation of IFT80–Cbl-b; ubiquitination assays; in vivo calvarial rescue","pmids":["35733270"],"confidence":"High","gaps":["Whether IFT80 is a direct Cbl-b substrate adaptor or enhances Cbl-b E3 activity is not resolved","Structural basis of IFT80–Cbl-b interaction unknown","Whether this cilia-independent role extends to other cell types is untested"]},{"year":2024,"claim":"Placing IFT80 upstream of the TAZ/RUNX2 axis in alveolar bone MSCs added another downstream effector branch and demonstrated IFT80's importance in bone regeneration contexts.","evidence":"Prx1Cre conditional KO mice; tooth extraction socket model; TAZ overexpression rescue","pmids":["38287672"],"confidence":"Medium","gaps":["Whether TAZ is activated through cilia-dependent mechanotransduction or Hh signaling is not distinguished","Single-lab finding"]},{"year":2025,"claim":"Demonstrating that IFT80 regulates TRPA1 expression and Ca²⁺ influx to drive mechanostimulation-induced osteogenesis via AKT/ERK linked IFT80's ciliary mechanosensing function to a specific ion channel effector.","evidence":"Prx1Cre conditional KO mice; exercise model; Ca²⁺ influx measurement; TRPA1 overexpression rescue","pmids":["39954781"],"confidence":"Medium","gaps":["Whether IFT80 directly regulates TRPA1 transcription or localization is unknown","How TRPA1-mediated Ca²⁺ feeds into AKT/ERK in this context is not mechanistically resolved","Single-lab finding"]},{"year":null,"claim":"The molecular mechanism by which IFT80 enables Hedgehog signal transduction within cilia — whether through Smoothened or Gli trafficking, processing, or other means — remains undefined, and how IFT80's cilia-dependent and cilia-independent functions are coordinated across cell types is unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of IFT80 within the IFT-B complex","Mechanism of Smoothened/Gli trafficking by IFT80 not established","How cilia-dependent and cilia-independent (Cbl-b/TRAF6) functions are differentially regulated is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4,5,6,8,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4,6,7,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9]}],"complexes":["IFT complex B"],"partners":["CBL-B","TRAF6","GLI2","TRPA1"],"other_free_text":[]},"mechanistic_narrative":"IFT80 is a component of intraflagellar transport complex B that is essential for ciliogenesis and cilium-dependent signaling across multiple tissues. IFT80 is required for Hedgehog pathway activation upstream of Gli2/Gli1, and loss of IFT80 impairs osteoblast, chondrocyte, and odontoblast differentiation through disruption of Hh, TGF-β/Smad2/3, FGF/AKT, and TAZ/RUNX2 signaling, with Gli2 overexpression rescuing differentiation defects in multiple mesenchymal cell types [PMID:22771375, PMID:23333501, PMID:31643106, PMID:38287672]. In osteoclasts, IFT80 functions independently of cilia by physically associating with the E3 ubiquitin ligase Cbl-b to promote proteasomal degradation of TRAF6, thereby suppressing RANKL/NF-κB–driven osteoclastogenesis [PMID:35733270]. IFT80 also couples cilia-based mechanosensing to bone formation through regulation of TRPA1 expression and Ca²⁺/AKT/ERK signaling [PMID:39954781]."},"prefetch_data":{"uniprot":{"accession":"Q9P2H3","full_name":"Intraflagellar transport protein 80 homolog","aliases":["WD repeat-containing protein 56"],"length_aa":777,"mass_kda":88.0,"function":"Component of the intraflagellar transport (IFT) complex B, which is essential for the development and maintenance of motile and sensory cilia","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, cilium axoneme","url":"https://www.uniprot.org/uniprotkb/Q9P2H3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFT80","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HSPB11","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/IFT80","total_profiled":1310},"omim":[{"mim_id":"620742","title":"INTRAFLAGELLAR TRANSPORT 70B; IFT70B","url":"https://www.omim.org/entry/620742"},{"mim_id":"620741","title":"INTRAFLAGELLAR TRANSPORT 70A; IFT70A","url":"https://www.omim.org/entry/620741"},{"mim_id":"620506","title":"INTRAFLAGELLAR TRANSPORT 46; IFT46","url":"https://www.omim.org/entry/620506"},{"mim_id":"616148","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 59; TRIM59","url":"https://www.omim.org/entry/616148"},{"mim_id":"615633","title":"SHORT-RIB THORACIC DYSPLASIA 11 WITH OR WITHOUT POLYDACTYLY; SRTD11","url":"https://www.omim.org/entry/615633"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFT80"},"hgnc":{"alias_symbol":["KIAA1374","FAP167","CFAP167"],"prev_symbol":["WDR56"]},"alphafold":{"accession":"Q9P2H3","domains":[{"cath_id":"2.130.10.10","chopping":"3-300","consensus_level":"medium","plddt":93.7533,"start":3,"end":300},{"cath_id":"-","chopping":"656-764","consensus_level":"medium","plddt":88.6469,"start":656,"end":764}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2H3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2H3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2H3-F1-predicted_aligned_error_v6.png","plddt_mean":92.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFT80","jax_strain_url":"https://www.jax.org/strain/search?query=IFT80"},"sequence":{"accession":"Q9P2H3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2H3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2H3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2H3"}},"corpus_meta":[{"pmid":"17468754","id":"PMC_17468754","title":"IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17468754","citation_count":237,"is_preprint":false},{"pmid":"21227999","id":"PMC_21227999","title":"An Ift80 mouse model of short rib polydactyly syndromes shows defects in hedgehog signalling without loss or malformation of cilia.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21227999","citation_count":75,"is_preprint":false},{"pmid":"19648123","id":"PMC_19648123","title":"Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum.","date":"2009","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19648123","citation_count":56,"is_preprint":false},{"pmid":"22771375","id":"PMC_22771375","title":"The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis.","date":"2012","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/22771375","citation_count":48,"is_preprint":false},{"pmid":"23333501","id":"PMC_23333501","title":"IFT80 is essential for chondrocyte differentiation by regulating Hedgehog and Wnt signaling pathways.","date":"2013","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/23333501","citation_count":43,"is_preprint":false},{"pmid":"20207966","id":"PMC_20207966","title":"The intraflagellar transport protein ift80 is essential for photoreceptor survival in a zebrafish model of jeune asphyxiating thoracic dystrophy.","date":"2010","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/20207966","citation_count":38,"is_preprint":false},{"pmid":"31643106","id":"PMC_31643106","title":"IFT80 Is Required for Fracture Healing Through Controlling the Regulation of TGF-β Signaling in Chondrocyte Differentiation and Function.","date":"2019","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/31643106","citation_count":34,"is_preprint":false},{"pmid":"33658855","id":"PMC_33658855","title":"Exosomal circ_IFT80 Enhances Tumorigenesis and Suppresses Radiosensitivity in Colorectal Cancer by Regulating miR-296-5p/MSI1 Axis.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33658855","citation_count":31,"is_preprint":false},{"pmid":"32227389","id":"PMC_32227389","title":"Ciliary IFT80 is essential for intervertebral disc development and maintenance.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32227389","citation_count":28,"is_preprint":false},{"pmid":"30683845","id":"PMC_30683845","title":"IFT80 is required for stem cell proliferation, differentiation, and odontoblast polarization during tooth development.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30683845","citation_count":27,"is_preprint":false},{"pmid":"31592124","id":"PMC_31592124","title":"Ciliary IFT80 regulates dental pulp stem cells differentiation by FGF/FGFR1 and Hh/BMP2 signaling.","date":"2019","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31592124","citation_count":22,"is_preprint":false},{"pmid":"35733270","id":"PMC_35733270","title":"IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35733270","citation_count":13,"is_preprint":false},{"pmid":"30453504","id":"PMC_30453504","title":"IFT80 Improves Invasion Ability in Gastric Cancer Cell Line via ift80/p75NGFR/MMP9 Signaling.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30453504","citation_count":9,"is_preprint":false},{"pmid":"18601909","id":"PMC_18601909","title":"Identification and characterization of a long isoform of human IFT80, IFT80-L.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18601909","citation_count":9,"is_preprint":false},{"pmid":"36085107","id":"PMC_36085107","title":"Truncation of IFT80 causes early embryonic loss in Holstein cattle associated with Holstein haplotype 2.","date":"2022","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/36085107","citation_count":9,"is_preprint":false},{"pmid":"29923190","id":"PMC_29923190","title":"IFT80 mutations cause a novel complex ciliopathy phenotype with retinal degeneration.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29923190","citation_count":6,"is_preprint":false},{"pmid":"30767363","id":"PMC_30767363","title":"Mutations in IFT80 cause SRPS Type IV. Report of two families and review.","date":"2019","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30767363","citation_count":5,"is_preprint":false},{"pmid":"38644709","id":"PMC_38644709","title":"The IFT80/Hedgehog Pathway Regulates the Osteogenic-adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells.","date":"2025","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38644709","citation_count":4,"is_preprint":false},{"pmid":"39954781","id":"PMC_39954781","title":"IFT80 and TRPA1 cooperatively regulate bone formation by calcium signaling in response to mechanical stimuli.","date":"2025","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/39954781","citation_count":4,"is_preprint":false},{"pmid":"36013326","id":"PMC_36013326","title":"The Effect of IFT80 Deficiency in Osteocytes on Orthodontic Loading-Induced and Physiologic Bone Remodeling: In Vivo Study.","date":"2022","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36013326","citation_count":3,"is_preprint":false},{"pmid":"38287672","id":"PMC_38287672","title":"IFT80 promotes early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway.","date":"2024","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38287672","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12003,"output_tokens":3340,"usd":0.043055},"stage2":{"model":"claude-opus-4-6","input_tokens":6729,"output_tokens":2354,"usd":0.138742},"total_usd":0.181797,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"IFT80 is a component of the intraflagellar transport (IFT) machinery required for cilia formation; morpholino knockdown of ift80 in zebrafish caused cystic kidneys, and knockdown in Tetrahymena produced shortened or absent cilia, establishing IFT80 as essential for ciliogenesis in vivo.\",\n      \"method\": \"Morpholino knockdown in zebrafish and Tetrahymena; loss-of-function phenotypic analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function in two model organisms with defined cellular phenotypes; foundational paper with 237 citations\",\n      \"pmids\": [\"17468754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of ift80 in zebrafish disrupts photoreceptor outer segment formation, causes opsin mislocalization in rods and cones, and shortens kinocilia of the ear and motile cilia in the kidney; Western blot analysis revealed a slight increase in the stability of other IFT proteins upon ift80 loss, suggesting Ift80 functions as a maintenance factor for the IFT particle.\",\n      \"method\": \"Morpholino knockdown, transmission electron microscopy, immunohistochemistry, Western blot\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (TEM, IHC, Western blot) in zebrafish model with defined cellular phenotypes\",\n      \"pmids\": [\"20207966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hypomorphic Ift80 mouse embryonic fibroblasts show significant reduction in Hedgehog pathway activation in response to Hedgehog agonist treatment without loss or malformation of cilia, demonstrating that IFT80 has an absolute requirement in Hh signaling that is separable from its role in ciliogenesis.\",\n      \"method\": \"Gene-trap hypomorphic mouse model; Hedgehog pathway activation assay in mouse embryonic fibroblasts; phenotypic analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with defined signaling readout; replicated concept across multiple downstream papers\",\n      \"pmids\": [\"21227999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Silencing IFT80 in murine mesenchymal progenitor cells causes shortening or loss of cilia, decreases Arl13b expression, inhibits osteoblast marker expression and ALP activity, and downregulates Gli2; Gli2 overexpression rescues the osteoblast differentiation defect, placing IFT80 upstream of Gli2 in the Hedgehog/Gli signaling pathway during osteogenesis.\",\n      \"method\": \"Lentivirus-mediated RNAi in C3H10T1/2 and bone marrow stromal cells; ALP assay; mineralization assay; rescue by Gli2 overexpression\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by rescue experiment; single lab\",\n      \"pmids\": [\"22771375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Silencing IFT80 in mouse bone marrow stromal cells impairs cilia formation, downregulates Hh signaling (Gli2), and upregulates Wnt signaling, inhibiting chondrogenic differentiation; Gli2 overexpression in IFT80-silenced cells promotes chondrogenesis, placing IFT80 as a regulator of both Hh and Wnt pathways in chondrocyte differentiation.\",\n      \"method\": \"RNAi knockdown; chondrogenic differentiation assay; pathway activation assays; rescue by Gli2 overexpression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via rescue; single lab with two orthogonal signaling readouts\",\n      \"pmids\": [\"23333501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional deletion of IFT80 in chondrocytes (Col2α1-CreER mice) reduces cilia formation, chondrocyte proliferation, and downregulates TGF-β signaling (TGF-βI, TGF-βR, and phospho-Smad2/3) in fracture callus, establishing IFT80 as required for fracture healing through the TGF-β/Smad2/3 pathway in chondrocytes.\",\n      \"method\": \"Conditional knockout mice; microCT; immunohistochemistry; in vitro primary chondrocyte culture; Western blot for Smad2/3 phosphorylation\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional in vivo KO with defined molecular pathway readout and in vitro corroboration\",\n      \"pmids\": [\"31643106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Deletion of IFT80 in odontoblast lineage disrupts dental pulp stem cell (DPSC) proliferation via impaired FGF2-FGFR1-PI3K-AKT signaling, and disrupts odontoblast differentiation via Hedgehog signaling; IFT80-deficient DPSCs show reduced FGFR1 expression, establishing IFT80 as an upstream regulator of both FGF/AKT and Hh pathways in tooth development.\",\n      \"method\": \"Conditional knockout mice; DPSC culture; Western blot; pathway inhibition/rescue assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO combined with in vitro pathway analysis; single lab\",\n      \"pmids\": [\"30683845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In IFT80-deficient dental pulp stem cells, reduced FGFR1 expression disrupts FGF2-FGFR1 signaling, which normally induces stress fiber rearrangement to promote cilia elongation and stimulates PI3K-AKT signaling to activate Hh/BMP2 signaling for odontogenic differentiation; loss of IFT80 uncouples these cooperative signaling mechanisms.\",\n      \"method\": \"IFT80 knockdown/KO in DPSCs; FGFR1 rescue; Western blot; actin cytoskeleton imaging; cilia length measurement\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic coupling established with rescue experiments; single lab\",\n      \"pmids\": [\"31592124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional deletion of IFT80 in type II collagen-positive cells causes cilia loss in growth plate and cartilage endplate, disorganizes intervertebral disc structure, increases cell apoptosis, and decreases expression of Hh signaling components Gli1 and Patched1; deletion in type I collagen-positive cells disorganizes outer annulus fibrosus, and Smoothened agonist rescues OAF cell proliferation, placing IFT80 upstream of Hh signaling in intervertebral disc maintenance.\",\n      \"method\": \"Conditional knockout mice (Col2-creERT and Col1-creERT); histology; immunohistochemistry; Smo agonist (SAG) rescue\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual conditional KO lines with pharmacological rescue; single lab\",\n      \"pmids\": [\"32227389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFT80 (an IFT complex B protein) negatively regulates osteoclast differentiation by physically associating with the E3 ubiquitin ligase Cbl-b to promote proteasomal degradation of TRAF6; IFT80 knockdown increases Cbl-b ubiquitination and elevates TRAF6 levels, thereby hyperactivating RANKL/NF-κB signaling and enhancing osteoclast formation; IFT80 overexpression rescues osteolysis in a calvarial model.\",\n      \"method\": \"Myeloid-specific conditional KO mice; co-immunoprecipitation (IFT80-Cbl-b association); ubiquitination assay; TRAF6 protein level analysis; calvarial rescue model by IFT80 overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — Co-IP for binding partner, ubiquitination mechanistic assay, in vivo rescue; multiple orthogonal methods\",\n      \"pmids\": [\"35733270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFT80 deficiency in mesenchymal stem cells (Prx1Cre; IFT80f/f mice) downregulates transient receptor potential ankyrin 1 (TRPA1) expression and TRPA1-mediated Ca2+ influx, which inhibits mechanical stimulation-induced osteoblastic differentiation via AKT and ERK signaling pathways; TRPA1 overexpression reverses the impaired bone formation.\",\n      \"method\": \"MSC-specific conditional KO mice; exercise/mechanical stimulation; Ca2+ influx measurement; TRPA1 overexpression rescue; Western blot for AKT and ERK\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with rescue by TRPA1 overexpression and defined signaling readout; single lab\",\n      \"pmids\": [\"39954781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Deletion of IFT80 in Prx1 mesenchymal lineage cells reduces osteogenic markers and impairs migration/proliferation of alveolar bone-derived MSCs; TAZ overexpression rescues these defects and upregulates RUNX2 and OSX, placing IFT80 upstream of the TAZ/RUNX2 pathway in osteogenesis.\",\n      \"method\": \"Prx1Cre conditional KO mice; tooth extraction socket model; lentivirus-mediated TAZ overexpression rescue; immunofluorescence; ALP/TRAP staining\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with pathway rescue; single lab\",\n      \"pmids\": [\"38287672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A long isoform of human IFT80 (IFT80-L) was identified; sequence analysis indicates it is an evolutionarily merged product of IFT80 and TRIM59 genes, sharing the C-terminal protein sequence with IFT80; IFT80-L is ubiquitously expressed and is highly expressed in rapidly proliferating cells but not in NGF-differentiated (cell cycle-withdrawn) cells.\",\n      \"method\": \"Sequence analysis; expression analysis by RT-PCR; NGF-induced differentiation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression-based characterization of isoform; no direct functional/mechanistic assay\",\n      \"pmids\": [\"18601909\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFT80 is a component of IFT complex B that is essential for cilia assembly and bidirectional intraflagellar transport; within cilia it transduces Hedgehog signaling (acting upstream of Gli2/Gli1) to regulate skeletal, chondrocyte, and dental cell differentiation, while in osteoclasts it operates independently of cilia by physically associating with the E3 ligase Cbl-b to promote TRAF6 proteasomal degradation and thereby suppress RANKL/NF-κB-driven osteoclastogenesis, and it additionally couples cilia-based mechanosensing to TRPA1-Ca2+-AKT/ERK signaling during mechanical stimulation-induced bone formation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IFT80 is a component of intraflagellar transport complex B that is essential for ciliogenesis and cilium-dependent signaling across multiple tissues. IFT80 is required for Hedgehog pathway activation upstream of Gli2/Gli1, and loss of IFT80 impairs osteoblast, chondrocyte, and odontoblast differentiation through disruption of Hh, TGF-β/Smad2/3, FGF/AKT, and TAZ/RUNX2 signaling, with Gli2 overexpression rescuing differentiation defects in multiple mesenchymal cell types [PMID:22771375, PMID:23333501, PMID:31643106, PMID:38287672]. In osteoclasts, IFT80 functions independently of cilia by physically associating with the E3 ubiquitin ligase Cbl-b to promote proteasomal degradation of TRAF6, thereby suppressing RANKL/NF-κB–driven osteoclastogenesis [PMID:35733270]. IFT80 also couples cilia-based mechanosensing to bone formation through regulation of TRPA1 expression and Ca²⁺/AKT/ERK signaling [PMID:39954781].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing IFT80 as an essential ciliogenesis factor resolved the question of whether this WD-repeat protein functions within the intraflagellar transport machinery, as knockdown in two divergent organisms produced cilia loss and associated tissue phenotypes.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish (cystic kidneys) and Tetrahymena (shortened/absent cilia)\",\n      \"pmids\": [\"17468754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise position within IFT-B subcomplex not defined\", \"Mechanism of IFT80 contribution to IFT particle assembly unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that IFT80 loss disrupts photoreceptor outer segment formation and causes opsin mislocalization extended its role from general ciliogenesis to specialized ciliary cargo transport, while altered IFT protein stability suggested a particle-maintenance function.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish; TEM, immunohistochemistry, and Western blot\",\n      \"pmids\": [\"20207966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFT80 directly stabilizes other IFT-B subunits or acts indirectly is unresolved\", \"Cargo specificity for outer segment transport not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that hypomorphic IFT80 cells retain cilia but lose Hedgehog responsiveness separated IFT80's signaling role from its structural ciliogenesis function, establishing a dual requirement.\",\n      \"evidence\": \"Gene-trap hypomorphic mouse model; Hedgehog agonist stimulation of MEFs\",\n      \"pmids\": [\"21227999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which IFT80 enables Hh signal transduction within cilia not determined\", \"Whether IFT80 directly affects Smoothened trafficking is unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Epistasis experiments placing IFT80 upstream of Gli2 in osteoblast and chondrocyte differentiation defined the signaling hierarchy through which IFT80 controls mesenchymal cell fate via Hedgehog signaling.\",\n      \"evidence\": \"RNAi knockdown in mesenchymal progenitors; Gli2 overexpression rescue of osteoblast and chondrocyte differentiation\",\n      \"pmids\": [\"22771375\", \"23333501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IFT80 acts on Gli2 transcription, processing, or trafficking is undefined\", \"Wnt pathway upregulation upon IFT80 loss lacks mechanistic explanation\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional knockout studies in chondrocytes and dental cells broadened IFT80's signaling repertoire beyond Hedgehog to TGF-β/Smad2/3 and FGF2/FGFR1/PI3K-AKT, showing tissue-specific pathway coupling through cilia.\",\n      \"evidence\": \"Col2α1-CreER and odontoblast-lineage conditional KO mice; Western blot for Smad2/3 phosphorylation; FGFR1 rescue in DPSCs\",\n      \"pmids\": [\"31643106\", \"30683845\", \"31592124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IFT80 directly regulates FGFR1 expression or acts indirectly through cilia structure is unclear\", \"Whether TGF-β pathway effects are cilia-dependent was not directly tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying a cilia-independent, cytoplasmic function of IFT80 — physical association with Cbl-b to promote TRAF6 proteasomal degradation — resolved how IFT80 suppresses osteoclastogenesis through the RANKL/NF-κB axis.\",\n      \"evidence\": \"Myeloid-specific conditional KO mice; co-immunoprecipitation of IFT80–Cbl-b; ubiquitination assays; in vivo calvarial rescue\",\n      \"pmids\": [\"35733270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFT80 is a direct Cbl-b substrate adaptor or enhances Cbl-b E3 activity is not resolved\", \"Structural basis of IFT80–Cbl-b interaction unknown\", \"Whether this cilia-independent role extends to other cell types is untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing IFT80 upstream of the TAZ/RUNX2 axis in alveolar bone MSCs added another downstream effector branch and demonstrated IFT80's importance in bone regeneration contexts.\",\n      \"evidence\": \"Prx1Cre conditional KO mice; tooth extraction socket model; TAZ overexpression rescue\",\n      \"pmids\": [\"38287672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TAZ is activated through cilia-dependent mechanotransduction or Hh signaling is not distinguished\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that IFT80 regulates TRPA1 expression and Ca²⁺ influx to drive mechanostimulation-induced osteogenesis via AKT/ERK linked IFT80's ciliary mechanosensing function to a specific ion channel effector.\",\n      \"evidence\": \"Prx1Cre conditional KO mice; exercise model; Ca²⁺ influx measurement; TRPA1 overexpression rescue\",\n      \"pmids\": [\"39954781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IFT80 directly regulates TRPA1 transcription or localization is unknown\", \"How TRPA1-mediated Ca²⁺ feeds into AKT/ERK in this context is not mechanistically resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which IFT80 enables Hedgehog signal transduction within cilia — whether through Smoothened or Gli trafficking, processing, or other means — remains undefined, and how IFT80's cilia-dependent and cilia-independent functions are coordinated across cell types is unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of IFT80 within the IFT-B complex\", \"Mechanism of Smoothened/Gli trafficking by IFT80 not established\", \"How cilia-dependent and cilia-independent (Cbl-b/TRAF6) functions are differentially regulated is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4, 5, 6, 8, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"IFT complex B\"\n    ],\n    \"partners\": [\n      \"Cbl-b\",\n      \"TRAF6\",\n      \"GLI2\",\n      \"TRPA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}