{"gene":"KIAA0586","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2006,"finding":"Talpid3/KIAA0586 is absolutely required for both Gli repressor and activator functions in the intracellular Hedgehog pathway; Gli3 processing is abnormal in talpid3 mutant cells, though Gli3 can still translocate to the nucleus. The protein localizes to the cytoplasm.","method":"Genetic rescue experiments in chicken embryos, Gli3 processing assays, subcellular localization studies in mutant vs. wild-type cells","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct rescue experiments establishing causal link, multiple embryonic regions analyzed, replicated in subsequent studies","pmids":["16702409"],"is_preprint":false},{"year":2009,"finding":"Talpid3/KIAA0586 is a centrosomal protein essential for primary cilia formation; in talpid3 mutant cells, basal bodies mature and dock is attempted but fail to dock with the apical membrane, are misorientated, and almost completely lack ciliary axonemes. A conserved coiled-coil domain region (exons 11-12) is required to rescue primary cilia formation and is sufficient for centrosomal localization. Marked changes in actin organisation were also detected in mutant cells.","method":"Immunofluorescence with anti-Talpid3 antibody, electron microscopy (ultrastructural analysis), rescue experiments with deletion constructs in talpid3 mutant embryos, antibody detection of Talpid3 at centrosome","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ultrastructural EM, domain mapping with rescue, antibody localization, replicated across multiple studies","pmids":["19144723"],"is_preprint":false},{"year":2014,"finding":"Talpid3 assembles a ring-like structure at the extreme distal end of centrioles and is a component of a CP110-containing protein complex. Ablation of Talpid3 causes aberrant distribution of centriolar satellites and mislocalization of Rab8a. Expression of activated Rab8a suppresses cilia assembly defects provoked by Talpid3 depletion, indicating Talpid3 affects cilia formation through Rab8a recruitment and/or activation. Talpid3 is also required for centriolar satellite dispersal preceding ciliary vesicle formation.","method":"Co-immunoprecipitation to identify CP110 complex, siRNA depletion, immunofluorescence, ultrastructural analysis, rescue with activated Rab8a","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA with defined phenotype, EM, functional rescue with activated Rab8a, multiple orthogonal methods","pmids":["24421332"],"is_preprint":false},{"year":2016,"finding":"PCM1 tethers the E3 ubiquitin ligase Mindbomb1 (Mib1) to centriolar satellites. In the absence of PCM1, Mib1 destabilizes Talpid3 through poly-ubiquitylation, suppressing cilium assembly. Loss of PCM1 blocks ciliogenesis by abrogating recruitment of ciliary vesicles associated with Talpid3-binding protein Rab8; this can be reversed by inactivating Mib1. Thus Mib1-mediated poly-ubiquitylation is a post-translational regulatory mechanism controlling Talpid3 abundance.","method":"PCM1 gene deletion in human cells, rescue with PCM1 domain constructs, ubiquitylation assays, Mib1 inactivation rescue experiments, immunofluorescence","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene deletion, ubiquitylation assay, multiple domain rescue constructs, epistasis via Mib1 inactivation, multiple orthogonal methods","pmids":["27146717"],"is_preprint":false},{"year":2014,"finding":"Centrosomal protein Cep120 is asymmetrically localized to the daughter centriole through its physical interaction with Talpid3 (Ta3), another centrosomal protein.","method":"Co-immunoprecipitation (pulldown), immunofluorescence localization in cerebellar granule neuron progenitors","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP demonstrating interaction, confirmed by localization studies, single lab","pmids":["25251415"],"is_preprint":false},{"year":2017,"finding":"Talpid3 interacts with PKA regulatory subunit PKARIIβ at centrioles; the centriolar localization region maps to the N-terminal region and the PKA-binding region to the C-terminal region of Ta3. Talpid3 mutation results in failure of PKARIIβ to localize at centrioles, leading to reduced Gli2 and Gli3 phosphorylation and impaired processing. Hedgehog signaling inhibits Gli2 and Gli3 phosphorylation by PKA in cilia.","method":"Co-immunoprecipitation (Talpid3–PKARIIβ interaction), immunofluorescence colocalization, domain mapping with N- and C-terminal constructs, phosphorylation assays in mutant vs. wild-type cells, Gli processing western blot","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus domain mapping plus functional phosphorylation assays, single lab with multiple methods","pmids":["28673820"],"is_preprint":false},{"year":2019,"finding":"CEP120 interacts with C2CD3 and Talpid3; loss of CEP120 impairs recruitment of C2CD3 and Talpid3 to the distal ends of centrioles, leading to defects in centriole appendage assembly and cilia formation. A disease-associated CEP120 mutant (I975S) has low affinity for C2CD3 binding and perturbs cilia assembly.","method":"Co-immunoprecipitation (CEP120 with C2CD3 and Talpid3), CRISPR/Cas9 CEP120 knockout in RPE1 cells, immunofluorescence, disease-mutant binding assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, CRISPR KO with defined phenotype, disease-mutant functional analysis, single lab","pmids":["30988386"],"is_preprint":false},{"year":2020,"finding":"TALPID3 and ANKRD26 form a protein complex with cilia-gating component FBF1 at transition fibers. Co-depletion of TALPID3 and ANKRD26 specifically impairs recruitment of FBF1 to transition fibers, disrupting cilia gating. This function is conserved in both C. elegans (TALP-3/ANKR-26/DYF-19) and mammalian cells (TALPID3/ANKRD26/FBF1).","method":"Forward genetic screen in C. elegans, genetic epistasis (co-depletion), co-immunoprecipitation (complex formation), immunofluorescence (FBF1 localization at transition fibers) in both C. elegans and mammalian cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — forward genetic screen, epistasis, Co-IP, localization assay, validated in two organisms with multiple orthogonal methods","pmids":["32366837"],"is_preprint":false},{"year":2011,"finding":"In zebrafish talpid3 mutants (MZta3), primary and motile cilia are absent and Hedgehog signaling is aberrant. GFP-tagged Gli2a localizes to basal bodies in the absence of primary cilia, and Gli2a protein is aberrantly processed in MZta3 embryos as shown by western blot, demonstrating a cilia-dependent mechanism for Gli processing.","method":"Zinc-finger nuclease mutagenesis, GFP-Gli2a localization by live imaging, western blot for Gli2a processing, germline replacement for maternal depletion","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — targeted mutagenesis, protein localization, biochemical processing assay, multiple orthogonal methods in a vertebrate model","pmids":["22028029"],"is_preprint":false},{"year":2011,"finding":"Deletion of conserved exons 11-12 of KIAA0586/Talpid3 in mice results in embryos lacking primary cilia with face, neural tube, and left/right asymmetry defects. Conditional deletion in limb mesenchyme causes polydactyly and brachydactyly attributable to abnormal Sonic hedgehog and Indian hedgehog signaling. Talpid3 mutant mouse cells migrate more slowly than wild-type cells.","method":"Constitutive and conditional gene deletion in mice, primary cilia immunofluorescence, cell migration assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive and conditional KO with defined cellular and tissue phenotypes, multiple readouts, replicated in two vertebrate models","pmids":["21750036"],"is_preprint":false},{"year":2013,"finding":"TALPID3 is required for centrosomal migration to the apical surface prior to ciliogenesis in ependymal multiciliate cells; talpid3 ependymal cells develop multiple centrosomes but these fail to migrate to the apical cell surface, though axoneme formation was sometimes observed. TALPID3 is not directly required for de novo centriologenesis, multiciliated fate, or axoneme formation.","method":"Immunofluorescence for centrosome markers, electron microscopy of ependymal cells, analysis of FOXJ1 expression in talpid3 vs. wild-type chicken embryos","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EM plus immunofluorescence, single lab, two orthogonal methods establishing subcellular mechanism","pmids":["23613203"],"is_preprint":false},{"year":2015,"finding":"KIAA0586 protein localizes to the basal body in human and mouse photoreceptors, and also in pericentriolar locations. Loss of TALPID3 function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites.","method":"Immunofluorescence localization in human and mouse photoreceptors, animal model analysis (chicken and mouse), homozygosity mapping and whole-exome sequencing identifying splice site mutation","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct immunofluorescence localization in photoreceptors, animal model phenotypic analysis, single lab","pmids":["26386247"],"is_preprint":false},{"year":2018,"finding":"In zebrafish talpid3 mutant photoreceptors, the majority of photoreceptors lack outer segment development due to defects in basal body positioning and docking at the apical cell surface. Overexpression of constitutively active Rab8a rescues outer segment formation in talpid3 mutant photoreceptors, indicating Ta3's role in early ciliogenesis lies upstream of Rab8a activation in photoreceptors.","method":"Zebrafish talpid3 mutant analysis, immunofluorescence for Rab8a localization, constitutively active Rab8a rescue experiment, electroretinograms for functional assessment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant, functional rescue with constitutively active Rab8a, epistasis established, single lab","pmids":["29396404"],"is_preprint":false},{"year":2020,"finding":"Talpid3 is localized to the mother centriole of radial glial cells (RGCs) and is required for their apical mitosis. Talpid3 associates with Ninein to regulate microtubule organization and maintain the integrity of adherens junctions to anchor RGCs. Genetic silencing of Talpid3 causes abnormal RGC delamination and impairs interkinetic nuclear migration in cell-autonomous and non-autonomous manners.","method":"Immunofluorescence localization, co-immunoprecipitation (Talpid3-Ninein interaction), genetic silencing (shRNA/conditional KO), adherens junction integrity assays, live imaging of nuclear migration","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for Ninein interaction, KO with defined cellular phenotype, localization studies, single lab","pmids":["33326788"],"is_preprint":false},{"year":2023,"finding":"Conditional deletion of Talpid3 in muscle stem cells (MuSC) impairs muscle regeneration and self-renewal after injury. Single-cell transcriptomics identified deregulation of Hh and Wnt signaling pathways in TA3-depleted MuSC progeny. Pharmacological activation of Wnt (but not Smoothened/Hh pathway activation) restores muscle regeneration in TA3 conditional KO mice.","method":"Tamoxifen-inducible conditional deletion in MuSC, cytotoxic injury model, single-cell transcriptomics, pharmacological rescue with Wnt activator and Smo agonist (purmorphamine)","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, scRNA-seq pathway analysis, pharmacological epistasis rescue, single lab","pmids":["37925530"],"is_preprint":false},{"year":2015,"finding":"Cells derived from patients with biallelic KIAA0586 mutations show defective ciliogenesis and abnormal response to SHH-signaling activation. Centriolar maturation appeared unaffected in mutant cells, but an abnormal extended pattern of CEP290 (a centriolar satellite protein) was observed. Rescue of cilia defect with full-length wild-type KIAA0586 confirmed the causal link. Gli3 processing is abnormal in mutant cells.","method":"Patient-derived fibroblast ciliogenesis assay, SHH stimulation assay, rescue with wild-type KIAA0586, immunofluorescence for CEP290 pattern, Gli3 processing western blot","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment, multiple cellular assays, patient-derived cells, single lab","pmids":["26166481"],"is_preprint":false}],"current_model":"KIAA0586/TALPID3 is a centrosomal protein that localizes to the distal end of centrioles (mother centriole/basal body) where it is required for basal body docking to the apical membrane and primary cilia formation; it functions in Hedgehog signaling by facilitating PKARIIβ-dependent phosphorylation of Gli2/Gli3 at centrioles and enabling Gli activator/repressor processing, acts upstream of Rab8a activation to promote ciliary vesicle formation, works with ANKRD26 to recruit FBF1 to transition fibers for cilia gating, interacts with CP110, CEP120, C2CD3, and Ninein at centrioles, and is subject to Mib1-mediated poly-ubiquitylation that is restrained by PCM1 tethering at centriolar satellites."},"narrative":{"mechanistic_narrative":"KIAA0586/TALPID3 is a centrosomal protein that assembles a ring-like structure at the distal end of centrioles (mother centriole/basal body) and is essential for primary cilia formation and Hedgehog signal transduction [PMID:19144723, PMID:24421332]. A conserved coiled-coil region encoded by exons 11-12 is required for centrosomal localization and sufficient to rescue ciliogenesis [PMID:19144723], and deletion of these exons in mice abolishes primary cilia and produces hallmark Hedgehog-dependent developmental defects in face, neural tube, left/right asymmetry, and digit number [PMID:21750036]. Mechanistically, TALPID3 governs basal body docking to the apical membrane: mutant basal bodies mature but fail to dock and lack ciliary axonemes, and TALPID3 acts upstream of Rab8a, with activated Rab8a rescuing the cilia and photoreceptor outer-segment defects of TALPID3-deficient cells [PMID:24421332, PMID:29396404]. It is a component of a CP110-containing complex and controls centriolar satellite dispersal that precedes ciliary vesicle formation [PMID:24421332]. Through its interaction with the PKA regulatory subunit PKARIIβ at centrioles, TALPID3 enables PKA-dependent phosphorylation and proper processing of Gli2/Gli3 into activator and repressor forms, providing a cilium-based mechanism for graded Hedgehog output [PMID:16702409, PMID:28673820, PMID:22028029]. TALPID3 further interacts with CEP120 and C2CD3 for distal centriole/appendage assembly [PMID:30988386], with ANKRD26 to recruit FBF1 to transition fibers for cilia gating [PMID:32366837], and with Ninein to organize microtubules and maintain adherens junctions during neural progenitor mitosis [PMID:33326788]. Its abundance is restrained by Mib1-mediated poly-ubiquitylation, which is held in check by PCM1 tethering at centriolar satellites [PMID:27146717]. Biallelic KIAA0586 mutations cause a human ciliopathy, with patient cells showing defective ciliogenesis, abnormal SHH response, and aberrant Gli3 processing rescued by wild-type KIAA0586 [PMID:26166481].","teleology":[{"year":2006,"claim":"Established that TALPID3 is required for both activator and repressor functions of the Hedgehog pathway by acting on Gli3 processing, placing it at a central regulatory node of Hh output.","evidence":"Genetic rescue and Gli3 processing assays in chicken embryos","pmids":["16702409"],"confidence":"High","gaps":["Cytoplasmic localization defined but subcellular site of action not yet resolved","Molecular partners mediating Gli processing unknown"]},{"year":2009,"claim":"Identified TALPID3 as a centrosomal protein required for basal body docking to the apical membrane and cilia formation, localizing the Hh defect to a ciliogenesis step.","evidence":"Anti-Talpid3 immunofluorescence, EM, and exon 11-12 deletion rescue in talpid3 mutant chicken embryos","pmids":["19144723"],"confidence":"High","gaps":["Molecular mechanism of docking not defined","Interacting partners at the distal centriole unidentified"]},{"year":2011,"claim":"Demonstrated in zebrafish and mouse that TALPID3 loss abolishes cilia and disrupts Gli processing and Hh-dependent patterning, confirming a conserved vertebrate cilia-dependent mechanism.","evidence":"Zinc-finger nuclease and gene-deletion mutants with Gli2a localization/processing and limb patterning analysis","pmids":["22028029","21750036"],"confidence":"High","gaps":["Did not define the biochemical step linking TALPID3 to Gli phosphorylation","Cell migration phenotype mechanism unresolved"]},{"year":2013,"claim":"Showed TALPID3 is required for centrosome migration to the apical surface but not for de novo centriologenesis or axoneme formation, distinguishing its docking role from centriole biogenesis.","evidence":"Immunofluorescence and EM of talpid3 ependymal multiciliate cells","pmids":["23613203"],"confidence":"Medium","gaps":["Single lab","Molecular basis of migration defect not defined"]},{"year":2014,"claim":"Defined the centriolar architecture and trafficking mechanism: TALPID3 forms a distal-end ring within a CP110 complex and controls satellite dispersal and Rab8a recruitment to drive ciliary vesicle formation.","evidence":"Co-IP, siRNA depletion, EM, and activated-Rab8a rescue; separate Co-IP mapping Cep120 to daughter centriole via Talpid3","pmids":["24421332","25251415"],"confidence":"High","gaps":["How TALPID3 activates/recruits Rab8a mechanistically unclear","Cep120 interaction from single Co-IP"]},{"year":2015,"claim":"Linked KIAA0586 to a human ciliopathy and confirmed causality, showing patient cells have defective ciliogenesis, abnormal SHH response, and aberrant Gli3 processing rescued by wild-type protein.","evidence":"Patient fibroblast ciliogenesis/SHH assays, CEP290 pattern, Gli3 western, and wild-type rescue; photoreceptor basal body localization","pmids":["26166481","26386247"],"confidence":"Medium","gaps":["Genotype-phenotype correlations not established","Single lab for localization data"]},{"year":2016,"claim":"Uncovered post-translational control of TALPID3 abundance: PCM1 tethers Mib1 at satellites to prevent Mib1-mediated poly-ubiquitylation and degradation of TALPID3, gating ciliogenesis.","evidence":"PCM1 deletion, ubiquitylation assays, domain rescue, and Mib1-inactivation epistasis in human cells","pmids":["27146717"],"confidence":"High","gaps":["Ubiquitylation sites on TALPID3 not mapped","Signals triggering Mib1 activity unclear"]},{"year":2017,"claim":"Provided a molecular mechanism for Gli processing by showing TALPID3 recruits PKARIIβ to centrioles via its C-terminus to enable PKA-dependent Gli2/Gli3 phosphorylation.","evidence":"Co-IP, domain mapping with N-/C-terminal constructs, and phosphorylation/Gli processing assays","pmids":["28673820"],"confidence":"Medium","gaps":["Single lab","Direct kinase-substrate relationship at centrioles not reconstituted"]},{"year":2018,"claim":"Extended the Rab8a-upstream model to photoreceptors, showing TALPID3 enables outer-segment formation through basal body docking upstream of Rab8a activation.","evidence":"Zebrafish talpid3 mutant analysis with constitutively active Rab8a rescue and electroretinograms","pmids":["29396404"],"confidence":"Medium","gaps":["Mechanism of Rab8a activation by TALPID3 unresolved","Single lab"]},{"year":2019,"claim":"Placed TALPID3 within a CEP120-C2CD3 distal centriole module, showing CEP120 recruits both to centriole distal ends for appendage assembly and cilia formation.","evidence":"Co-IP, CRISPR CEP120 knockout in RPE1 cells, and disease-mutant binding assay","pmids":["30988386"],"confidence":"Medium","gaps":["Single lab","Order of assembly among CEP120/C2CD3/TALPID3 not fully defined"]},{"year":2020,"claim":"Defined a cilia-gating function and a neurodevelopmental role: TALPID3 forms an ANKRD26-FBF1 complex recruiting FBF1 to transition fibers, and associates with Ninein to organize microtubules and maintain radial glial integrity.","evidence":"C. elegans forward screen, epistasis, and Co-IP for the FBF1 complex; Co-IP, silencing, and live imaging for Ninein and radial glia","pmids":["32366837","33326788"],"confidence":"High","gaps":["How TALPID3 selects transition fiber vs. distal centriole functions unclear","Ninein interaction from single lab"]},{"year":2023,"claim":"Revealed a tissue-specific requirement in muscle stem cell self-renewal where the regeneration defect is rescued by Wnt rather than Hedgehog activation, indicating context-dependent pathway coupling.","evidence":"Conditional MuSC deletion, scRNA-seq, and pharmacological Wnt vs. Smo rescue in mice","pmids":["37925530"],"confidence":"Medium","gaps":["Mechanism linking TALPID3/cilia to Wnt regulation undefined","Single lab"]},{"year":null,"claim":"How TALPID3 mechanistically activates Rab8a and integrates its distal-centriole, transition-fiber, PKA-scaffolding, and Wnt-related roles into a unified molecular function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the TALPID3 distal-end ring","Direct biochemical activity of TALPID3 not defined","Mechanism coupling ciliary function to Wnt signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5,7,13]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,2,11,13]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,2,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,8,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,13,14]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,12]}],"complexes":["CP110 complex","TALPID3-ANKRD26-FBF1 transition fiber complex","CEP120-C2CD3-TALPID3 distal centriole module"],"partners":["CP110","CEP120","C2CD3","ANKRD26","FBF1","PRKAR2B","NIN","RAB8A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BVV6","full_name":"Protein TALPID3","aliases":[],"length_aa":1533,"mass_kda":169.3,"function":"Required for ciliogenesis and sonic hedgehog/SHH signaling. Required for the centrosomal recruitment of RAB8A and for the targeting of centriole satellite proteins to centrosomes such as of PCM1. May play a role in early ciliogenesis in the disappearance of centriolar satellites that preceeds ciliary vesicle formation (PubMed:24421332). Involved in regulation of cell intracellular organization. Involved in regulation of cell polarity (By similarity). Required for asymmetrical localization of CEP120 to daughter centrioles (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Photoreceptor inner segment; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q9BVV6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIAA0586","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIAA0586","total_profiled":1310},"omim":[{"mim_id":"616546","title":"SHORT-RIB THORACIC DYSPLASIA 14 WITH POLYDACTYLY; SRTD14","url":"https://www.omim.org/entry/616546"},{"mim_id":"616490","title":"JOUBERT SYNDROME 23; JBTS23","url":"https://www.omim.org/entry/616490"},{"mim_id":"610178","title":"KIAA0586 GENE; KIAA0586","url":"https://www.omim.org/entry/610178"},{"mim_id":"213300","title":"JOUBERT SYNDROME 1; JBTS1","url":"https://www.omim.org/entry/213300"},{"mim_id":"208500","title":"SHORT-RIB THORACIC DYSPLASIA 1 WITH OR WITHOUT POLYDACTYLY; SRTD1","url":"https://www.omim.org/entry/208500"}],"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/KIAA0586"},"hgnc":{"alias_symbol":["Talpid3","JBTS23"],"prev_symbol":[]},"alphafold":{"accession":"Q9BVV6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVV6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVV6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVV6-F1-predicted_aligned_error_v6.png","plddt_mean":47.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIAA0586","jax_strain_url":"https://www.jax.org/strain/search?query=KIAA0586"},"sequence":{"accession":"Q9BVV6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BVV6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BVV6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVV6"}},"corpus_meta":[{"pmid":"19144723","id":"PMC_19144723","title":"The Talpid3 gene (KIAA0586) encodes a centrosomal protein that is essential for primary cilia 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The protein localizes to the cytoplasm.\",\n      \"method\": \"Genetic rescue experiments in chicken embryos, Gli3 processing assays, subcellular localization studies in mutant vs. wild-type cells\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct rescue experiments establishing causal link, multiple embryonic regions analyzed, replicated in subsequent studies\",\n      \"pmids\": [\"16702409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Talpid3/KIAA0586 is a centrosomal protein essential for primary cilia formation; in talpid3 mutant cells, basal bodies mature and dock is attempted but fail to dock with the apical membrane, are misorientated, and almost completely lack ciliary axonemes. A conserved coiled-coil domain region (exons 11-12) is required to rescue primary cilia formation and is sufficient for centrosomal localization. Marked changes in actin organisation were also detected in mutant cells.\",\n      \"method\": \"Immunofluorescence with anti-Talpid3 antibody, electron microscopy (ultrastructural analysis), rescue experiments with deletion constructs in talpid3 mutant embryos, antibody detection of Talpid3 at centrosome\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ultrastructural EM, domain mapping with rescue, antibody localization, replicated across multiple studies\",\n      \"pmids\": [\"19144723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Talpid3 assembles a ring-like structure at the extreme distal end of centrioles and is a component of a CP110-containing protein complex. Ablation of Talpid3 causes aberrant distribution of centriolar satellites and mislocalization of Rab8a. Expression of activated Rab8a suppresses cilia assembly defects provoked by Talpid3 depletion, indicating Talpid3 affects cilia formation through Rab8a recruitment and/or activation. Talpid3 is also required for centriolar satellite dispersal preceding ciliary vesicle formation.\",\n      \"method\": \"Co-immunoprecipitation to identify CP110 complex, siRNA depletion, immunofluorescence, ultrastructural analysis, rescue with activated Rab8a\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA with defined phenotype, EM, functional rescue with activated Rab8a, multiple orthogonal methods\",\n      \"pmids\": [\"24421332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PCM1 tethers the E3 ubiquitin ligase Mindbomb1 (Mib1) to centriolar satellites. In the absence of PCM1, Mib1 destabilizes Talpid3 through poly-ubiquitylation, suppressing cilium assembly. Loss of PCM1 blocks ciliogenesis by abrogating recruitment of ciliary vesicles associated with Talpid3-binding protein Rab8; this can be reversed by inactivating Mib1. Thus Mib1-mediated poly-ubiquitylation is a post-translational regulatory mechanism controlling Talpid3 abundance.\",\n      \"method\": \"PCM1 gene deletion in human cells, rescue with PCM1 domain constructs, ubiquitylation assays, Mib1 inactivation rescue experiments, immunofluorescence\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene deletion, ubiquitylation assay, multiple domain rescue constructs, epistasis via Mib1 inactivation, multiple orthogonal methods\",\n      \"pmids\": [\"27146717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Centrosomal protein Cep120 is asymmetrically localized to the daughter centriole through its physical interaction with Talpid3 (Ta3), another centrosomal protein.\",\n      \"method\": \"Co-immunoprecipitation (pulldown), immunofluorescence localization in cerebellar granule neuron progenitors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP demonstrating interaction, confirmed by localization studies, single lab\",\n      \"pmids\": [\"25251415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Talpid3 interacts with PKA regulatory subunit PKARIIβ at centrioles; the centriolar localization region maps to the N-terminal region and the PKA-binding region to the C-terminal region of Ta3. Talpid3 mutation results in failure of PKARIIβ to localize at centrioles, leading to reduced Gli2 and Gli3 phosphorylation and impaired processing. Hedgehog signaling inhibits Gli2 and Gli3 phosphorylation by PKA in cilia.\",\n      \"method\": \"Co-immunoprecipitation (Talpid3–PKARIIβ interaction), immunofluorescence colocalization, domain mapping with N- and C-terminal constructs, phosphorylation assays in mutant vs. wild-type cells, Gli processing western blot\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus domain mapping plus functional phosphorylation assays, single lab with multiple methods\",\n      \"pmids\": [\"28673820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CEP120 interacts with C2CD3 and Talpid3; loss of CEP120 impairs recruitment of C2CD3 and Talpid3 to the distal ends of centrioles, leading to defects in centriole appendage assembly and cilia formation. A disease-associated CEP120 mutant (I975S) has low affinity for C2CD3 binding and perturbs cilia assembly.\",\n      \"method\": \"Co-immunoprecipitation (CEP120 with C2CD3 and Talpid3), CRISPR/Cas9 CEP120 knockout in RPE1 cells, immunofluorescence, disease-mutant binding assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, CRISPR KO with defined phenotype, disease-mutant functional analysis, single lab\",\n      \"pmids\": [\"30988386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TALPID3 and ANKRD26 form a protein complex with cilia-gating component FBF1 at transition fibers. Co-depletion of TALPID3 and ANKRD26 specifically impairs recruitment of FBF1 to transition fibers, disrupting cilia gating. This function is conserved in both C. elegans (TALP-3/ANKR-26/DYF-19) and mammalian cells (TALPID3/ANKRD26/FBF1).\",\n      \"method\": \"Forward genetic screen in C. elegans, genetic epistasis (co-depletion), co-immunoprecipitation (complex formation), immunofluorescence (FBF1 localization at transition fibers) in both C. elegans and mammalian cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen, epistasis, Co-IP, localization assay, validated in two organisms with multiple orthogonal methods\",\n      \"pmids\": [\"32366837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In zebrafish talpid3 mutants (MZta3), primary and motile cilia are absent and Hedgehog signaling is aberrant. GFP-tagged Gli2a localizes to basal bodies in the absence of primary cilia, and Gli2a protein is aberrantly processed in MZta3 embryos as shown by western blot, demonstrating a cilia-dependent mechanism for Gli processing.\",\n      \"method\": \"Zinc-finger nuclease mutagenesis, GFP-Gli2a localization by live imaging, western blot for Gli2a processing, germline replacement for maternal depletion\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — targeted mutagenesis, protein localization, biochemical processing assay, multiple orthogonal methods in a vertebrate model\",\n      \"pmids\": [\"22028029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Deletion of conserved exons 11-12 of KIAA0586/Talpid3 in mice results in embryos lacking primary cilia with face, neural tube, and left/right asymmetry defects. Conditional deletion in limb mesenchyme causes polydactyly and brachydactyly attributable to abnormal Sonic hedgehog and Indian hedgehog signaling. Talpid3 mutant mouse cells migrate more slowly than wild-type cells.\",\n      \"method\": \"Constitutive and conditional gene deletion in mice, primary cilia immunofluorescence, cell migration assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive and conditional KO with defined cellular and tissue phenotypes, multiple readouts, replicated in two vertebrate models\",\n      \"pmids\": [\"21750036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TALPID3 is required for centrosomal migration to the apical surface prior to ciliogenesis in ependymal multiciliate cells; talpid3 ependymal cells develop multiple centrosomes but these fail to migrate to the apical cell surface, though axoneme formation was sometimes observed. TALPID3 is not directly required for de novo centriologenesis, multiciliated fate, or axoneme formation.\",\n      \"method\": \"Immunofluorescence for centrosome markers, electron microscopy of ependymal cells, analysis of FOXJ1 expression in talpid3 vs. wild-type chicken embryos\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EM plus immunofluorescence, single lab, two orthogonal methods establishing subcellular mechanism\",\n      \"pmids\": [\"23613203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIAA0586 protein localizes to the basal body in human and mouse photoreceptors, and also in pericentriolar locations. Loss of TALPID3 function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites.\",\n      \"method\": \"Immunofluorescence localization in human and mouse photoreceptors, animal model analysis (chicken and mouse), homozygosity mapping and whole-exome sequencing identifying splice site mutation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct immunofluorescence localization in photoreceptors, animal model phenotypic analysis, single lab\",\n      \"pmids\": [\"26386247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In zebrafish talpid3 mutant photoreceptors, the majority of photoreceptors lack outer segment development due to defects in basal body positioning and docking at the apical cell surface. Overexpression of constitutively active Rab8a rescues outer segment formation in talpid3 mutant photoreceptors, indicating Ta3's role in early ciliogenesis lies upstream of Rab8a activation in photoreceptors.\",\n      \"method\": \"Zebrafish talpid3 mutant analysis, immunofluorescence for Rab8a localization, constitutively active Rab8a rescue experiment, electroretinograms for functional assessment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant, functional rescue with constitutively active Rab8a, epistasis established, single lab\",\n      \"pmids\": [\"29396404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Talpid3 is localized to the mother centriole of radial glial cells (RGCs) and is required for their apical mitosis. Talpid3 associates with Ninein to regulate microtubule organization and maintain the integrity of adherens junctions to anchor RGCs. Genetic silencing of Talpid3 causes abnormal RGC delamination and impairs interkinetic nuclear migration in cell-autonomous and non-autonomous manners.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation (Talpid3-Ninein interaction), genetic silencing (shRNA/conditional KO), adherens junction integrity assays, live imaging of nuclear migration\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for Ninein interaction, KO with defined cellular phenotype, localization studies, single lab\",\n      \"pmids\": [\"33326788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional deletion of Talpid3 in muscle stem cells (MuSC) impairs muscle regeneration and self-renewal after injury. Single-cell transcriptomics identified deregulation of Hh and Wnt signaling pathways in TA3-depleted MuSC progeny. Pharmacological activation of Wnt (but not Smoothened/Hh pathway activation) restores muscle regeneration in TA3 conditional KO mice.\",\n      \"method\": \"Tamoxifen-inducible conditional deletion in MuSC, cytotoxic injury model, single-cell transcriptomics, pharmacological rescue with Wnt activator and Smo agonist (purmorphamine)\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, scRNA-seq pathway analysis, pharmacological epistasis rescue, single lab\",\n      \"pmids\": [\"37925530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cells derived from patients with biallelic KIAA0586 mutations show defective ciliogenesis and abnormal response to SHH-signaling activation. Centriolar maturation appeared unaffected in mutant cells, but an abnormal extended pattern of CEP290 (a centriolar satellite protein) was observed. Rescue of cilia defect with full-length wild-type KIAA0586 confirmed the causal link. Gli3 processing is abnormal in mutant cells.\",\n      \"method\": \"Patient-derived fibroblast ciliogenesis assay, SHH stimulation assay, rescue with wild-type KIAA0586, immunofluorescence for CEP290 pattern, Gli3 processing western blot\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment, multiple cellular assays, patient-derived cells, single lab\",\n      \"pmids\": [\"26166481\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIAA0586/TALPID3 is a centrosomal protein that localizes to the distal end of centrioles (mother centriole/basal body) where it is required for basal body docking to the apical membrane and primary cilia formation; it functions in Hedgehog signaling by facilitating PKARIIβ-dependent phosphorylation of Gli2/Gli3 at centrioles and enabling Gli activator/repressor processing, acts upstream of Rab8a activation to promote ciliary vesicle formation, works with ANKRD26 to recruit FBF1 to transition fibers for cilia gating, interacts with CP110, CEP120, C2CD3, and Ninein at centrioles, and is subject to Mib1-mediated poly-ubiquitylation that is restrained by PCM1 tethering at centriolar satellites.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIAA0586/TALPID3 is a centrosomal protein that assembles a ring-like structure at the distal end of centrioles (mother centriole/basal body) and is essential for primary cilia formation and Hedgehog signal transduction [#1, #2]. A conserved coiled-coil region encoded by exons 11-12 is required for centrosomal localization and sufficient to rescue ciliogenesis [#1], and deletion of these exons in mice abolishes primary cilia and produces hallmark Hedgehog-dependent developmental defects in face, neural tube, left/right asymmetry, and digit number [#9]. Mechanistically, TALPID3 governs basal body docking to the apical membrane: mutant basal bodies mature but fail to dock and lack ciliary axonemes, and TALPID3 acts upstream of Rab8a, with activated Rab8a rescuing the cilia and photoreceptor outer-segment defects of TALPID3-deficient cells [#2, #12]. It is a component of a CP110-containing complex and controls centriolar satellite dispersal that precedes ciliary vesicle formation [#2]. Through its interaction with the PKA regulatory subunit PKARII\\u03b2 at centrioles, TALPID3 enables PKA-dependent phosphorylation and proper processing of Gli2/Gli3 into activator and repressor forms, providing a cilium-based mechanism for graded Hedgehog output [#0, #5, #8]. TALPID3 further interacts with CEP120 and C2CD3 for distal centriole/appendage assembly [#6], with ANKRD26 to recruit FBF1 to transition fibers for cilia gating [#7], and with Ninein to organize microtubules and maintain adherens junctions during neural progenitor mitosis [#13]. Its abundance is restrained by Mib1-mediated poly-ubiquitylation, which is held in check by PCM1 tethering at centriolar satellites [#3]. Biallelic KIAA0586 mutations cause a human ciliopathy, with patient cells showing defective ciliogenesis, abnormal SHH response, and aberrant Gli3 processing rescued by wild-type KIAA0586 [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that TALPID3 is required for both activator and repressor functions of the Hedgehog pathway by acting on Gli3 processing, placing it at a central regulatory node of Hh output.\",\n      \"evidence\": \"Genetic rescue and Gli3 processing assays in chicken embryos\",\n      \"pmids\": [\"16702409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic localization defined but subcellular site of action not yet resolved\", \"Molecular partners mediating Gli processing unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified TALPID3 as a centrosomal protein required for basal body docking to the apical membrane and cilia formation, localizing the Hh defect to a ciliogenesis step.\",\n      \"evidence\": \"Anti-Talpid3 immunofluorescence, EM, and exon 11-12 deletion rescue in talpid3 mutant chicken embryos\",\n      \"pmids\": [\"19144723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of docking not defined\", \"Interacting partners at the distal centriole unidentified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated in zebrafish and mouse that TALPID3 loss abolishes cilia and disrupts Gli processing and Hh-dependent patterning, confirming a conserved vertebrate cilia-dependent mechanism.\",\n      \"evidence\": \"Zinc-finger nuclease and gene-deletion mutants with Gli2a localization/processing and limb patterning analysis\",\n      \"pmids\": [\"22028029\", \"21750036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical step linking TALPID3 to Gli phosphorylation\", \"Cell migration phenotype mechanism unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed TALPID3 is required for centrosome migration to the apical surface but not for de novo centriologenesis or axoneme formation, distinguishing its docking role from centriole biogenesis.\",\n      \"evidence\": \"Immunofluorescence and EM of talpid3 ependymal multiciliate cells\",\n      \"pmids\": [\"23613203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular basis of migration defect not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the centriolar architecture and trafficking mechanism: TALPID3 forms a distal-end ring within a CP110 complex and controls satellite dispersal and Rab8a recruitment to drive ciliary vesicle formation.\",\n      \"evidence\": \"Co-IP, siRNA depletion, EM, and activated-Rab8a rescue; separate Co-IP mapping Cep120 to daughter centriole via Talpid3\",\n      \"pmids\": [\"24421332\", \"25251415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TALPID3 activates/recruits Rab8a mechanistically unclear\", \"Cep120 interaction from single Co-IP\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked KIAA0586 to a human ciliopathy and confirmed causality, showing patient cells have defective ciliogenesis, abnormal SHH response, and aberrant Gli3 processing rescued by wild-type protein.\",\n      \"evidence\": \"Patient fibroblast ciliogenesis/SHH assays, CEP290 pattern, Gli3 western, and wild-type rescue; photoreceptor basal body localization\",\n      \"pmids\": [\"26166481\", \"26386247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-phenotype correlations not established\", \"Single lab for localization data\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered post-translational control of TALPID3 abundance: PCM1 tethers Mib1 at satellites to prevent Mib1-mediated poly-ubiquitylation and degradation of TALPID3, gating ciliogenesis.\",\n      \"evidence\": \"PCM1 deletion, ubiquitylation assays, domain rescue, and Mib1-inactivation epistasis in human cells\",\n      \"pmids\": [\"27146717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitylation sites on TALPID3 not mapped\", \"Signals triggering Mib1 activity unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a molecular mechanism for Gli processing by showing TALPID3 recruits PKARII\\u03b2 to centrioles via its C-terminus to enable PKA-dependent Gli2/Gli3 phosphorylation.\",\n      \"evidence\": \"Co-IP, domain mapping with N-/C-terminal constructs, and phosphorylation/Gli processing assays\",\n      \"pmids\": [\"28673820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct kinase-substrate relationship at centrioles not reconstituted\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the Rab8a-upstream model to photoreceptors, showing TALPID3 enables outer-segment formation through basal body docking upstream of Rab8a activation.\",\n      \"evidence\": \"Zebrafish talpid3 mutant analysis with constitutively active Rab8a rescue and electroretinograms\",\n      \"pmids\": [\"29396404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Rab8a activation by TALPID3 unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed TALPID3 within a CEP120-C2CD3 distal centriole module, showing CEP120 recruits both to centriole distal ends for appendage assembly and cilia formation.\",\n      \"evidence\": \"Co-IP, CRISPR CEP120 knockout in RPE1 cells, and disease-mutant binding assay\",\n      \"pmids\": [\"30988386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Order of assembly among CEP120/C2CD3/TALPID3 not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a cilia-gating function and a neurodevelopmental role: TALPID3 forms an ANKRD26-FBF1 complex recruiting FBF1 to transition fibers, and associates with Ninein to organize microtubules and maintain radial glial integrity.\",\n      \"evidence\": \"C. elegans forward screen, epistasis, and Co-IP for the FBF1 complex; Co-IP, silencing, and live imaging for Ninein and radial glia\",\n      \"pmids\": [\"32366837\", \"33326788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TALPID3 selects transition fiber vs. distal centriole functions unclear\", \"Ninein interaction from single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a tissue-specific requirement in muscle stem cell self-renewal where the regeneration defect is rescued by Wnt rather than Hedgehog activation, indicating context-dependent pathway coupling.\",\n      \"evidence\": \"Conditional MuSC deletion, scRNA-seq, and pharmacological Wnt vs. Smo rescue in mice\",\n      \"pmids\": [\"37925530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking TALPID3/cilia to Wnt regulation undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TALPID3 mechanistically activates Rab8a and integrates its distal-centriole, transition-fiber, PKA-scaffolding, and Wnt-related roles into a unified molecular function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the TALPID3 distal-end ring\", \"Direct biochemical activity of TALPID3 not defined\", \"Mechanism coupling ciliary function to Wnt signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5, 7, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 2, 11, 13]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"GO:0005813\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 8, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 13, 14]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"complexes\": [\n      \"CP110 complex\",\n      \"TALPID3-ANKRD26-FBF1 transition fiber complex\",\n      \"CEP120-C2CD3-TALPID3 distal centriole module\"\n    ],\n    \"partners\": [\n      \"CP110\",\n      \"CEP120\",\n      \"C2CD3\",\n      \"ANKRD26\",\n      \"FBF1\",\n      \"PRKAR2B\",\n      \"NIN\",\n      \"RAB8A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}