{"gene":"INVS","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2003,"finding":"Inversin (INVS/NPHP2) physically interacts with nephrocystin (NPHP1 product), and both proteins colocalize with beta-tubulin to primary cilia of renal tubular cells; knockdown of invs in zebrafish produces PKD-like renal cysts and randomizes heart looping.","method":"Co-immunoprecipitation (molecular interaction), immunofluorescence colocalization, zebrafish morpholino knockdown","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus colocalization plus in vivo loss-of-function, independently foundational paper with multiple orthogonal methods","pmids":["12872123"],"is_preprint":false},{"year":2004,"finding":"Inversin forms a stable complex with tubulin in renal epithelial cells, localizes to ciliary, random, and polarized microtubule pools, is recruited to mitotic spindle fibers during cell division, and its association with tubulin is dependent on microtubule polymerization (dissociates after colcemid-mediated depolymerization).","method":"Co-immunoprecipitation, co-pelleting assay, immunofluorescence microscopy, microtubule depolymerization/stabilization pharmacology","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus co-pelleting plus pharmacological perturbation, single lab","pmids":["15213257"],"is_preprint":false},{"year":2004,"finding":"Alternative splicing of INVS produces multiple transcript isoforms with skipping of exons 5, 11, or 13, causing loss of specific protein motifs including ankyrin repeats, IQ domains, destruction boxes, and nuclear localization signals.","method":"Northern blot, RT-PCR, sequence analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple molecular biology methods in single lab establishing transcript diversity","pmids":["15533716"],"is_preprint":false},{"year":2005,"finding":"Inversin localizes to distal tubules in the kidney and to multiple extrarenal tissues including hepatic bile ducts, pancreatic cells, intestinal epithelium, bronchiolar epithelium, cerebellar Purkinje cell dendrites, retinal neural cells, and spermatocytes/spermatids.","method":"Laser confocal microscopy of paraffin-embedded murine tissue sections with immunostaining","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — systematic immunolocalization across multiple tissues in single lab","pmids":["16007506"],"is_preprint":false},{"year":2012,"finding":"C. elegans NPHP-2 (inversin ortholog) localizes to the middle segment (Inversin compartment) of sensory cilia and genetically interacts with nphp-1, nphp-4, and MKS pathway genes (mks-1, mks-3, mks-6, mksr-1, mksr-2) to control cilia formation and placement; NPHP-2 is not required for localization of NPHP/MKS transition zone proteins or for intraflagellar transport.","method":"Fluorescent protein tagging/live imaging, genetic epistasis, double-mutant analysis in C. elegans","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization imaging plus systematic genetic epistasis with multiple gene combinations establishing pathway position","pmids":["22393243"],"is_preprint":false},{"year":2012,"finding":"NEK8 (NPHP9) acts downstream of Inv/NPHP2 in zebrafish pronephros morphogenesis and left-right axis establishment; nek8 mRNA rescues inv morphant phenotypes, but inv mRNA cannot rescue nek8 morphant phenotypes; simultaneous knockdown of nek8 and inv synergistically worsens defects.","method":"Zebrafish morpholino knockdown, mRNA rescue epistasis experiments","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by mRNA rescue in vivo, single lab, clear directional relationship established","pmids":["22687244"],"is_preprint":false},{"year":2013,"finding":"ANKS6 connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3 in a proximal cilium module; the oxygen sensor HIF1AN hydroxylates both ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 complex.","method":"Protein interaction mapping, co-immunoprecipitation, knockdown in zebrafish and Xenopus, identification of HIF1AN as hydroxylase","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — post-translational modification identified with writer enzyme, complex composition determined, multiple model organisms, multiple methods","pmids":["23793029"],"is_preprint":false},{"year":2013,"finding":"NPHP2/Inversin directly interacts with Aurora A kinase, inhibits Aurora A phosphorylation/activation and reduces its kinase activity in vitro, thereby interfering with HDAC6-mediated cilia disassembly; NPHP2 knockdown in MDCK cells reduces cilia number, and Aurora A/HDAC inhibitors rescue this ciliogenesis defect.","method":"Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown in MDCK cells, pharmacological rescue","journal":"Nephrology, dialysis, transplantation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus Co-IP plus cellular KD with pharmacological rescue, single lab with multiple orthogonal methods","pmids":["24026243"],"is_preprint":false},{"year":2014,"finding":"The EF hand (calcium-binding) domain of NPHP-2 (C. elegans inversin) is required for its targeting to the Inversin compartment of cilia; the InvC (NPHP-2 domain) and doublet region (ARL-13 domain) are distinct ciliary compartments that interact to regulate ciliogenesis via cilia placement, microtubule ultrastructure, and protein localization.","method":"Fluorescent protein tagging, domain deletion/mutation analysis, live imaging in C. elegans, genetic epistasis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis plus live localization imaging plus genetic interaction mapping, single lab","pmids":["25501555"],"is_preprint":false},{"year":2015,"finding":"The Inversin compartment length corresponds to the microtubule doublet region of renal primary cilia; in multiciliated tracheal cells of inv mutant mice, Inv protein is retained at the basal body rather than accumulating in the ciliary Inv compartment, and inv mutant respiratory cilia show rootlet malformation, reduced beating frequency, and reduced beating angle.","method":"Electron microscopy, immunofluorescence, ciliary beat frequency measurement in inv mutant mouse","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ultrastructural analysis plus functional ciliary measurements in defined mutant model, single lab","pmids":["26615802"],"is_preprint":false},{"year":2014,"finding":"A truncating mutation in the IQ1 domain of inversin causes mislocalization of the mutant protein: in control fibroblasts inversin is present in the ciliary axoneme and basal body, whereas mutant inversin is detected only at the basal body and not in the ciliary axoneme.","method":"Immunofluorescence localization in patient-derived fibroblasts, exome sequencing","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment in patient cells with clear functional consequence (loss of axonemal targeting), single lab","pmids":["24677454"],"is_preprint":false},{"year":2010,"finding":"INVS mutation deleting the C-terminus of inversin is associated with abnormal expression of β-catenin and Dishevelled-1 in renal tubular cells, supporting up-regulated canonical Wnt pathway activity.","method":"Immunohistochemistry/protein expression analysis in patient kidney tissue","journal":"Nephrology, dialysis, transplantation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method protein expression analysis in patient tissue, no direct mechanistic manipulation","pmids":["20798123"],"is_preprint":false},{"year":2011,"finding":"In inv/inv (NPHP2) mouse kidneys, p38 MAPK phosphorylation is elevated; pharmacological inhibition of p38 MAPK reduces renal fibrosis and extracellular matrix gene expression without preventing cyst expansion; MEK/ERK inhibition reduces both cyst expansion and fibrosis independently of p38 MAPK, indicating p38 MAPK and ERK pathways independently regulate different aspects of the inv mutant renal phenotype.","method":"Pharmacological inhibition (FR167653 p38 inhibitor; MEK inhibitor) in inv/inv mouse model, western blot, histology, qPCR","journal":"Nephrology, dialysis, transplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of two pathways with distinct readouts in defined mouse model, single lab","pmids":["22076433"],"is_preprint":false},{"year":2023,"finding":"Epithelial-specific knockout of Invs in mice causes renal cyst formation and severe stromal fibrosis, while stromal-specific Invs deletion produces no observable phenotype, establishing an epithelial-cell-autonomous role for Invs and a role for epithelial-stromal crosstalk; concomitant genetic removal of cilia partially suppresses the Invs mutant kidney phenotype, indicating that cilia mediate at least part of Invs function in vivo; valproic acid (HDAC inhibitor) reduces cyst burden and cell proliferation.","method":"Cell-type-specific conditional knockout (Cre-lox), genetic cilia removal, pharmacological treatment (VPA), histology, kidney function assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional knockouts with defined cellular readouts plus genetic epistasis with cilia removal, replicated internally with orthogonal approaches","pmids":["36920028"],"is_preprint":false},{"year":2023,"finding":"NPHP2/Inversin cooperates with Vangl2 and NPHP1 in planar cell polarity (PCP) signaling during zebrafish cloaca formation; simultaneous depletion of nphp1 and vangl2 in invssa36157 mutants markedly increases cloaca malformations associated with reduced apoptotic activity, while pronephric cell migration and cellular fate are unaffected.","method":"Zebrafish mutant line (invssa36157 stop codon), morpholino knockdown, time-lapse imaging, in situ hybridization, apoptosis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in defined zebrafish mutant with live imaging and molecular markers, single lab","pmids":["37352572"],"is_preprint":false}],"current_model":"Inversin (INVS/NPHP2) is a ciliary scaffold protein that localizes to the proximal 'Inversin compartment' of primary cilia via its EF-hand domain, where it forms a molecular complex with nephrocystin (NPHP1) and beta-tubulin; it is also hydroxylated by HIF1AN and incorporated into an ANKS6-INVS-NPHP3-NEK8 module at the proximal cilium; mechanistically, inversin inhibits Aurora A kinase activity to suppress HDAC6-mediated cilia disassembly, associates with microtubules throughout the cell cycle (including mitotic spindles), participates in planar cell polarity signaling through Dishevelled/Vangl2, and its loss in renal epithelial cells drives cyst formation and stromal fibrosis through cilia-dependent mechanisms and activation of p38 MAPK and ERK pathways."},"narrative":{"mechanistic_narrative":"Inversin (INVS/NPHP2) is a ciliary scaffold protein that organizes a proximal compartment of primary and motile cilia and links ciliary architecture to renal epithelial homeostasis [PMID:12872123, PMID:22393243]. It binds tubulin and associates with ciliary, cytoplasmic, and mitotic-spindle microtubule pools in a polymerization-dependent manner [PMID:15213257], and its EF-hand domain targets it to the microtubule-doublet 'Inversin compartment' of the cilium, while loss of distal motifs by mutation restricts the protein to the basal body and abolishes axonemal targeting [PMID:25501555, PMID:26615802, PMID:24677454]. Within this compartment, inversin nucleates a proximal-cilium module in which ANKS6 bridges NEK8 to INVS and NPHP3, a complex whose composition is tuned by HIF1AN-mediated hydroxylation of both ANKS6 and INVS, placing the assembly downstream of oxygen sensing; NEK8 acts genetically downstream of inversin in left-right axis and pronephros morphogenesis [PMID:22687244, PMID:23793029]. Inversin also restrains ciliary turnover by directly binding and inhibiting Aurora A kinase, thereby blocking HDAC6-dependent cilia disassembly [PMID:24026243]. Functionally, inversin participates in planar cell polarity signaling together with NPHP1 and Vangl2 [PMID:37352572], and its epithelial-cell-autonomous loss drives renal cyst formation and stromal fibrosis through cilia-dependent mechanisms, with the fibrotic and cystic components separable into p38 MAPK- and MEK/ERK-regulated arms [PMID:22076433, PMID:36920028]. A truncating IQ-domain mutation linking INVS to human cystic kidney disease produces the same axonemal-targeting defect seen in disease fibroblasts [PMID:24677454].","teleology":[{"year":2003,"claim":"Established inversin as a ciliary protein physically partnered with nephrocystin, connecting the gene to nephronophthisis biology and laterality determination rather than leaving it an orphan locus.","evidence":"Co-IP, immunofluorescence colocalization with beta-tubulin, and zebrafish morpholino knockdown","pmids":["12872123"],"confidence":"High","gaps":["Did not define the molecular activity of inversin within the cilium","Did not map the interaction interface with NPHP1"]},{"year":2004,"claim":"Showed inversin is a microtubule-associated protein spanning ciliary, cytoplasmic, and mitotic-spindle tubulin pools, framing it as a cytoskeletal scaffold rather than a cilium-exclusive factor.","evidence":"Co-IP, co-pelleting assay, immunofluorescence, and microtubule depolymerization pharmacology in renal epithelial cells","pmids":["15213257"],"confidence":"Medium","gaps":["Did not identify the inversin domain mediating tubulin binding","Functional consequence of spindle localization not tested"]},{"year":2004,"claim":"Defined transcript diversity that can selectively delete functional motifs, raising the possibility of isoform-specific inversin activities.","evidence":"Northern blot, RT-PCR, and sequence analysis of INVS splice variants","pmids":["15533716"],"confidence":"Medium","gaps":["Functional differences between isoforms not characterized","Tissue distribution of each isoform not resolved"]},{"year":2005,"claim":"Mapped inversin expression across renal and many extrarenal tissues, predicting a broad physiological footprint beyond the kidney.","evidence":"Confocal immunostaining of murine tissue sections","pmids":["16007506"],"confidence":"Medium","gaps":["Did not test function in any extrarenal tissue","Subcellular localization within each tissue not resolved"]},{"year":2010,"claim":"Linked C-terminal inversin loss to dysregulated canonical Wnt readouts in patient kidney, hinting at a Wnt-modulating role.","evidence":"Immunohistochemistry of beta-catenin and Dishevelled-1 in patient kidney tissue","pmids":["20798123"],"confidence":"Low","gaps":["Single-method protein expression analysis with no mechanistic manipulation","Cannot distinguish direct effect from secondary cystic remodeling"]},{"year":2011,"claim":"Separated the cystic and fibrotic components of inversin loss into distinct kinase pathways, showing the renal phenotype is not a single downstream cascade.","evidence":"Pharmacological p38 and MEK/ERK inhibition in inv/inv mice with western blot, histology, qPCR","pmids":["22076433"],"confidence":"Medium","gaps":["How inversin loss activates p38 and ERK is unknown","Cell type driving each signaling arm not defined"]},{"year":2012,"claim":"Positioned inversin within the ciliary gene network by genetic epistasis, defining its compartment and its relationships to NPHP/MKS transition-zone pathways.","evidence":"Live imaging and double-mutant epistasis with nphp/mks genes in C. elegans; mRNA-rescue epistasis placing NEK8 downstream of inv in zebrafish","pmids":["22393243","22687244"],"confidence":"High","gaps":["Biochemical basis of the directional inv→NEK8 relationship not resolved","Inversin's effect on transition-zone protein function vs localization not separated"]},{"year":2013,"claim":"Defined the inversin module's composition and an oxygen-sensing input, and identified a direct enzymatic target through which inversin controls cilia stability.","evidence":"Interaction mapping/Co-IP with HIF1AN hydroxylation analysis (zebrafish/Xenopus); in vitro Aurora A kinase assay, Co-IP, MDCK siRNA knockdown with pharmacological rescue","pmids":["23793029","24026243"],"confidence":"High","gaps":["Functional consequence of INVS hydroxylation on module activity not fully defined","How Aurora A inhibition is spatially restricted to the cilium not established"]},{"year":2014,"claim":"Pinpointed the EF-hand and IQ domains as determinants of ciliary targeting and linked an IQ-domain truncation to human disease via loss of axonemal localization.","evidence":"Domain deletion/mutation with live imaging in C. elegans; immunofluorescence in patient-derived fibroblasts with exome sequencing","pmids":["25501555","24677454"],"confidence":"Medium","gaps":["Targeting receptor recognizing the EF-hand not identified","Whether calcium binding modulates targeting not tested"]},{"year":2015,"claim":"Connected the Inversin compartment to a defined ultrastructural region and showed inversin is required for normal motile-cilia architecture and beating, extending its role beyond signaling cilia.","evidence":"Electron microscopy, immunofluorescence, and ciliary beat frequency measurement in inv mutant mice","pmids":["26615802"],"confidence":"Medium","gaps":["Mechanism linking inversin loss to rootlet malformation unknown","Whether motile-cilia defects contribute to organismal phenotype not addressed"]},{"year":2023,"claim":"Established that inversin acts cell-autonomously in renal epithelium through cilia-dependent mechanisms and operates in planar cell polarity with NPHP1 and Vangl2, integrating its scaffold, signaling, and disease roles.","evidence":"Cell-type-specific conditional knockouts with genetic cilia removal and VPA treatment in mice; zebrafish invs mutant epistasis with nphp1 and vangl2 with live imaging and apoptosis assays","pmids":["36920028","37352572"],"confidence":"High","gaps":["Nature of the epithelial-stromal crosstalk driving fibrosis not defined","Molecular link between inversin and PCP-associated apoptosis unresolved"]},{"year":null,"claim":"How the molecular activities of inversin — tubulin scaffolding, Aurora A inhibition, hydroxylation-tuned module assembly, and PCP signaling — are integrated into a single mechanism that prevents renal cyst formation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking the ciliary module to downstream p38/ERK and Wnt/PCP outputs","Direct catalytic or structural activity of inversin itself unproven","Isoform-specific contributions to function untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,4,8,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[9,10]}],"pathway":[],"complexes":["ANKS6-INVS-NPHP3-NEK8 proximal cilium module"],"partners":["NPHP1","ANKS6","NPHP3","NEK8","HIF1AN","AURKA","VANGL2","TUBB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y283","full_name":"Inversin","aliases":["Inversion of embryo turning homolog","Nephrocystin-2"],"length_aa":1065,"mass_kda":117.8,"function":"Required for normal renal development and establishment of left-right axis. Probably acts as a molecular switch between different Wnt signaling pathways. Inhibits the canonical Wnt pathway by targeting cytoplasmic disheveled (DVL1) for degradation by the ubiquitin-proteasome. This suggests that it is required in renal development to oppose the repression of terminal differentiation of tubular epithelial cells by Wnt signaling. Involved in the organization of apical junctions in kidney cells together with NPHP1, NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, spindle; Membrane; Nucleus; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q9Y283/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INVS","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/INVS","total_profiled":1310},"omim":[{"mim_id":"615382","title":"NEPHRONOPHTHISIS 16; NPHP16","url":"https://www.omim.org/entry/615382"},{"mim_id":"615370","title":"ANKYRIN REPEAT AND STERILE ALPHA MOTIF DOMAINS-CONTAINING PROTEIN 6; ANKS6","url":"https://www.omim.org/entry/615370"},{"mim_id":"614848","title":"CENTROSOMAL PROTEIN, 164-KD; CEP164","url":"https://www.omim.org/entry/614848"},{"mim_id":"610436","title":"ROTATIN; RTTN","url":"https://www.omim.org/entry/610436"},{"mim_id":"609799","title":"NIMA-RELATED KINASE 8; NEK8","url":"https://www.omim.org/entry/609799"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Primary cilium","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INVS"},"hgnc":{"alias_symbol":[],"prev_symbol":["NPHP2"]},"alphafold":{"accession":"Q9Y283","domains":[{"cath_id":"1.25.40.20","chopping":"12-137","consensus_level":"medium","plddt":93.1075,"start":12,"end":137},{"cath_id":"1.20.5","chopping":"561-588","consensus_level":"medium","plddt":87.4332,"start":561,"end":588},{"cath_id":"1.20.5","chopping":"895-932","consensus_level":"medium","plddt":75.0616,"start":895,"end":932}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y283","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y283-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y283-F1-predicted_aligned_error_v6.png","plddt_mean":70.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INVS","jax_strain_url":"https://www.jax.org/strain/search?query=INVS"},"sequence":{"accession":"Q9Y283","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y283.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y283/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y283"}},"corpus_meta":[{"pmid":"12872123","id":"PMC_12872123","title":"Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12872123","citation_count":497,"is_preprint":false},{"pmid":"23793029","id":"PMC_23793029","title":"ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23793029","citation_count":170,"is_preprint":false},{"pmid":"19177160","id":"PMC_19177160","title":"Mutations of NPHP2 and NPHP3 in infantile nephronophthisis.","date":"2009","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/19177160","citation_count":89,"is_preprint":false},{"pmid":"22076433","id":"PMC_22076433","title":"Inhibition of the p38 MAPK pathway ameliorates renal fibrosis in an NPHP2 mouse model.","date":"2011","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/22076433","citation_count":54,"is_preprint":false},{"pmid":"22393243","id":"PMC_22393243","title":"Ciliogenesis in Caenorhabditis elegans requires genetic interactions between ciliary middle segment localized NPHP-2 (inversin) and transition zone-associated proteins.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22393243","citation_count":42,"is_preprint":false},{"pmid":"15213257","id":"PMC_15213257","title":"The Invs gene encodes a microtubule-associated protein.","date":"2004","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/15213257","citation_count":34,"is_preprint":false},{"pmid":"25501555","id":"PMC_25501555","title":"The nphp-2 and arl-13 genetic modules interact to regulate ciliogenesis and ciliary microtubule patterning in C. elegans.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25501555","citation_count":32,"is_preprint":false},{"pmid":"16522655","id":"PMC_16522655","title":"Retinitis pigmentosa and renal failure in a patient with mutations in INVS.","date":"2006","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - 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knockdown of invs in zebrafish produces PKD-like renal cysts and randomizes heart looping.\",\n      \"method\": \"Co-immunoprecipitation (molecular interaction), immunofluorescence colocalization, zebrafish morpholino knockdown\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus colocalization plus in vivo loss-of-function, independently foundational paper with multiple orthogonal methods\",\n      \"pmids\": [\"12872123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Inversin forms a stable complex with tubulin in renal epithelial cells, localizes to ciliary, random, and polarized microtubule pools, is recruited to mitotic spindle fibers during cell division, and its association with tubulin is dependent on microtubule polymerization (dissociates after colcemid-mediated depolymerization).\",\n      \"method\": \"Co-immunoprecipitation, co-pelleting assay, immunofluorescence microscopy, microtubule depolymerization/stabilization pharmacology\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus co-pelleting plus pharmacological perturbation, single lab\",\n      \"pmids\": [\"15213257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Alternative splicing of INVS produces multiple transcript isoforms with skipping of exons 5, 11, or 13, causing loss of specific protein motifs including ankyrin repeats, IQ domains, destruction boxes, and nuclear localization signals.\",\n      \"method\": \"Northern blot, RT-PCR, sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple molecular biology methods in single lab establishing transcript diversity\",\n      \"pmids\": [\"15533716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Inversin localizes to distal tubules in the kidney and to multiple extrarenal tissues including hepatic bile ducts, pancreatic cells, intestinal epithelium, bronchiolar epithelium, cerebellar Purkinje cell dendrites, retinal neural cells, and spermatocytes/spermatids.\",\n      \"method\": \"Laser confocal microscopy of paraffin-embedded murine tissue sections with immunostaining\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — systematic immunolocalization across multiple tissues in single lab\",\n      \"pmids\": [\"16007506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"C. elegans NPHP-2 (inversin ortholog) localizes to the middle segment (Inversin compartment) of sensory cilia and genetically interacts with nphp-1, nphp-4, and MKS pathway genes (mks-1, mks-3, mks-6, mksr-1, mksr-2) to control cilia formation and placement; NPHP-2 is not required for localization of NPHP/MKS transition zone proteins or for intraflagellar transport.\",\n      \"method\": \"Fluorescent protein tagging/live imaging, genetic epistasis, double-mutant analysis in C. elegans\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization imaging plus systematic genetic epistasis with multiple gene combinations establishing pathway position\",\n      \"pmids\": [\"22393243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NEK8 (NPHP9) acts downstream of Inv/NPHP2 in zebrafish pronephros morphogenesis and left-right axis establishment; nek8 mRNA rescues inv morphant phenotypes, but inv mRNA cannot rescue nek8 morphant phenotypes; simultaneous knockdown of nek8 and inv synergistically worsens defects.\",\n      \"method\": \"Zebrafish morpholino knockdown, mRNA rescue epistasis experiments\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by mRNA rescue in vivo, single lab, clear directional relationship established\",\n      \"pmids\": [\"22687244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ANKS6 connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3 in a proximal cilium module; the oxygen sensor HIF1AN hydroxylates both ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 complex.\",\n      \"method\": \"Protein interaction mapping, co-immunoprecipitation, knockdown in zebrafish and Xenopus, identification of HIF1AN as hydroxylase\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — post-translational modification identified with writer enzyme, complex composition determined, multiple model organisms, multiple methods\",\n      \"pmids\": [\"23793029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NPHP2/Inversin directly interacts with Aurora A kinase, inhibits Aurora A phosphorylation/activation and reduces its kinase activity in vitro, thereby interfering with HDAC6-mediated cilia disassembly; NPHP2 knockdown in MDCK cells reduces cilia number, and Aurora A/HDAC inhibitors rescue this ciliogenesis defect.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown in MDCK cells, pharmacological rescue\",\n      \"journal\": \"Nephrology, dialysis, transplantation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus Co-IP plus cellular KD with pharmacological rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24026243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The EF hand (calcium-binding) domain of NPHP-2 (C. elegans inversin) is required for its targeting to the Inversin compartment of cilia; the InvC (NPHP-2 domain) and doublet region (ARL-13 domain) are distinct ciliary compartments that interact to regulate ciliogenesis via cilia placement, microtubule ultrastructure, and protein localization.\",\n      \"method\": \"Fluorescent protein tagging, domain deletion/mutation analysis, live imaging in C. elegans, genetic epistasis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis plus live localization imaging plus genetic interaction mapping, single lab\",\n      \"pmids\": [\"25501555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The Inversin compartment length corresponds to the microtubule doublet region of renal primary cilia; in multiciliated tracheal cells of inv mutant mice, Inv protein is retained at the basal body rather than accumulating in the ciliary Inv compartment, and inv mutant respiratory cilia show rootlet malformation, reduced beating frequency, and reduced beating angle.\",\n      \"method\": \"Electron microscopy, immunofluorescence, ciliary beat frequency measurement in inv mutant mouse\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ultrastructural analysis plus functional ciliary measurements in defined mutant model, single lab\",\n      \"pmids\": [\"26615802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A truncating mutation in the IQ1 domain of inversin causes mislocalization of the mutant protein: in control fibroblasts inversin is present in the ciliary axoneme and basal body, whereas mutant inversin is detected only at the basal body and not in the ciliary axoneme.\",\n      \"method\": \"Immunofluorescence localization in patient-derived fibroblasts, exome sequencing\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment in patient cells with clear functional consequence (loss of axonemal targeting), single lab\",\n      \"pmids\": [\"24677454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"INVS mutation deleting the C-terminus of inversin is associated with abnormal expression of β-catenin and Dishevelled-1 in renal tubular cells, supporting up-regulated canonical Wnt pathway activity.\",\n      \"method\": \"Immunohistochemistry/protein expression analysis in patient kidney tissue\",\n      \"journal\": \"Nephrology, dialysis, transplantation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method protein expression analysis in patient tissue, no direct mechanistic manipulation\",\n      \"pmids\": [\"20798123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In inv/inv (NPHP2) mouse kidneys, p38 MAPK phosphorylation is elevated; pharmacological inhibition of p38 MAPK reduces renal fibrosis and extracellular matrix gene expression without preventing cyst expansion; MEK/ERK inhibition reduces both cyst expansion and fibrosis independently of p38 MAPK, indicating p38 MAPK and ERK pathways independently regulate different aspects of the inv mutant renal phenotype.\",\n      \"method\": \"Pharmacological inhibition (FR167653 p38 inhibitor; MEK inhibitor) in inv/inv mouse model, western blot, histology, qPCR\",\n      \"journal\": \"Nephrology, dialysis, transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of two pathways with distinct readouts in defined mouse model, single lab\",\n      \"pmids\": [\"22076433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Epithelial-specific knockout of Invs in mice causes renal cyst formation and severe stromal fibrosis, while stromal-specific Invs deletion produces no observable phenotype, establishing an epithelial-cell-autonomous role for Invs and a role for epithelial-stromal crosstalk; concomitant genetic removal of cilia partially suppresses the Invs mutant kidney phenotype, indicating that cilia mediate at least part of Invs function in vivo; valproic acid (HDAC inhibitor) reduces cyst burden and cell proliferation.\",\n      \"method\": \"Cell-type-specific conditional knockout (Cre-lox), genetic cilia removal, pharmacological treatment (VPA), histology, kidney function assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional knockouts with defined cellular readouts plus genetic epistasis with cilia removal, replicated internally with orthogonal approaches\",\n      \"pmids\": [\"36920028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NPHP2/Inversin cooperates with Vangl2 and NPHP1 in planar cell polarity (PCP) signaling during zebrafish cloaca formation; simultaneous depletion of nphp1 and vangl2 in invssa36157 mutants markedly increases cloaca malformations associated with reduced apoptotic activity, while pronephric cell migration and cellular fate are unaffected.\",\n      \"method\": \"Zebrafish mutant line (invssa36157 stop codon), morpholino knockdown, time-lapse imaging, in situ hybridization, apoptosis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in defined zebrafish mutant with live imaging and molecular markers, single lab\",\n      \"pmids\": [\"37352572\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Inversin (INVS/NPHP2) is a ciliary scaffold protein that localizes to the proximal 'Inversin compartment' of primary cilia via its EF-hand domain, where it forms a molecular complex with nephrocystin (NPHP1) and beta-tubulin; it is also hydroxylated by HIF1AN and incorporated into an ANKS6-INVS-NPHP3-NEK8 module at the proximal cilium; mechanistically, inversin inhibits Aurora A kinase activity to suppress HDAC6-mediated cilia disassembly, associates with microtubules throughout the cell cycle (including mitotic spindles), participates in planar cell polarity signaling through Dishevelled/Vangl2, and its loss in renal epithelial cells drives cyst formation and stromal fibrosis through cilia-dependent mechanisms and activation of p38 MAPK and ERK pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Inversin (INVS/NPHP2) is a ciliary scaffold protein that organizes a proximal compartment of primary and motile cilia and links ciliary architecture to renal epithelial homeostasis [#0, #4]. It binds tubulin and associates with ciliary, cytoplasmic, and mitotic-spindle microtubule pools in a polymerization-dependent manner [#1], and its EF-hand domain targets it to the microtubule-doublet 'Inversin compartment' of the cilium, while loss of distal motifs by mutation restricts the protein to the basal body and abolishes axonemal targeting [#8, #9, #10]. Within this compartment, inversin nucleates a proximal-cilium module in which ANKS6 bridges NEK8 to INVS and NPHP3, a complex whose composition is tuned by HIF1AN-mediated hydroxylation of both ANKS6 and INVS, placing the assembly downstream of oxygen sensing; NEK8 acts genetically downstream of inversin in left-right axis and pronephros morphogenesis [#5, #6]. Inversin also restrains ciliary turnover by directly binding and inhibiting Aurora A kinase, thereby blocking HDAC6-dependent cilia disassembly [#7]. Functionally, inversin participates in planar cell polarity signaling together with NPHP1 and Vangl2 [#14], and its epithelial-cell-autonomous loss drives renal cyst formation and stromal fibrosis through cilia-dependent mechanisms, with the fibrotic and cystic components separable into p38 MAPK- and MEK/ERK-regulated arms [#12, #13]. A truncating IQ-domain mutation linking INVS to human cystic kidney disease produces the same axonemal-targeting defect seen in disease fibroblasts [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established inversin as a ciliary protein physically partnered with nephrocystin, connecting the gene to nephronophthisis biology and laterality determination rather than leaving it an orphan locus.\",\n      \"evidence\": \"Co-IP, immunofluorescence colocalization with beta-tubulin, and zebrafish morpholino knockdown\",\n      \"pmids\": [\"12872123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular activity of inversin within the cilium\", \"Did not map the interaction interface with NPHP1\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed inversin is a microtubule-associated protein spanning ciliary, cytoplasmic, and mitotic-spindle tubulin pools, framing it as a cytoskeletal scaffold rather than a cilium-exclusive factor.\",\n      \"evidence\": \"Co-IP, co-pelleting assay, immunofluorescence, and microtubule depolymerization pharmacology in renal epithelial cells\",\n      \"pmids\": [\"15213257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the inversin domain mediating tubulin binding\", \"Functional consequence of spindle localization not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined transcript diversity that can selectively delete functional motifs, raising the possibility of isoform-specific inversin activities.\",\n      \"evidence\": \"Northern blot, RT-PCR, and sequence analysis of INVS splice variants\",\n      \"pmids\": [\"15533716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional differences between isoforms not characterized\", \"Tissue distribution of each isoform not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped inversin expression across renal and many extrarenal tissues, predicting a broad physiological footprint beyond the kidney.\",\n      \"evidence\": \"Confocal immunostaining of murine tissue sections\",\n      \"pmids\": [\"16007506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test function in any extrarenal tissue\", \"Subcellular localization within each tissue not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked C-terminal inversin loss to dysregulated canonical Wnt readouts in patient kidney, hinting at a Wnt-modulating role.\",\n      \"evidence\": \"Immunohistochemistry of beta-catenin and Dishevelled-1 in patient kidney tissue\",\n      \"pmids\": [\"20798123\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method protein expression analysis with no mechanistic manipulation\", \"Cannot distinguish direct effect from secondary cystic remodeling\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Separated the cystic and fibrotic components of inversin loss into distinct kinase pathways, showing the renal phenotype is not a single downstream cascade.\",\n      \"evidence\": \"Pharmacological p38 and MEK/ERK inhibition in inv/inv mice with western blot, histology, qPCR\",\n      \"pmids\": [\"22076433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How inversin loss activates p38 and ERK is unknown\", \"Cell type driving each signaling arm not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Positioned inversin within the ciliary gene network by genetic epistasis, defining its compartment and its relationships to NPHP/MKS transition-zone pathways.\",\n      \"evidence\": \"Live imaging and double-mutant epistasis with nphp/mks genes in C. elegans; mRNA-rescue epistasis placing NEK8 downstream of inv in zebrafish\",\n      \"pmids\": [\"22393243\", \"22687244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical basis of the directional inv→NEK8 relationship not resolved\", \"Inversin's effect on transition-zone protein function vs localization not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the inversin module's composition and an oxygen-sensing input, and identified a direct enzymatic target through which inversin controls cilia stability.\",\n      \"evidence\": \"Interaction mapping/Co-IP with HIF1AN hydroxylation analysis (zebrafish/Xenopus); in vitro Aurora A kinase assay, Co-IP, MDCK siRNA knockdown with pharmacological rescue\",\n      \"pmids\": [\"23793029\", \"24026243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of INVS hydroxylation on module activity not fully defined\", \"How Aurora A inhibition is spatially restricted to the cilium not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Pinpointed the EF-hand and IQ domains as determinants of ciliary targeting and linked an IQ-domain truncation to human disease via loss of axonemal localization.\",\n      \"evidence\": \"Domain deletion/mutation with live imaging in C. elegans; immunofluorescence in patient-derived fibroblasts with exome sequencing\",\n      \"pmids\": [\"25501555\", \"24677454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Targeting receptor recognizing the EF-hand not identified\", \"Whether calcium binding modulates targeting not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected the Inversin compartment to a defined ultrastructural region and showed inversin is required for normal motile-cilia architecture and beating, extending its role beyond signaling cilia.\",\n      \"evidence\": \"Electron microscopy, immunofluorescence, and ciliary beat frequency measurement in inv mutant mice\",\n      \"pmids\": [\"26615802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking inversin loss to rootlet malformation unknown\", \"Whether motile-cilia defects contribute to organismal phenotype not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that inversin acts cell-autonomously in renal epithelium through cilia-dependent mechanisms and operates in planar cell polarity with NPHP1 and Vangl2, integrating its scaffold, signaling, and disease roles.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts with genetic cilia removal and VPA treatment in mice; zebrafish invs mutant epistasis with nphp1 and vangl2 with live imaging and apoptosis assays\",\n      \"pmids\": [\"36920028\", \"37352572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nature of the epithelial-stromal crosstalk driving fibrosis not defined\", \"Molecular link between inversin and PCP-associated apoptosis unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the molecular activities of inversin — tubulin scaffolding, Aurora A inhibition, hydroxylation-tuned module assembly, and PCP signaling — are integrated into a single mechanism that prevents renal cyst formation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking the ciliary module to downstream p38/ERK and Wnt/PCP outputs\", \"Direct catalytic or structural activity of inversin itself unproven\", \"Isoform-specific contributions to function untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 4, 8, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\n      \"ANKS6-INVS-NPHP3-NEK8 proximal cilium module\"\n    ],\n    \"partners\": [\n      \"NPHP1\",\n      \"ANKS6\",\n      \"NPHP3\",\n      \"NEK8\",\n      \"HIF1AN\",\n      \"AURKA\",\n      \"VANGL2\",\n      \"TUBB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}