{"gene":"SLCO1C1","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2004,"finding":"Mouse Oatp14 (SLCO1C1 ortholog) transports T4 and rT3 with high affinity (Km ~0.34 and ~0.46 µM, respectively) and T3 with ~4-fold lower affinity, as demonstrated by functional expression in HEK293 cells; taurocholate, probenecid, and estrone-3-sulfate were identified as moderate inhibitors, while digoxin and benzylpenicillin had no effect.","method":"Functional expression in HEK293 cells with radiolabeled substrate uptake assays; in situ brain perfusion technique in mice; Western blot of brain capillaries and choroid plexus; immunohistochemistry","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro functional assay with kinetics, in vivo brain perfusion, and protein localization; single lab but multiple orthogonal methods","pmids":["15166123"],"is_preprint":false},{"year":2008,"finding":"OATP1C1 (SLCO1C1) mRNA and protein are strongly enriched in mouse and rat cerebral microvessels (blood-brain barrier) but not in human microvessels; in rat, Oatp14 protein localizes to both luminal and abluminal microvessel membranes, and in choroid plexus it localizes primarily to the basolateral surface.","method":"Quantitative RT-PCR, Western blot of isolated cerebral microvessels, immunofluorescence localization in brain sections and choroid plexus from human, mouse, and rat","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (mRNA and protein), multiple species, with functional implications for BBB thyroid hormone transport","pmids":["18687783"],"is_preprint":false},{"year":2012,"finding":"Oatp1c1 knockout mice show decreased brain T4 and T3 content, increased type 2 and decreased type 3 deiodinase activities in brain (indicating mild central hypothyroidism), and down-regulated T3-regulated gene expression in brain, despite normal serum TH levels; this demonstrates that Oatp1c1 specifically facilitates T4 transport across the blood-brain barrier.","method":"Genetic knockout mouse model; brain TH content measurement; deiodinase activity assays; qPCR of TH-regulated target genes; serum TH measurements","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal readouts (TH content, deiodinase activity, gene expression), strong mechanistic conclusions","pmids":["22294745"],"is_preprint":false},{"year":2014,"finding":"OATP1C1 transports T4 (prohormone) across the blood-brain barrier; Mct8/Oatp1c1 double-knockout mice show strongly reduced uptake of both T3 and T4 into the brain (unlike single Mct8 KO where T4 entry is preserved via OATP1C1), resulting in severe CNS TH deprivation, compromised cerebellar development, reduced myelination, pronounced locomotor abnormalities, and impaired GABAergic interneuron differentiation.","method":"Double-knockout mouse model; brain TH content measurement; deiodinase activity assays; TH target gene expression; histological analysis of cerebellar development, myelination, and cortical interneurons; locomotor behavioral tests","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with double KO, multiple orthogonal phenotypic readouts; replicated findings across labs; high citation count","pmids":["24691440"],"is_preprint":false},{"year":2013,"finding":"OATP1C1 (SLCO1C1) mediates cell-specific sulforhodamine 101 (SR101) uptake in hippocampal and cortical astrocytes, as demonstrated by transcriptome analysis of region-specific astrocytes, two-photon microscopy, and mouse genetics using Oatp1c1-deficient mice.","method":"Region-specific astrocyte isolation with transcriptome analysis, two-photon excitation microscopy, Oatp1c1 knockout mouse genetics","journal":"Brain structure & function","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic KO confirmation; identifies novel substrate (SR101) and cell-specific function","pmids":["24129767"],"is_preprint":false},{"year":2010,"finding":"Site-directed mutagenesis of Oatp1c1 identified key residues for T4 transport: W277A/W278A mutation abolished transport; W277F/W278F increased high-affinity Km ~10-fold; G399A/G409A and G399V/G409V mutants showed diminished T4 transport at high substrate concentrations (suggesting substrate binding site collapse); R601S and P609A (transmembrane domain 11) showed partial activity with reduced Vmax and higher Km. A 3D structural model was generated using MFS transporter templates, revealing evolutionary conservation with bacterial MFS members.","method":"Site-directed mutagenesis of nine residues; transient transfection in HEK293 cells; 125I-T4 transport uptake assays; plasma membrane localization assessment; homology modeling using MFS transporter crystal structures","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with functional transport assay and structural modeling; multiple mutants tested with clear structure-function relationships","pmids":["20881245"],"is_preprint":false},{"year":2018,"finding":"A homozygous missense mutation (D252N) in OATP1C1 in a human patient causes impaired plasma membrane localization of the mutant protein and decreased cellular thyroxine uptake in vitro, associated with brain-specific hypothyroidism and juvenile neurodegeneration.","method":"Exome sequencing; in vitro thyroxine uptake studies; immunoblotting; immunocytochemistry for plasma membrane localization","journal":"Thyroid","confidence":"High","confidence_rationale":"Tier 1-2 — functional validation of human mutation with in vitro transport assay plus localization studies; first human OATP1C1 loss-of-function case","pmids":["30296914"],"is_preprint":false},{"year":2016,"finding":"SR101 oligodendrocyte labeling depends on OATP1C1-mediated uptake into astrocytes followed by transfer to oligodendrocytes via heterotypic gap junctions; competitive inhibition of OATP1C1 by L-thyroxin significantly reduced oligodendrocyte SR101 labeling, demonstrating that OATP1C1 is the primary transporter mediating SR101 astrocyte entry.","method":"Pharmacological inhibition with L-thyroxin (competitive inhibitor of OATP1C1); SR101 labeling in hippocampal slices of PLP-EGFP mice; fluorescence microscopy","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological inhibition supports mechanism but no direct genetic confirmation in this study (builds on prior KO data)","pmids":["27519929"],"is_preprint":false},{"year":2017,"finding":"Xenopus oatp1c1 transports T4 but not T3, MIT, or DIT, consistent with mammalian OATP1C1 substrate selectivity, as demonstrated by radiolabeled hormone uptake assay in COS-1 cells; temporal and spatial expression in Xenopus brain increases during development.","method":"Cloning of Xenopus oatp1c1; radiolabeled hormone in vitro uptake assay in COS-1 cells; RT-qPCR; in situ hybridization","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro transport assay with multiple substrates tested; single lab, Xenopus ortholog confirms substrate selectivity","pmids":["28591769"],"is_preprint":false},{"year":2015,"finding":"LPS-induced endotoxemia causes robust downregulation of OATP1C1 mRNA specifically in brain blood vessels within 9 hours, followed by upregulation at 24-48 hours, with OATP1C1 protein decreasing markedly in vessels by 24 hours; OATP1C1 mRNA in astrocytes was unchanged. This demonstrates inflammation-dependent regulation of OATP1C1 expression at the BBB.","method":"In situ hybridization, qPCR, and immunofluorescence for OATP1C1 mRNA and protein in rat and mouse forebrain after LPS injection; cell-type-specific analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (ISH, qPCR, IF) in two species with cell-type resolution; establishes regulatory mechanism","pmids":["25594699"],"is_preprint":false},{"year":2018,"finding":"MCT8 and OATP1C1 are both upregulated in activated satellite cells during skeletal muscle regeneration; Mct8/Oatp1c1 double-knockout mice showed strongly reduced numbers of differentiated satellite cells and impaired skeletal muscle regeneration; conditional deletion of both transporters exclusively in satellite cells also impaired regeneration, demonstrating a gate-keeper function for these transporters in myogenic stem cell activation.","method":"Mct8/Oatp1c1 double-knockout mouse analysis; satellite cell-specific conditional knockout; satellite cell isolation; tissue TH content measurement; TH-regulated gene expression; histological muscle regeneration assays","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with both global and conditional KO, multiple readouts, cell-autonomous function demonstrated","pmids":["29706500"],"is_preprint":false},{"year":2021,"finding":"OATP1C1 and MCT8 are strongly expressed in adult mouse subventricular zone neural stem cells (NSCs); Mct8/Oatp1c1 double-knockout mice show severely affected NSC proliferation and determination to neuronal (but not oligodendroglial) fates in the SVZ, establishing a role for OATP1C1 in adult neurogenesis.","method":"Immunofluorescence localization in adult mouse SVZ; Mct8/Oatp1c1 double-knockout mouse analysis; bromodeoxyuridine lineage tracing; cell fate marker analysis","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined cellular phenotype and lineage tracing; double KO precludes attribution solely to OATP1C1","pmids":["33450189"],"is_preprint":false},{"year":2013,"finding":"Oatp1c1 localizes to both luminal and abluminal membranes of retinal capillary endothelial cells and to the basolateral membrane of retinal pigment epithelial cells at the blood-retinal barrier, as demonstrated by immunoblot and immunohistochemistry with co-localization with GLUT1.","method":"Guinea pig polyclonal antibodies to Oatp1c1; immunoblot; immunohistochemistry with co-localization markers in rat retina","journal":"Fluids and barriers of the CNS","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization by immunohistochemistry/immunoblot; single method, single lab","pmids":["24083450"],"is_preprint":false},{"year":2019,"finding":"OATP1C1 transports multiple fluorescent substrates including sulforhodamine 101, sulforhodamine G, sulforhodamine B, Live/Dead Green, and Live-or-Dye 488 dyes, as demonstrated by uptake assays in HEK-293 and A431 cells overexpressing OATP1C1; OATP1C1 transport activity can be inhibited by third-generation P-gp inhibitors elacridar, tariquidar, and zosuquidar.","method":"Fluorescent dye uptake assays in OATP1C1-overexpressing HEK-293 and A431 cells; pharmacological inhibition studies","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional transport assay with multiple substrates and inhibitors; identifies novel substrates and inhibitors","pmids":["31770475"],"is_preprint":false},{"year":2024,"finding":"Tetrabromobisphenol A (TBBPA), PFOS, PFOA, pentachlorophenol, and quercetin were identified as OATP1C1 inhibitors of T4 uptake; TBBPA was the most potent OATP1C1 inhibitor, more potent than reference chemicals. This was demonstrated using OATP1C1-overexpressing cell models with radiolabeled T4 uptake.","method":"Radiolabeled 125I-T4 uptake assay in OATP1C1-overexpressing cell lines; chemical inhibitor screen","journal":"Archives of toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional transport assay with multiple chemicals; identifies environmental disruptors of OATP1C1 T4 transport","pmids":["38761188"],"is_preprint":false},{"year":2020,"finding":"In oatp1c1-deficient zebrafish, oatp1c1 is expressed in endothelial cells, neurons, and astrocytes; loss of oatp1c1 results in hyperactivity of the hypothalamic-pituitary-thyroid axis, structural alterations in radial glial cells, shorter neuronal axons, and enlarged thyroid gland (goiter); TH analogs (TRIAC) but not THs can reduce thyroid gland enlargement.","method":"Zebrafish oatp1c1 mutant generation; HPT axis activity measurement; behavioral locomotor assays; neuropathological analysis by immunofluorescence; pharmacological treatment with TH analogs","journal":"Thyroid","confidence":"Medium","confidence_rationale":"Tier 2 — genetic zebrafish model with multiple cellular and physiological readouts; ortholog with consistent function","pmids":["31797746"],"is_preprint":false},{"year":2022,"finding":"Oatp1c1 gene expression is detected in subsets of progenitors, neurons, and niche cells in the adult dentate gyrus; absence of Oatp1c1 results in increased neuroblast numbers and reduced immature neuron numbers in 6-month-old Oatp1c1 knockout mice, indicating a specific role of Oatp1c1 in neuroblast-to-immature neuron transition in adult hippocampal neurogenesis.","method":"Oatp1c1 single-KO and Mct8/Oatp1c1 double-KO mouse analysis; EdU labeling for neuron production; immunofluorescence for neurogenic stage markers; open field anxiety behavior testing","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — single and double KO with cell-type-specific phenotype analysis and EdU lineage tracing","pmids":["35159334"],"is_preprint":false},{"year":2025,"finding":"Mct8/Oatp1c1 double-knockout mice show increased seizure susceptibility (faster status epilepticus onset and more severe responses), associated with abnormal development of GABAergic, glutamatergic, and cholinergic systems in the hippocampus and ectopic somatostatin expression in CA3 neurons; conditional neuron-specific deletion does not replicate the phenotype, indicating these alterations stem from the global TH deficit rather than cell-autonomous transporter function.","method":"Pilocarpine seizure model; immunofluorescence; in situ hybridization; qPCR; conditional (neuron-specific) knockout mouse lines for validation","journal":"Progress in neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — global and conditional KO with mechanistic pathway analysis; establishes TH transport-dependent mechanism for neurotransmitter system development","pmids":["39986448"],"is_preprint":false}],"current_model":"SLCO1C1 (OATP1C1) encodes a multispecific organic anion transporting polypeptide that functions as the primary T4 (thyroxine) transporter at the blood-brain barrier, localizing to both luminal and abluminal membranes of brain capillary endothelial cells and to the basolateral surface of choroid plexus epithelium in rodents, mediating T4 entry into the CNS via a mechanism requiring specific transmembrane residues (notably W277/W278) and N-glycosylation; loss of OATP1C1 causes brain-specific hypothyroidism that impairs myelination, GABAergic interneuron differentiation, adult neurogenesis, and skeletal muscle regeneration, and in humans, inactivating mutations lead to juvenile neurodegeneration with brain hypometabolism."},"narrative":{"teleology":[{"year":2004,"claim":"Identifying the substrate selectivity of OATP1C1 established it as a high-affinity T4/rT3 transporter, distinguishing it from other OATPs that preferentially transport T3 or bile acids.","evidence":"Radiolabeled substrate uptake in HEK293 cells expressing mouse Oatp14, with kinetic analysis and inhibitor profiling","pmids":["15166123"],"confidence":"High","gaps":["Human OATP1C1 kinetics not directly measured in this study","Endogenous regulators of transport activity unknown"]},{"year":2008,"claim":"Determining the precise subcellular localization of OATP1C1 at luminal and abluminal BBB membranes and basolateral choroid plexus resolved how T4 traverses the blood-brain and blood-CSF barriers, while also revealing species differences (low/absent expression in human microvessels).","evidence":"qRT-PCR, Western blot of isolated microvessels, and immunofluorescence in human, mouse, and rat brain","pmids":["18687783"],"confidence":"High","gaps":["Human BBB expression discrepancy raises questions about compensatory mechanisms","Post-translational regulation of membrane targeting not addressed"]},{"year":2010,"claim":"Structure-function mutagenesis identified W277/W278 as essential for T4 transport and mapped additional residues (G399/G409, R601, P609) to substrate binding and translocation, providing the first molecular model of the OATP1C1 transport mechanism.","evidence":"Site-directed mutagenesis of nine residues with 125I-T4 uptake assays in HEK293 cells; homology modeling on MFS transporter templates","pmids":["20881245"],"confidence":"High","gaps":["No experimental structure; model relies on distant MFS homology","Mechanism of substrate translocation conformational change not resolved"]},{"year":2012,"claim":"The Oatp1c1 single-knockout mouse demonstrated that OATP1C1 is necessary for maintaining normal brain T4/T3 levels and T3-responsive gene expression despite normal serum thyroid hormones, establishing it as a non-redundant BBB T4 gate.","evidence":"Oatp1c1 KO mice; brain TH content, deiodinase activities, and qPCR of TH target genes","pmids":["22294745"],"confidence":"High","gaps":["Phenotypic severity relatively mild compared to double KO, leaving MCT8 compensation unclear","No behavioral or developmental phenotyping in single KO at this stage"]},{"year":2013,"claim":"Discovery that OATP1C1 mediates astrocyte-specific uptake of sulforhodamine 101 expanded its known substrate repertoire beyond thyroid hormones and identified it as a determinant of cell-type-specific dye labeling in neuroscience.","evidence":"Oatp1c1 KO mice; two-photon microscopy; region-specific astrocyte transcriptomics","pmids":["24129767"],"confidence":"High","gaps":["Structural basis for SR101 recognition versus T4 recognition unknown","Whether SR101 transport reflects a physiological organic anion substrate remains unclear"]},{"year":2014,"claim":"The Mct8/Oatp1c1 double-knockout mouse revealed that OATP1C1 is the critical compensatory T4 entry route when MCT8 is absent, and combined loss produces severe CNS hypothyroidism with compromised cerebellar development, myelination, and GABAergic interneuron differentiation.","evidence":"Double-KO mouse with brain TH measurement, histological analysis of cerebellum, myelin, cortical interneurons, and locomotor behavioral testing","pmids":["24691440"],"confidence":"High","gaps":["Cell-autonomous versus non-cell-autonomous contributions of each transporter to specific phenotypes not fully dissected","Temporal windows of vulnerability not defined"]},{"year":2015,"claim":"Demonstrating that LPS-induced inflammation rapidly downregulates OATP1C1 in BBB endothelium established a mechanism by which systemic infection could reduce brain T4 supply, linking innate immunity to central thyroid hormone economy.","evidence":"In situ hybridization, qPCR, and immunofluorescence for OATP1C1 in rat and mouse forebrain after LPS injection","pmids":["25594699"],"confidence":"Medium","gaps":["Transcription factor(s) mediating LPS-dependent downregulation not identified","Functional consequence on brain TH levels not directly measured"]},{"year":2018,"claim":"Identification of a human homozygous D252N mutation in OATP1C1 causing impaired plasma membrane localization, reduced T4 uptake, and juvenile neurodegeneration established SLCO1C1 as a Mendelian disease gene and confirmed its non-redundant role in the human brain.","evidence":"Exome sequencing of affected patient; in vitro T4 uptake and immunocytochemistry of mutant protein","pmids":["30296914"],"confidence":"High","gaps":["Only a single family reported; additional patients needed to define phenotypic spectrum","Whether residual transporter activity exists in vivo is unknown"]},{"year":2018,"claim":"Showing that OATP1C1 (with MCT8) gates thyroid hormone entry into satellite cells during skeletal muscle regeneration extended OATP1C1 function beyond the CNS to stem cell biology in peripheral tissues.","evidence":"Global and satellite cell-specific conditional Mct8/Oatp1c1 double-KO mice; muscle regeneration histology and TH-regulated gene expression","pmids":["29706500"],"confidence":"High","gaps":["Individual contribution of OATP1C1 versus MCT8 in satellite cells not resolved","Mechanism of upregulation during activation unknown"]},{"year":2020,"claim":"A zebrafish oatp1c1 mutant demonstrated conserved transporter function across vertebrates and revealed HPT axis hyperactivation and radial glial/axonal defects, providing a non-mammalian model for OATP1C1 deficiency.","evidence":"Zebrafish oatp1c1 mutant; HPT axis and thyroid morphology analysis; locomotor behavior; immunofluorescence neuropathology","pmids":["31797746"],"confidence":"Medium","gaps":["Zebrafish BBB organization differs from mammals; direct translational relevance uncertain","Compensatory transporters in zebrafish brain not characterized"]},{"year":2022,"claim":"Analysis of adult hippocampal neurogenesis in Oatp1c1 single-KO mice pinpointed a specific defect in the neuroblast-to-immature neuron transition, attributable to OATP1C1 alone rather than combined MCT8 loss.","evidence":"Oatp1c1 single-KO and double-KO mice; EdU labeling; stage-specific neurogenic marker immunofluorescence in dentate gyrus","pmids":["35159334"],"confidence":"Medium","gaps":["Downstream T3-responsive transcriptional programs in neuroblasts not identified","Whether the defect is cell-autonomous in neuroblasts or mediated by niche cells is unclear"]},{"year":2025,"claim":"Mct8/Oatp1c1 double-KO mice exhibit increased seizure susceptibility linked to impaired GABAergic, glutamatergic, and cholinergic development; conditional neuron-specific deletion does not reproduce this, indicating the phenotype arises from global TH deficit rather than neuronal transporter function.","evidence":"Pilocarpine seizure model; neurotransmitter system marker analysis; global versus neuron-specific conditional KO comparison","pmids":["39986448"],"confidence":"Medium","gaps":["Which non-neuronal cell types (endothelial, glial) are responsible for the TH supply deficit driving seizure susceptibility is unresolved","Whether OATP1C1 alone contributes to seizure phenotype independent of MCT8 is not tested"]},{"year":null,"claim":"Key open questions include the high-resolution structure of OATP1C1 with bound T4, the regulatory mechanisms controlling its expression at the BBB (including inflammation-responsive transcription factors), whether additional human patients with SLCO1C1 mutations exist, and the individual contribution of OATP1C1 versus MCT8 to each neurodevelopmental phenotype.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental or cryo-EM structure available","Full phenotypic spectrum of human OATP1C1 deficiency unknown from a single case","Cell-type-specific conditional OATP1C1-only KO studies in brain are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,3,5,6,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5,6,12]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,11,16]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,17]}],"complexes":[],"partners":["MCT8"],"other_free_text":[]},"mechanistic_narrative":"SLCO1C1 (OATP1C1) is the principal thyroxine (T4) transporter at the blood-brain barrier, mediating high-affinity T4 uptake (Km ~0.34 µM) into the central nervous system and thereby controlling local thyroid hormone availability for brain development, myelination, and neurogenesis [PMID:15166123, PMID:22294745, PMID:24691440]. The transporter localizes to both luminal and abluminal membranes of brain capillary endothelial cells and to the basolateral surface of choroid plexus and retinal pigment epithelium, and its transport function depends on conserved transmembrane residues including W277/W278 and requires proper N-glycosylation and plasma membrane targeting [PMID:18687783, PMID:20881245, PMID:24083450]. Loss of OATP1C1 in mice causes brain-specific hypothyroidism with impaired myelination, disrupted GABAergic interneuron differentiation, defective adult hippocampal neurogenesis, and compromised skeletal muscle satellite cell activation, phenotypes dramatically worsened by combined loss of MCT8 [PMID:24691440, PMID:35159334, PMID:29706500]. In humans, a homozygous D252N missense mutation in OATP1C1 causes juvenile neurodegeneration with brain hypometabolism [PMID:30296914]."},"prefetch_data":{"uniprot":{"accession":"Q9NYB5","full_name":"Solute carrier organic anion transporter family member 1C1","aliases":["Organic anion transporter 1C1","OATP1C1","Organic anion transporter F","OATP-F","Organic anion transporter polypeptide-related protein 5","OAT-RP-5","OATP-RP5","Organic anion-transporting polypeptide 14","OATP-14","Solute carrier family 21 member 14","Thyroxine transporter"],"length_aa":712,"mass_kda":78.7,"function":"Mediates the Na(+)-independent high affinity transport of organic anions such as the thyroid hormones L-thyroxine (T4), L-thyroxine sulfate (T4S), and 3,3',5'-triiodo-L-thyronine (reverse T3, rT3) at the plasma membrane (PubMed:12351693, PubMed:18566113, PubMed:19129463). Regulates T4 levels in different brain regions by transporting T4, and also by serving as an export pump for T4S, which is a source of T4 after hydrolysis by local sulfatases (PubMed:18566113). Increases the access of these substrates to the intracellular sites where they are metabolized by the deiodinases (PubMed:18566113). Other potential substrates, such as triiodothyronine (T3), 17-beta-glucuronosyl estradiol (17beta-estradiol 17-O-(beta-D-glucuronate)), estrone-3-sulfate (E1S) and sulfobromophthalein (BSP) are transported with much lower efficiency (PubMed:12351693, PubMed:19129463). Transports T4 and E1S in a pH-insensitive manner (PubMed:19129463). Facilitates the transport of thyroid hormones across the blood-brain barrier and into glia and neuronal cells in the brain (PubMed:30296914)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NYB5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLCO1C1","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/SLCO1C1","total_profiled":1310},"omim":[{"mim_id":"613389","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1C1; SLCO1C1","url":"https://www.omim.org/entry/613389"},{"mim_id":"608870","title":"LEUCINE-RICH REPEATS- AND IMMUNOGLOBULIN-LIKE DOMAINS-CONTAINING PROTEIN 3; LRIG3","url":"https://www.omim.org/entry/608870"},{"mim_id":"300095","title":"SOLUTE CARRIER FAMILY 16 (MONOCARBOXYLIC ACID TRANSPORTER), MEMBER 2; SLC16A2","url":"https://www.omim.org/entry/300095"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":19.6},{"tissue":"choroid plexus","ntpm":16.3},{"tissue":"pituitary gland","ntpm":7.7}],"url":"https://www.proteinatlas.org/search/SLCO1C1"},"hgnc":{"alias_symbol":["OATP-F","OATP1C1","OATP1"],"prev_symbol":["SLC21A14"]},"alphafold":{"accession":"Q9NYB5","domains":[{"cath_id":"1.20.1250.20","chopping":"38-142_186-301","consensus_level":"medium","plddt":88.7106,"start":38,"end":301},{"cath_id":"1.20.1250.20","chopping":"342-447_546-686","consensus_level":"medium","plddt":89.6028,"start":342,"end":686},{"cath_id":"-","chopping":"450-543","consensus_level":"medium","plddt":81.7255,"start":450,"end":543}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYB5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYB5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYB5-F1-predicted_aligned_error_v6.png","plddt_mean":78.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLCO1C1","jax_strain_url":"https://www.jax.org/strain/search?query=SLCO1C1"},"sequence":{"accession":"Q9NYB5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NYB5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NYB5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYB5"}},"corpus_meta":[{"pmid":"18687783","id":"PMC_18687783","title":"Expression of the thyroid hormone transporters monocarboxylate transporter-8 (SLC16A2) and organic ion transporter-14 (SLCO1C1) at the blood-brain barrier.","date":"2008","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18687783","citation_count":268,"is_preprint":false},{"pmid":"24691440","id":"PMC_24691440","title":"Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24691440","citation_count":220,"is_preprint":false},{"pmid":"9632674","id":"PMC_9632674","title":"Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9632674","citation_count":210,"is_preprint":false},{"pmid":"11713643","id":"PMC_11713643","title":"Localization of organic anion transporting polypeptide 4 (Oatp4) in rat liver and comparison of its substrate specificity with Oatp1, Oatp2 and Oatp3.","date":"2001","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11713643","citation_count":140,"is_preprint":false},{"pmid":"15166123","id":"PMC_15166123","title":"Involvement of multispecific organic anion transporter, Oatp14 (Slc21a14), in the transport of thyroxine across the blood-brain barrier.","date":"2004","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15166123","citation_count":125,"is_preprint":false},{"pmid":"10198348","id":"PMC_10198348","title":"Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10198348","citation_count":112,"is_preprint":false},{"pmid":"22294745","id":"PMC_22294745","title":"Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22294745","citation_count":106,"is_preprint":false},{"pmid":"9453431","id":"PMC_9453431","title":"Expression of the liver Na+-independent organic anion transporting polypeptide (oatp-1) in rats with bile duct ligation.","date":"1997","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/9453431","citation_count":81,"is_preprint":false},{"pmid":"9875555","id":"PMC_9875555","title":"Roles of MRP2 and oatp1 in hepatocellular export of reduced glutathione.","date":"1998","source":"Seminars in liver disease","url":"https://pubmed.ncbi.nlm.nih.gov/9875555","citation_count":73,"is_preprint":false},{"pmid":"12842829","id":"PMC_12842829","title":"Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake.","date":"2003","source":"American journal of physiology. 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taurocholate, probenecid, and estrone-3-sulfate were identified as moderate inhibitors, while digoxin and benzylpenicillin had no effect.\",\n      \"method\": \"Functional expression in HEK293 cells with radiolabeled substrate uptake assays; in situ brain perfusion technique in mice; Western blot of brain capillaries and choroid plexus; immunohistochemistry\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro functional assay with kinetics, in vivo brain perfusion, and protein localization; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15166123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OATP1C1 (SLCO1C1) mRNA and protein are strongly enriched in mouse and rat cerebral microvessels (blood-brain barrier) but not in human microvessels; in rat, Oatp14 protein localizes to both luminal and abluminal microvessel membranes, and in choroid plexus it localizes primarily to the basolateral surface.\",\n      \"method\": \"Quantitative RT-PCR, Western blot of isolated cerebral microvessels, immunofluorescence localization in brain sections and choroid plexus from human, mouse, and rat\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (mRNA and protein), multiple species, with functional implications for BBB thyroid hormone transport\",\n      \"pmids\": [\"18687783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Oatp1c1 knockout mice show decreased brain T4 and T3 content, increased type 2 and decreased type 3 deiodinase activities in brain (indicating mild central hypothyroidism), and down-regulated T3-regulated gene expression in brain, despite normal serum TH levels; this demonstrates that Oatp1c1 specifically facilitates T4 transport across the blood-brain barrier.\",\n      \"method\": \"Genetic knockout mouse model; brain TH content measurement; deiodinase activity assays; qPCR of TH-regulated target genes; serum TH measurements\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal readouts (TH content, deiodinase activity, gene expression), strong mechanistic conclusions\",\n      \"pmids\": [\"22294745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OATP1C1 transports T4 (prohormone) across the blood-brain barrier; Mct8/Oatp1c1 double-knockout mice show strongly reduced uptake of both T3 and T4 into the brain (unlike single Mct8 KO where T4 entry is preserved via OATP1C1), resulting in severe CNS TH deprivation, compromised cerebellar development, reduced myelination, pronounced locomotor abnormalities, and impaired GABAergic interneuron differentiation.\",\n      \"method\": \"Double-knockout mouse model; brain TH content measurement; deiodinase activity assays; TH target gene expression; histological analysis of cerebellar development, myelination, and cortical interneurons; locomotor behavioral tests\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with double KO, multiple orthogonal phenotypic readouts; replicated findings across labs; high citation count\",\n      \"pmids\": [\"24691440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OATP1C1 (SLCO1C1) mediates cell-specific sulforhodamine 101 (SR101) uptake in hippocampal and cortical astrocytes, as demonstrated by transcriptome analysis of region-specific astrocytes, two-photon microscopy, and mouse genetics using Oatp1c1-deficient mice.\",\n      \"method\": \"Region-specific astrocyte isolation with transcriptome analysis, two-photon excitation microscopy, Oatp1c1 knockout mouse genetics\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic KO confirmation; identifies novel substrate (SR101) and cell-specific function\",\n      \"pmids\": [\"24129767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Site-directed mutagenesis of Oatp1c1 identified key residues for T4 transport: W277A/W278A mutation abolished transport; W277F/W278F increased high-affinity Km ~10-fold; G399A/G409A and G399V/G409V mutants showed diminished T4 transport at high substrate concentrations (suggesting substrate binding site collapse); R601S and P609A (transmembrane domain 11) showed partial activity with reduced Vmax and higher Km. A 3D structural model was generated using MFS transporter templates, revealing evolutionary conservation with bacterial MFS members.\",\n      \"method\": \"Site-directed mutagenesis of nine residues; transient transfection in HEK293 cells; 125I-T4 transport uptake assays; plasma membrane localization assessment; homology modeling using MFS transporter crystal structures\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional transport assay and structural modeling; multiple mutants tested with clear structure-function relationships\",\n      \"pmids\": [\"20881245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A homozygous missense mutation (D252N) in OATP1C1 in a human patient causes impaired plasma membrane localization of the mutant protein and decreased cellular thyroxine uptake in vitro, associated with brain-specific hypothyroidism and juvenile neurodegeneration.\",\n      \"method\": \"Exome sequencing; in vitro thyroxine uptake studies; immunoblotting; immunocytochemistry for plasma membrane localization\",\n      \"journal\": \"Thyroid\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional validation of human mutation with in vitro transport assay plus localization studies; first human OATP1C1 loss-of-function case\",\n      \"pmids\": [\"30296914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SR101 oligodendrocyte labeling depends on OATP1C1-mediated uptake into astrocytes followed by transfer to oligodendrocytes via heterotypic gap junctions; competitive inhibition of OATP1C1 by L-thyroxin significantly reduced oligodendrocyte SR101 labeling, demonstrating that OATP1C1 is the primary transporter mediating SR101 astrocyte entry.\",\n      \"method\": \"Pharmacological inhibition with L-thyroxin (competitive inhibitor of OATP1C1); SR101 labeling in hippocampal slices of PLP-EGFP mice; fluorescence microscopy\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibition supports mechanism but no direct genetic confirmation in this study (builds on prior KO data)\",\n      \"pmids\": [\"27519929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Xenopus oatp1c1 transports T4 but not T3, MIT, or DIT, consistent with mammalian OATP1C1 substrate selectivity, as demonstrated by radiolabeled hormone uptake assay in COS-1 cells; temporal and spatial expression in Xenopus brain increases during development.\",\n      \"method\": \"Cloning of Xenopus oatp1c1; radiolabeled hormone in vitro uptake assay in COS-1 cells; RT-qPCR; in situ hybridization\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro transport assay with multiple substrates tested; single lab, Xenopus ortholog confirms substrate selectivity\",\n      \"pmids\": [\"28591769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LPS-induced endotoxemia causes robust downregulation of OATP1C1 mRNA specifically in brain blood vessels within 9 hours, followed by upregulation at 24-48 hours, with OATP1C1 protein decreasing markedly in vessels by 24 hours; OATP1C1 mRNA in astrocytes was unchanged. This demonstrates inflammation-dependent regulation of OATP1C1 expression at the BBB.\",\n      \"method\": \"In situ hybridization, qPCR, and immunofluorescence for OATP1C1 mRNA and protein in rat and mouse forebrain after LPS injection; cell-type-specific analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (ISH, qPCR, IF) in two species with cell-type resolution; establishes regulatory mechanism\",\n      \"pmids\": [\"25594699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MCT8 and OATP1C1 are both upregulated in activated satellite cells during skeletal muscle regeneration; Mct8/Oatp1c1 double-knockout mice showed strongly reduced numbers of differentiated satellite cells and impaired skeletal muscle regeneration; conditional deletion of both transporters exclusively in satellite cells also impaired regeneration, demonstrating a gate-keeper function for these transporters in myogenic stem cell activation.\",\n      \"method\": \"Mct8/Oatp1c1 double-knockout mouse analysis; satellite cell-specific conditional knockout; satellite cell isolation; tissue TH content measurement; TH-regulated gene expression; histological muscle regeneration assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with both global and conditional KO, multiple readouts, cell-autonomous function demonstrated\",\n      \"pmids\": [\"29706500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OATP1C1 and MCT8 are strongly expressed in adult mouse subventricular zone neural stem cells (NSCs); Mct8/Oatp1c1 double-knockout mice show severely affected NSC proliferation and determination to neuronal (but not oligodendroglial) fates in the SVZ, establishing a role for OATP1C1 in adult neurogenesis.\",\n      \"method\": \"Immunofluorescence localization in adult mouse SVZ; Mct8/Oatp1c1 double-knockout mouse analysis; bromodeoxyuridine lineage tracing; cell fate marker analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined cellular phenotype and lineage tracing; double KO precludes attribution solely to OATP1C1\",\n      \"pmids\": [\"33450189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Oatp1c1 localizes to both luminal and abluminal membranes of retinal capillary endothelial cells and to the basolateral membrane of retinal pigment epithelial cells at the blood-retinal barrier, as demonstrated by immunoblot and immunohistochemistry with co-localization with GLUT1.\",\n      \"method\": \"Guinea pig polyclonal antibodies to Oatp1c1; immunoblot; immunohistochemistry with co-localization markers in rat retina\",\n      \"journal\": \"Fluids and barriers of the CNS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization by immunohistochemistry/immunoblot; single method, single lab\",\n      \"pmids\": [\"24083450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OATP1C1 transports multiple fluorescent substrates including sulforhodamine 101, sulforhodamine G, sulforhodamine B, Live/Dead Green, and Live-or-Dye 488 dyes, as demonstrated by uptake assays in HEK-293 and A431 cells overexpressing OATP1C1; OATP1C1 transport activity can be inhibited by third-generation P-gp inhibitors elacridar, tariquidar, and zosuquidar.\",\n      \"method\": \"Fluorescent dye uptake assays in OATP1C1-overexpressing HEK-293 and A431 cells; pharmacological inhibition studies\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional transport assay with multiple substrates and inhibitors; identifies novel substrates and inhibitors\",\n      \"pmids\": [\"31770475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tetrabromobisphenol A (TBBPA), PFOS, PFOA, pentachlorophenol, and quercetin were identified as OATP1C1 inhibitors of T4 uptake; TBBPA was the most potent OATP1C1 inhibitor, more potent than reference chemicals. This was demonstrated using OATP1C1-overexpressing cell models with radiolabeled T4 uptake.\",\n      \"method\": \"Radiolabeled 125I-T4 uptake assay in OATP1C1-overexpressing cell lines; chemical inhibitor screen\",\n      \"journal\": \"Archives of toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional transport assay with multiple chemicals; identifies environmental disruptors of OATP1C1 T4 transport\",\n      \"pmids\": [\"38761188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In oatp1c1-deficient zebrafish, oatp1c1 is expressed in endothelial cells, neurons, and astrocytes; loss of oatp1c1 results in hyperactivity of the hypothalamic-pituitary-thyroid axis, structural alterations in radial glial cells, shorter neuronal axons, and enlarged thyroid gland (goiter); TH analogs (TRIAC) but not THs can reduce thyroid gland enlargement.\",\n      \"method\": \"Zebrafish oatp1c1 mutant generation; HPT axis activity measurement; behavioral locomotor assays; neuropathological analysis by immunofluorescence; pharmacological treatment with TH analogs\",\n      \"journal\": \"Thyroid\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic zebrafish model with multiple cellular and physiological readouts; ortholog with consistent function\",\n      \"pmids\": [\"31797746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Oatp1c1 gene expression is detected in subsets of progenitors, neurons, and niche cells in the adult dentate gyrus; absence of Oatp1c1 results in increased neuroblast numbers and reduced immature neuron numbers in 6-month-old Oatp1c1 knockout mice, indicating a specific role of Oatp1c1 in neuroblast-to-immature neuron transition in adult hippocampal neurogenesis.\",\n      \"method\": \"Oatp1c1 single-KO and Mct8/Oatp1c1 double-KO mouse analysis; EdU labeling for neuron production; immunofluorescence for neurogenic stage markers; open field anxiety behavior testing\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single and double KO with cell-type-specific phenotype analysis and EdU lineage tracing\",\n      \"pmids\": [\"35159334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mct8/Oatp1c1 double-knockout mice show increased seizure susceptibility (faster status epilepticus onset and more severe responses), associated with abnormal development of GABAergic, glutamatergic, and cholinergic systems in the hippocampus and ectopic somatostatin expression in CA3 neurons; conditional neuron-specific deletion does not replicate the phenotype, indicating these alterations stem from the global TH deficit rather than cell-autonomous transporter function.\",\n      \"method\": \"Pilocarpine seizure model; immunofluorescence; in situ hybridization; qPCR; conditional (neuron-specific) knockout mouse lines for validation\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — global and conditional KO with mechanistic pathway analysis; establishes TH transport-dependent mechanism for neurotransmitter system development\",\n      \"pmids\": [\"39986448\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLCO1C1 (OATP1C1) encodes a multispecific organic anion transporting polypeptide that functions as the primary T4 (thyroxine) transporter at the blood-brain barrier, localizing to both luminal and abluminal membranes of brain capillary endothelial cells and to the basolateral surface of choroid plexus epithelium in rodents, mediating T4 entry into the CNS via a mechanism requiring specific transmembrane residues (notably W277/W278) and N-glycosylation; loss of OATP1C1 causes brain-specific hypothyroidism that impairs myelination, GABAergic interneuron differentiation, adult neurogenesis, and skeletal muscle regeneration, and in humans, inactivating mutations lead to juvenile neurodegeneration with brain hypometabolism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLCO1C1 (OATP1C1) is the principal thyroxine (T4) transporter at the blood-brain barrier, mediating high-affinity T4 uptake (Km ~0.34 µM) into the central nervous system and thereby controlling local thyroid hormone availability for brain development, myelination, and neurogenesis [PMID:15166123, PMID:22294745, PMID:24691440]. The transporter localizes to both luminal and abluminal membranes of brain capillary endothelial cells and to the basolateral surface of choroid plexus and retinal pigment epithelium, and its transport function depends on conserved transmembrane residues including W277/W278 and requires proper N-glycosylation and plasma membrane targeting [PMID:18687783, PMID:20881245, PMID:24083450]. Loss of OATP1C1 in mice causes brain-specific hypothyroidism with impaired myelination, disrupted GABAergic interneuron differentiation, defective adult hippocampal neurogenesis, and compromised skeletal muscle satellite cell activation, phenotypes dramatically worsened by combined loss of MCT8 [PMID:24691440, PMID:35159334, PMID:29706500]. In humans, a homozygous D252N missense mutation in OATP1C1 causes juvenile neurodegeneration with brain hypometabolism [PMID:30296914].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying the substrate selectivity of OATP1C1 established it as a high-affinity T4/rT3 transporter, distinguishing it from other OATPs that preferentially transport T3 or bile acids.\",\n      \"evidence\": \"Radiolabeled substrate uptake in HEK293 cells expressing mouse Oatp14, with kinetic analysis and inhibitor profiling\",\n      \"pmids\": [\"15166123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human OATP1C1 kinetics not directly measured in this study\", \"Endogenous regulators of transport activity unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Determining the precise subcellular localization of OATP1C1 at luminal and abluminal BBB membranes and basolateral choroid plexus resolved how T4 traverses the blood-brain and blood-CSF barriers, while also revealing species differences (low/absent expression in human microvessels).\",\n      \"evidence\": \"qRT-PCR, Western blot of isolated microvessels, and immunofluorescence in human, mouse, and rat brain\",\n      \"pmids\": [\"18687783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human BBB expression discrepancy raises questions about compensatory mechanisms\", \"Post-translational regulation of membrane targeting not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Structure-function mutagenesis identified W277/W278 as essential for T4 transport and mapped additional residues (G399/G409, R601, P609) to substrate binding and translocation, providing the first molecular model of the OATP1C1 transport mechanism.\",\n      \"evidence\": \"Site-directed mutagenesis of nine residues with 125I-T4 uptake assays in HEK293 cells; homology modeling on MFS transporter templates\",\n      \"pmids\": [\"20881245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental structure; model relies on distant MFS homology\", \"Mechanism of substrate translocation conformational change not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The Oatp1c1 single-knockout mouse demonstrated that OATP1C1 is necessary for maintaining normal brain T4/T3 levels and T3-responsive gene expression despite normal serum thyroid hormones, establishing it as a non-redundant BBB T4 gate.\",\n      \"evidence\": \"Oatp1c1 KO mice; brain TH content, deiodinase activities, and qPCR of TH target genes\",\n      \"pmids\": [\"22294745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phenotypic severity relatively mild compared to double KO, leaving MCT8 compensation unclear\", \"No behavioral or developmental phenotyping in single KO at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that OATP1C1 mediates astrocyte-specific uptake of sulforhodamine 101 expanded its known substrate repertoire beyond thyroid hormones and identified it as a determinant of cell-type-specific dye labeling in neuroscience.\",\n      \"evidence\": \"Oatp1c1 KO mice; two-photon microscopy; region-specific astrocyte transcriptomics\",\n      \"pmids\": [\"24129767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for SR101 recognition versus T4 recognition unknown\", \"Whether SR101 transport reflects a physiological organic anion substrate remains unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The Mct8/Oatp1c1 double-knockout mouse revealed that OATP1C1 is the critical compensatory T4 entry route when MCT8 is absent, and combined loss produces severe CNS hypothyroidism with compromised cerebellar development, myelination, and GABAergic interneuron differentiation.\",\n      \"evidence\": \"Double-KO mouse with brain TH measurement, histological analysis of cerebellum, myelin, cortical interneurons, and locomotor behavioral testing\",\n      \"pmids\": [\"24691440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous versus non-cell-autonomous contributions of each transporter to specific phenotypes not fully dissected\", \"Temporal windows of vulnerability not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that LPS-induced inflammation rapidly downregulates OATP1C1 in BBB endothelium established a mechanism by which systemic infection could reduce brain T4 supply, linking innate immunity to central thyroid hormone economy.\",\n      \"evidence\": \"In situ hybridization, qPCR, and immunofluorescence for OATP1C1 in rat and mouse forebrain after LPS injection\",\n      \"pmids\": [\"25594699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor(s) mediating LPS-dependent downregulation not identified\", \"Functional consequence on brain TH levels not directly measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of a human homozygous D252N mutation in OATP1C1 causing impaired plasma membrane localization, reduced T4 uptake, and juvenile neurodegeneration established SLCO1C1 as a Mendelian disease gene and confirmed its non-redundant role in the human brain.\",\n      \"evidence\": \"Exome sequencing of affected patient; in vitro T4 uptake and immunocytochemistry of mutant protein\",\n      \"pmids\": [\"30296914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only a single family reported; additional patients needed to define phenotypic spectrum\", \"Whether residual transporter activity exists in vivo is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that OATP1C1 (with MCT8) gates thyroid hormone entry into satellite cells during skeletal muscle regeneration extended OATP1C1 function beyond the CNS to stem cell biology in peripheral tissues.\",\n      \"evidence\": \"Global and satellite cell-specific conditional Mct8/Oatp1c1 double-KO mice; muscle regeneration histology and TH-regulated gene expression\",\n      \"pmids\": [\"29706500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of OATP1C1 versus MCT8 in satellite cells not resolved\", \"Mechanism of upregulation during activation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A zebrafish oatp1c1 mutant demonstrated conserved transporter function across vertebrates and revealed HPT axis hyperactivation and radial glial/axonal defects, providing a non-mammalian model for OATP1C1 deficiency.\",\n      \"evidence\": \"Zebrafish oatp1c1 mutant; HPT axis and thyroid morphology analysis; locomotor behavior; immunofluorescence neuropathology\",\n      \"pmids\": [\"31797746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Zebrafish BBB organization differs from mammals; direct translational relevance uncertain\", \"Compensatory transporters in zebrafish brain not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Analysis of adult hippocampal neurogenesis in Oatp1c1 single-KO mice pinpointed a specific defect in the neuroblast-to-immature neuron transition, attributable to OATP1C1 alone rather than combined MCT8 loss.\",\n      \"evidence\": \"Oatp1c1 single-KO and double-KO mice; EdU labeling; stage-specific neurogenic marker immunofluorescence in dentate gyrus\",\n      \"pmids\": [\"35159334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream T3-responsive transcriptional programs in neuroblasts not identified\", \"Whether the defect is cell-autonomous in neuroblasts or mediated by niche cells is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mct8/Oatp1c1 double-KO mice exhibit increased seizure susceptibility linked to impaired GABAergic, glutamatergic, and cholinergic development; conditional neuron-specific deletion does not reproduce this, indicating the phenotype arises from global TH deficit rather than neuronal transporter function.\",\n      \"evidence\": \"Pilocarpine seizure model; neurotransmitter system marker analysis; global versus neuron-specific conditional KO comparison\",\n      \"pmids\": [\"39986448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which non-neuronal cell types (endothelial, glial) are responsible for the TH supply deficit driving seizure susceptibility is unresolved\", \"Whether OATP1C1 alone contributes to seizure phenotype independent of MCT8 is not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the high-resolution structure of OATP1C1 with bound T4, the regulatory mechanisms controlling its expression at the BBB (including inflammation-responsive transcription factors), whether additional human patients with SLCO1C1 mutations exist, and the individual contribution of OATP1C1 versus MCT8 to each neurodevelopmental phenotype.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental or cryo-EM structure available\", \"Full phenotypic spectrum of human OATP1C1 deficiency unknown from a single case\", \"Cell-type-specific conditional OATP1C1-only KO studies in brain are lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 6, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0382551\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 11, 16]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MCT8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}