{"gene":"UNC5C","run_date":"2026-04-28T21:43:01","timeline":{"discoveries":[{"year":2012,"finding":"DSCAM physically interacts with UNC5C, and this interaction is stimulated by netrin-1 in primary cortical neurons and cerebellar granule cells. Netrin-1 induces growth cone collapse via UNC5C/DSCAM, and this requires Src family kinase-dependent tyrosine phosphorylation of UNC5C, DSCAM, FAK, Fyn, and PAK1. DSCAM knockdown inhibits netrin-1-induced tyrosine phosphorylation of UNC5C and Fyn, placing DSCAM upstream of UNC5C-Fyn signaling.","method":"Co-immunoprecipitation, shRNA knockdown, dominant negative overexpression, phosphorylation assays, Src family kinase inhibition, growth cone collapse assay in primary neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple orthogonal methods (KD, DN, kinase inhibition, phospho-assays), functional readout in primary neurons","pmids":["22685302"],"is_preprint":false},{"year":2017,"finding":"UNC5C directly interacts with polymerized TUBB3 (neuron-specific β-tubulin) in microtubules, and netrin-1 reduces this interaction and their colocalization in growth cones. Disengagement of UNC5C from TUBB3 is required for netrin-1/UNC5C-mediated axon repulsion, and knockdown of either protein blocks repulsion and causes DRG axon projection defects in vivo. Netrin-1 increases microtubule dynamics differentially in the growth cone during repulsion.","method":"In vitro cosedimentation assay, Co-IP, shRNA knockdown, live-cell EB3-GFP imaging, in vivo DRG axon projection analysis","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro cosedimentation (biochemical reconstitution), live imaging, KD with in vivo phenotype, multiple orthogonal methods","pmids":["28483977"],"is_preprint":false},{"year":2021,"finding":"δ-secretase (asparagine endopeptidase/AEP) cleaves UNC5C at N467 and N547 residues, enhancing its proapoptotic/caspase-3 activating activity. Netrin-1 deficiency activates δ-secretase, which truncates UNC5C; blocking this cleavage diminishes the T835M mutant's proapoptotic activity. Viral expression of δ-secretase-truncated UNC5C fragments in APP/PS1 mice accelerates AD pathologies and impairs learning/memory, while UNC5C deletion from netrin-1-depleted mice attenuates AD pathologies.","method":"In vitro cleavage assay with mutagenesis (N467/N547 sites), caspase-3 activation assay, viral expression in transgenic mice, behavioral testing, genetic deletion","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — site-specific mutagenesis identifying cleavage sites, in vitro assay, in vivo viral expression and genetic deletion with functional readouts","pmids":["33863723"],"is_preprint":false},{"year":2022,"finding":"AEP (asparagine endopeptidase) cleaves UNC5C in Parkinson's disease, facilitating dopaminergic neuronal loss. Netrin-1 deprivation induces AEP and caspase-3 activation, triggering UNC5C proteolytic fragmentation. Blocking UNC5C cleavage by AEP attenuates neuronal death and motor disorders; overexpression of AEP-truncated UNC5C intracellular fragment elicits α-synuclein aggregation and dopaminergic loss in transgenic mice.","method":"In vitro cleavage assay, primary neuron cultures, viral overexpression in transgenic mice, behavioral motor testing, biochemical fractionation","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro cleavage, mutagenesis-implied blocking, in vivo viral expression with behavioral phenotype, replicated AEP cleavage mechanism from AD study","pmids":["35023303"],"is_preprint":false},{"year":2014,"finding":"The T835M mutation in UNC5C, altering a conserved residue in the hinge region, leads to increased neuronal cell death in HEK293T cells and rodent neurons, and increases susceptibility to cell death from Aβ, glutamate, and staurosporine. This establishes T835M as a gain-of-proapoptotic-function mutation.","method":"In vitro transfection of human HEK293T cells and rodent neurons, cell death assays with multiple neurotoxic stimuli, segregation analysis in AD families","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — direct functional assay in multiple cell types with multiple stimuli, replicated in subsequent mouse KI study","pmids":["25419706"],"is_preprint":false},{"year":2007,"finding":"UNC5C functions as a dependence receptor that induces apoptosis in the absence of its ligand netrin-1. In vivo, UNC5C inactivation in mice increases intestinal tumor progression and decreases tumor cell apoptosis, confirming tumor suppressor activity. UNC5C expression is suppressed in colorectal cancer primarily through promoter methylation.","method":"UNC5C/APC1638N double-mutant mice (genetic epistasis), apoptosis measurement in intestinal tumors, LOH and methylation analysis in human tumors","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in double-mutant mice with direct apoptosis readout, corroborated by human tumor data","pmids":["17967459"],"is_preprint":false},{"year":2011,"finding":"The UNC5C variant A628K significantly reduces apoptosis (measured by active caspase-3 assay) when transfected into HEK293T cells, demonstrating a loss-of-proapoptotic-function mechanism that increases colorectal cancer risk.","method":"Transfection of HEK293T cells with wild-type vs. A628K UNC5C, active caspase-3 apoptosis assay","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay in cell line, single lab, single method","pmids":["21893118"],"is_preprint":false},{"year":2006,"finding":"Unc5c is required in vivo for repulsion-based guidance of trochlear cranial nerve axons and spinal motor (phrenic nerve) axons; Unc5c null mice on C57BL/6J background show ventral/ipsilateral trochlear misprojections and incomplete phrenic nerve innervation of the diaphragm. DCC, Neogenin1, and netrin1 are dispensable for these specific guidance events, placing Unc5c as a non-redundant repulsive receptor for these axon types.","method":"Unc5c null mouse analysis, comparison with DCC/Neogenin1/netrin1 null mice (genetic epistasis), genome scan for modifier loci","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple null mutants, specific axon guidance phenotypes, in vivo","pmids":["16723533"],"is_preprint":false},{"year":2007,"finding":"UNC5C is required for spinal accessory motor neuron (SACMN) migration away from the ventral midline; in UNC5C null mice, SACMN cell bodies fail to migrate dorsally and cluster inappropriately in the ventrolateral spinal cord, while UNC5A null mice have normal SACMN development.","method":"UNC5C and UNC5A null mouse analysis, cell body position analysis in spinal cord","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function in vivo with specific cellular phenotype, comparison with paralog null mice","pmids":["17543537"],"is_preprint":false},{"year":2011,"finding":"UNC5C is required for dorsal guidance of inferior olivary and pontine axons after crossing the midline, and for dorsal guidance of medial deep cerebellar and external cuneate axons. Transgenic re-expression of Unc5c in deep/pontine neurons via Atoh1 promoter rescues these specific defects, demonstrating cell-autonomous function of UNC5C in axon guidance.","method":"Unc5c null mice, axonal trajectory analysis, cell-autonomous rescue by Atoh1-driven transgenic Unc5c expression","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific axon guidance phenotype, cell-autonomous rescue experiment","pmids":["21307253"],"is_preprint":false},{"year":2014,"finding":"DCC and Unc5C expression is under direct negative transcriptional regulation by the cortical projection neuron transcription factors Satb2 and Ctip2, respectively. Netrin1-Unc5C/DCC signaling controls interhemispheric (callosal) projections in deep-layer neurons, placing Unc5C downstream of Ctip2 in a pathway controlling corpus callosum formation.","method":"Genetic epistasis (Satb2/Ctip2 mutant mice), axon tracing, gene expression analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with axon tracing, but direct transcriptional regulation validation methods not fully detailed in abstract","pmids":["24739528"],"is_preprint":false},{"year":2007,"finding":"The homeodomain protein RHOX5 transcriptionally represses Unc5c expression in the testis via a responsive element in the Unc5c 5'-UTR, requiring a Sertoli cell-specific cofactor. RHOX2, RHOX3 (mouse), and RHOXF2/PEPP2 (human) also repress Unc5c, indicating conserved RHOX-dependent regulation. Unc5c mutant mice have decreased germ cell apoptosis in the testis, consistent with Rhox5 promoting germ-cell survival by suppressing Unc5c.","method":"Transfection/reporter analysis of Unc5c 5'-UTR, in vivo expression analysis in Rhox5 mutant testis, Unc5c mutant mouse germ cell apoptosis quantification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — reporter assay + in vivo expression + KO phenotype, but transcriptional mechanism partially validated","pmids":["18077458"],"is_preprint":false},{"year":2019,"finding":"Unc5c, expressed in retinal ganglion cells (RGCs), is necessary and sufficient to guide a subset of RGC axons to the opposite retina (retino-retinal projection). Netrin1 in the ventral diencephalon repels Unc5c-positive retinal axons away from the brain, directing them to the contralateral retina.","method":"Unc5c null mouse analysis, ectopic Unc5c expression, axon tracing, Netrin1 expression mapping","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with specific axon guidance phenotype in vivo","pmids":["30905607"],"is_preprint":false},{"year":2024,"finding":"TRIM9, a brain-enriched E3 ubiquitin ligase, physically interacts with UNC5C and is required for netrin-1-dependent changes in UNC5C surface levels and total levels in the growth cone. TRIM9 regulates the mobility of UNC5C in the plasma membrane and repulsive axon turning responses to netrin-1. Knockdown of UNC5C blocks repulsive turning in a netrin-1 gradient.","method":"Co-immunoprecipitation, Trim9 knockout, shRNA knockdown, pH-mScarlet-UNC5C live imaging, microfluidic netrin-1 gradient, growth cone turning assay","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, KO and KD with specific functional readout, live receptor imaging, multiple orthogonal methods","pmids":["39871643"],"is_preprint":false},{"year":2013,"finding":"unc5c haploinsufficiency in mice leads to increased tyrosine hydroxylase expression selectively in the medial prefrontal cortex (but not nucleus accumbens) and diminished amphetamine-induced locomotion, phenocopying dcc haploinsufficiency, suggesting DCC/UNC5C may act in a complex to regulate mesocortical dopamine development.","method":"unc5c heterozygous mice, immunofluorescence for TH and UNC5C, amphetamine behavioral testing, comparison with dcc heterozygotes","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — haploinsufficiency with specific molecular and behavioral phenotype, but DCC/UNC5C complex not directly demonstrated","pmids":["23738838"],"is_preprint":false},{"year":2024,"finding":"Dopamine axon growth toward the prefrontal cortex during adolescence is guided by a transient gradient of Netrin-1-expressing cells and requires UNC5C; disrupting the Netrin-1 gradient reroutes dopamine axons away from their target. UNC5C expression in dopamine neurons is phase-locked with the timing of mesocortical dopamine axon growth.","method":"Netrin-1 gradient disruption in rodent models (mice and Siberian hamsters), UNC5C expression analysis, axon tracing","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gradient disruption with axon targeting phenotype, but KO/KD of UNC5C itself not directly shown","pmids":["39056276"],"is_preprint":false},{"year":2025,"finding":"The T835M knock-in mutation in UNC5C causes hippocampal volume reduction, ventricular enlargement, dendritic disorganization, neuronal apoptosis (caspase 3/7 activation, TUNEL), upregulation of oxidative stress markers (JNK phosphorylation, NADPH oxidase), and astrocyte/microglial morphological changes by 12-18 months of age. Crossing with AppNL-G-F mice exacerbates these changes and increases Aβ42 levels.","method":"T835M knock-in mouse model, MRI volumetry, TUNEL, caspase 3/7 assay, proteomics, immunohistochemistry, JNK phosphorylation assay, NADPH oxidase assay, cross with AppNL-G-F mice","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 1-2 — knock-in mouse model with multiple orthogonal biochemical and histological readouts, mechanistic pathway delineation","pmids":["40468412"],"is_preprint":false},{"year":2022,"finding":"UNC5C receptor loss in Unc5crcm male mice leads to accumulation of transit-amplifying progenitor spermatogonia, increase in quiescent undifferentiated progenitors, and decline in spermatocyte I numbers with age, without altering cell death rates. In vitro, Netrin-1 repulses both undifferentiated and differentiating spermatogonia, indicating UNC5C mediates repulsion to regulate spermatogonial adhesion/migration and differentiation.","method":"Unc5c mutant mice (rcm allele), histological and flow cytometric analysis of spermatogonial populations, in vitro Netrin-1 repulsion assay","journal":"Stem cell research","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific cellular phenotype, in vitro repulsion assay, single study","pmids":["35247845"],"is_preprint":false},{"year":2026,"finding":"Schisandrin A binds directly to the ZU5 domain of UNC5C with equimolar stoichiometry, driven by enthalpy change with van der Waals forces and hydrogen bonds as main interactions. Key residues Leu61 and Leu96 of ZU5 contribute the greatest binding energy, and binding follows an induced-fit mechanism involving loop fluctuations and secondary structure changes.","method":"Phage display peptide library screening, fluorescence spectroscopy, isothermal titration calorimetry, molecular dynamics simulation","journal":"Bioorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — ITC and fluorescence spectroscopy directly measure binding, but functional consequence not validated in cellular context","pmids":["41724002"],"is_preprint":false}],"current_model":"UNC5C is a transmembrane netrin-1 receptor that functions as a dependence receptor (inducing apoptosis via caspase-3 when unliganded), mediates axon repulsion through multiple mechanisms including DSCAM co-receptor engagement, Src/FAK/Fyn kinase signaling, and dissociation from polymerized TUBB3 in microtubules; it is regulated by proteolytic cleavage by δ-secretase/AEP (which enhances its neurotoxicity), by transcriptional repression via RHOX homeodomain proteins, and by the E3 ubiquitin ligase TRIM9 (which controls its surface levels and mobility); its T835M mutation causes gain-of-proapoptotic function through oxidative stress and JNK/caspase-mediated neurodegeneration, and loss-of-function (via promoter methylation or truncating mutations) confers tumor progression advantage in multiple cancers."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that UNC5C is non-redundantly required for repulsive guidance of specific motor axon populations resolved that DCC, Neogenin1, and Netrin1 are dispensable for these guidance events, positioning UNC5C as an independent repulsive receptor in vivo.","evidence":"Unc5c null mice compared with DCC/Neogenin1/netrin1 null mice; trochlear and phrenic nerve projection analysis","pmids":["16723533"],"confidence":"High","gaps":["Ligand for UNC5C in these guidance events not identified (netrin1 dispensable)","Downstream signaling mechanism unknown at this time"]},{"year":2007,"claim":"Two parallel discoveries established UNC5C's dual biological roles: as a dependence receptor whose loss promotes colorectal tumorigenesis by reducing apoptosis, and as a guidance receptor for spinal accessory motor neuron migration, with its expression regulated by RHOX homeodomain proteins in the testis to control germ cell survival.","evidence":"UNC5C/APC1638N double-mutant mice with apoptosis quantification; UNC5C null mice for SACMN migration; Rhox5 mutant testis with reporter analysis and Unc5c mutant germ cell apoptosis","pmids":["17967459","17543537","18077458"],"confidence":"High","gaps":["Mechanism of UNC5C-induced apoptosis (caspase activation pathway) not yet delineated","Whether RHOX regulation of UNC5C occurs outside the testis unknown","Direct binding of RHOX proteins to Unc5c regulatory elements not shown by ChIP"]},{"year":2011,"claim":"Cell-autonomous rescue experiments and functional variant analysis defined both the guidance and apoptotic mechanisms more precisely: UNC5C is cell-autonomously required for dorsal axon guidance of precerebellar neurons, and the A628K variant directly reduces caspase-3 activation, linking loss of proapoptotic function to colorectal cancer risk.","evidence":"Unc5c null mice with Atoh1-driven transgenic rescue for axon guidance; HEK293T transfection with A628K variant and caspase-3 assay","pmids":["21307253","21893118"],"confidence":"High","gaps":["Structural basis for how A628K impairs death domain signaling unknown","Whether additional UNC5 paralogs compensate in precerebellar circuits not tested"]},{"year":2012,"claim":"Identification of DSCAM as a co-receptor that physically associates with UNC5C and is required for netrin-1-induced growth cone collapse revealed the upstream signaling cascade (DSCAM→UNC5C→Fyn/FAK/PAK1) mediating repulsive guidance.","evidence":"Reciprocal Co-IP, shRNA knockdown, Src kinase inhibition, phosphorylation assays, growth cone collapse in primary cortical and cerebellar granule neurons","pmids":["22685302"],"confidence":"High","gaps":["Whether DSCAM-UNC5C interaction is direct or scaffold-mediated not fully resolved","Structural basis of the netrin-1-stimulated interaction unknown"]},{"year":2014,"claim":"The T835M variant was identified as a gain-of-proapoptotic-function mutation in UNC5C that enhances neuronal vulnerability to multiple neurotoxic stimuli, establishing a genetic link between UNC5C and late-onset Alzheimer's disease risk.","evidence":"HEK293T and rodent neuron transfection with cell death assays under Aβ, glutamate, and staurosporine; segregation in AD families","pmids":["25419706"],"confidence":"High","gaps":["Molecular mechanism by which T835M enhances apoptosis (downstream pathway) not yet identified","Population-level replication of AD risk association limited"]},{"year":2017,"claim":"Discovery that UNC5C directly binds polymerized TUBB3 and that netrin-1 triggers their dissociation revealed a microtubule-based mechanism for repulsive turning, showing that receptor-cytoskeleton coupling is dynamically regulated during guidance.","evidence":"In vitro cosedimentation, Co-IP, EB3-GFP live imaging, shRNA knockdown, in vivo DRG axon analysis","pmids":["28483977"],"confidence":"High","gaps":["Which UNC5C domain mediates TUBB3 binding not mapped","How TUBB3 dissociation is coordinated with DSCAM/Src signaling unclear"]},{"year":2019,"claim":"Demonstration that UNC5C is necessary and sufficient for retino-retinal axon guidance, repelled by a Netrin-1 gradient in the ventral diencephalon, extended the receptor's known guidance roles to a novel projection type.","evidence":"Unc5c null mice, ectopic UNC5C expression, axon tracing, Netrin-1 expression mapping","pmids":["30905607"],"confidence":"High","gaps":["Whether co-receptors (DSCAM, DCC) participate in retino-retinal guidance not tested"]},{"year":2021,"claim":"Identification of δ-secretase/AEP cleavage at N467 and N547 as a mechanism that amplifies UNC5C's proapoptotic activity provided a proteolytic link between netrin-1 deficiency and neurodegeneration: AEP-generated fragments drive AD pathology in vivo.","evidence":"In vitro cleavage assay with site mutagenesis, viral expression of truncated fragments in APP/PS1 mice, UNC5C genetic deletion in netrin-1-depleted mice","pmids":["33863723"],"confidence":"High","gaps":["Whether AEP cleavage occurs at endogenous levels in human AD brain not directly shown","Crystal structure of AEP-UNC5C complex unavailable"]},{"year":2022,"claim":"The AEP-UNC5C cleavage mechanism was extended to Parkinson's disease, where the intracellular fragment elicits α-synuclein aggregation and dopaminergic loss, while UNC5C was also shown to regulate spermatogonial differentiation through netrin-1-mediated repulsion in the testis.","evidence":"Viral overexpression of AEP-truncated UNC5C in PD transgenic mice with behavioral testing; Unc5c rcm mutant mice with spermatogonial flow cytometry and in vitro repulsion assay","pmids":["35023303","35247845"],"confidence":"High","gaps":["Whether AEP cleavage is the primary pathogenic event or secondary to other protease cascades in PD unknown","Mechanism linking UNC5C to spermatogonial differentiation versus adhesion not distinguished"]},{"year":2024,"claim":"Two advances clarified UNC5C regulation and in vivo neurodevelopmental function: TRIM9 was identified as an E3 ligase controlling UNC5C surface levels and mobility required for repulsive turning, and a transient Netrin-1 gradient was shown to guide UNC5C-expressing dopamine axons to the prefrontal cortex during adolescence.","evidence":"Co-IP, Trim9 KO, shRNA, live pH-mScarlet-UNC5C imaging in microfluidic gradient; Netrin-1 gradient disruption in rodent models with axon tracing","pmids":["39871643","39056276"],"confidence":"High","gaps":["Whether TRIM9 ubiquitinates UNC5C directly or acts through adaptor not resolved","UNC5C conditional knockout in dopamine neurons not performed"]},{"year":2025,"claim":"The T835M knock-in mouse model delineated the in vivo degenerative cascade: oxidative stress via NADPH oxidase, JNK phosphorylation, caspase-3/7 activation, hippocampal atrophy, and exacerbation of amyloid pathology when crossed with AD mice, establishing a full mechanistic pathway from mutation to neurodegeneration.","evidence":"T835M knock-in mice, MRI volumetry, TUNEL, proteomics, JNK/caspase assays, NADPH oxidase measurement, cross with AppNL-G-F mice","pmids":["40468412"],"confidence":"High","gaps":["Whether oxidative stress is upstream or downstream of caspase activation not resolved","Therapeutic rescue of T835M phenotype not demonstrated"]},{"year":null,"claim":"Key unresolved questions include the structural basis of UNC5C death domain signaling, how AEP cleavage fragments interact with α-synuclein aggregation machinery, whether TRIM9-mediated ubiquitination is direct, and how DSCAM/TUBB3/Src pathways are integrated during growth cone repulsion.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of UNC5C intracellular domain in active/inactive state","Integration of DSCAM, TUBB3, and TRIM9 regulatory arms not tested in unified system","Human in vivo validation of AEP-UNC5C cleavage in neurodegeneration lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,5,7,9,12,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,13]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8,9,10,12,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3,4,5,6,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4,5,6,16]}],"complexes":[],"partners":["DSCAM","TUBB3","TRIM9","NTN1","FAK","FYN","DCC"],"other_free_text":[]},"mechanistic_narrative":"UNC5C is a transmembrane netrin-1 receptor that mediates repulsive axon guidance and functions as a dependence receptor, triggering caspase-3-dependent apoptosis in the absence of ligand [PMID:17967459, PMID:25419706]. In the nervous system, UNC5C is non-redundantly required for repulsion-based guidance of cranial, spinal, cerebellar, retinal, and mesocortical dopaminergic axons, acting cell-autonomously through mechanisms involving DSCAM co-receptor engagement and Src/FAK/Fyn/PAK1 kinase signaling, dissociation from polymerized TUBB3 in growth cone microtubules, and regulation of surface levels by the E3 ubiquitin ligase TRIM9 [PMID:22685302, PMID:28483977, PMID:21307253, PMID:39871643]. The proapoptotic activity of UNC5C is amplified by δ-secretase/AEP-mediated cleavage at N467 and N547, generating neurotoxic intracellular fragments that promote Alzheimer's and Parkinson's disease-related neurodegeneration in vivo, while the T835M gain-of-function mutation causes progressive neuronal apoptosis through oxidative stress and JNK/caspase activation [PMID:33863723, PMID:35023303, PMID:40468412]. Loss of UNC5C dependence receptor function—via promoter methylation, loss-of-function mutations such as A628K, or gene inactivation—reduces tumor cell apoptosis and promotes colorectal cancer progression [PMID:17967459, PMID:21893118]."},"prefetch_data":{"uniprot":{"accession":"O95185","full_name":"Netrin receptor UNC5C","aliases":["Protein unc-5 homolog 3","Protein unc-5 homolog C"],"length_aa":931,"mass_kda":103.1,"function":"Receptor for netrin required for axon guidance (By similarity). Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding (By similarity). NTN1/Netrin-1 binding might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion (PubMed:28483977). Axon repulsion in growth cones may also be caused by its association with DCC that may trigger signaling for repulsion (By similarity). Might also collaborate with DSCAM in NTN1-mediated axon repulsion independently of DCC (By similarity). Also involved in corticospinal tract axon guidance independently of DCC (By similarity). Involved in dorsal root ganglion axon projection towards the spinal cord (PubMed:28483977). It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand (By similarity)","subcellular_location":"Cell membrane; Cell surface; Synapse, synaptosome; Cell projection, axon; Cell projection, dendrite; Cell projection, growth cone; Cell projection, lamellipodium; Cell projection, filopodium","url":"https://www.uniprot.org/uniprotkb/O95185/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UNC5C","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/UNC5C","total_profiled":1310},"omim":[{"mim_id":"617464","title":"UNC5 FAMILY C-TERMINAL-LIKE PROTEIN; UNC5CL","url":"https://www.omim.org/entry/617464"},{"mim_id":"607870","title":"UNC5 NETRIN RECEPTOR B; UNC5B","url":"https://www.omim.org/entry/607870"},{"mim_id":"607869","title":"UNC5 NETRIN RECEPTOR A; UNC5A","url":"https://www.omim.org/entry/607869"},{"mim_id":"603610","title":"UNC5 NETRIN RECEPTOR C; UNC5C","url":"https://www.omim.org/entry/603610"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"thyroid gland","ntpm":11.1}],"url":"https://www.proteinatlas.org/search/UNC5C"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O95185","domains":[{"cath_id":"2.60.40.10","chopping":"62-163","consensus_level":"high","plddt":90.8401,"start":62,"end":163},{"cath_id":"2.60.40.10","chopping":"166-257","consensus_level":"medium","plddt":94.0355,"start":166,"end":257},{"cath_id":"2.20.100.10","chopping":"261-310","consensus_level":"medium","plddt":92.147,"start":261,"end":310},{"cath_id":"2.20.100.10","chopping":"317-360","consensus_level":"medium","plddt":86.912,"start":317,"end":360},{"cath_id":"2.60.40","chopping":"680-813","consensus_level":"high","plddt":91.3056,"start":680,"end":813},{"cath_id":"1.10.533.10","chopping":"842-931","consensus_level":"medium","plddt":83.2738,"start":842,"end":931}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95185","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95185-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95185-F1-predicted_aligned_error_v6.png","plddt_mean":78.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UNC5C","jax_strain_url":"https://www.jax.org/strain/search?query=UNC5C"},"sequence":{"accession":"O95185","fasta_url":"https://rest.uniprot.org/uniprotkb/O95185.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95185/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95185"}},"corpus_meta":[{"pmid":"25419706","id":"PMC_25419706","title":"A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death.","date":"2014","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25419706","citation_count":129,"is_preprint":false},{"pmid":"17967459","id":"PMC_17967459","title":"Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.","date":"2007","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/17967459","citation_count":107,"is_preprint":false},{"pmid":"18054557","id":"PMC_18054557","title":"Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.","date":"2007","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/18054557","citation_count":89,"is_preprint":false},{"pmid":"22685302","id":"PMC_22685302","title":"Down syndrome cell adhesion molecule (DSCAM) associates with uncoordinated-5C (UNC5C) in netrin-1-mediated growth cone collapse.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22685302","citation_count":65,"is_preprint":false},{"pmid":"24739528","id":"PMC_24739528","title":"Unc5C and DCC act downstream of Ctip2 and Satb2 and contribute to corpus callosum formation.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24739528","citation_count":59,"is_preprint":false},{"pmid":"16723533","id":"PMC_16723533","title":"Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16723533","citation_count":52,"is_preprint":false},{"pmid":"21307253","id":"PMC_21307253","title":"The UNC5C netrin receptor regulates dorsal guidance of mouse hindbrain axons.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21307253","citation_count":50,"is_preprint":false},{"pmid":"33863723","id":"PMC_33863723","title":"Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33863723","citation_count":42,"is_preprint":false},{"pmid":"28483977","id":"PMC_28483977","title":"Uncoupling of UNC5C with Polymerized TUBB3 in Microtubules Mediates Netrin-1 Repulsion.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28483977","citation_count":38,"is_preprint":false},{"pmid":"17543537","id":"PMC_17543537","title":"UNC5C is required for spinal accessory motor neuron development.","date":"2007","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/17543537","citation_count":34,"is_preprint":false},{"pmid":"21893118","id":"PMC_21893118","title":"Variants in the netrin-1 receptor UNC5C prevent apoptosis and increase risk of familial colorectal cancer.","date":"2011","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/21893118","citation_count":31,"is_preprint":false},{"pmid":"19242752","id":"PMC_19242752","title":"Aberrant methylation of the netrin-1 receptor genes UNC5C and DCC detected in advanced colorectal cancer.","date":"2009","source":"World journal of surgery","url":"https://pubmed.ncbi.nlm.nih.gov/19242752","citation_count":28,"is_preprint":false},{"pmid":"30905607","id":"PMC_30905607","title":"A Retino-retinal Projection Guided by Unc5c Emerged in Species with Retinal Waves.","date":"2019","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/30905607","citation_count":28,"is_preprint":false},{"pmid":"18077458","id":"PMC_18077458","title":"The RHOX5 homeodomain protein mediates transcriptional repression of the netrin-1 receptor gene Unc5c.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18077458","citation_count":28,"is_preprint":false},{"pmid":"9782087","id":"PMC_9782087","title":"Cloning and mapping of the UNC5C gene to human chromosome 4q21-q23.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9782087","citation_count":27,"is_preprint":false},{"pmid":"35023303","id":"PMC_35023303","title":"UNC5C Receptor Proteolytic Cleavage by Active AEP Promotes Dopaminergic Neuronal Degeneration in Parkinson's Disease.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35023303","citation_count":25,"is_preprint":false},{"pmid":"21600761","id":"PMC_21600761","title":"Genetic and epigenetic control of UNC5C expression in human renal cell carcinoma.","date":"2011","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/21600761","citation_count":24,"is_preprint":false},{"pmid":"29951500","id":"PMC_29951500","title":"The role of UNC5C in Alzheimer's disease.","date":"2018","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29951500","citation_count":23,"is_preprint":false},{"pmid":"26660111","id":"PMC_26660111","title":"The Impact of UNC5C Genetic Variations on Neuroimaging in Alzheimer's Disease.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26660111","citation_count":23,"is_preprint":false},{"pmid":"31789389","id":"PMC_31789389","title":"UNC5C‑knockdown enhances the growth and metastasis of breast cancer cells by potentiating the integrin α6/β4 signaling pathway.","date":"2019","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31789389","citation_count":16,"is_preprint":false},{"pmid":"19331160","id":"PMC_19331160","title":"Aberrant methylation of the UNC5C gene is frequently detected in advanced colorectal cancer.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19331160","citation_count":15,"is_preprint":false},{"pmid":"20032384","id":"PMC_20032384","title":"Changes in UNC5C gene methylation during human gastric carcinogenesis.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20032384","citation_count":12,"is_preprint":false},{"pmid":"24415873","id":"PMC_24415873","title":"Evaluation of the colorectal cancer risk conferred by rare UNC5C alleles.","date":"2014","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/24415873","citation_count":12,"is_preprint":false},{"pmid":"28761931","id":"PMC_28761931","title":"UNC5C variants are associated with cerebral amyloid angiopathy.","date":"2017","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28761931","citation_count":12,"is_preprint":false},{"pmid":"23738838","id":"PMC_23738838","title":"unc5c haploinsufficient phenotype: striking similarities with the dcc haploinsufficiency model.","date":"2013","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23738838","citation_count":12,"is_preprint":false},{"pmid":"26852919","id":"PMC_26852919","title":"Scarce evidence of the causal role of germline mutations in UNC5C in hereditary colorectal cancer and polyposis.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26852919","citation_count":10,"is_preprint":false},{"pmid":"29801399","id":"PMC_29801399","title":"Significant Pattern of Promoter Hypermethylation of UNC5C Gene in Colorectal Cancer and Its Implication in Late Stage Disease.","date":"2018","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/29801399","citation_count":9,"is_preprint":false},{"pmid":"39056276","id":"PMC_39056276","title":"The scheduling of adolescence with Netrin-1 and UNC5C.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/39056276","citation_count":8,"is_preprint":false},{"pmid":"38540364","id":"PMC_38540364","title":"UNC5C: Novel Gene Associated with Psychiatric Disorders Impacts Dysregulation of Axon Guidance Pathways.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38540364","citation_count":8,"is_preprint":false},{"pmid":"33706130","id":"PMC_33706130","title":"A global integrated analysis of UNC5C down-regulation in cancers: insights from mechanism and combined treatment strategy.","date":"2021","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/33706130","citation_count":7,"is_preprint":false},{"pmid":"24333968","id":"PMC_24333968","title":"Target-dependent expression of the netrin-1 receptor, UNC5C, in projection neurons of the ventral tegmental area.","date":"2013","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24333968","citation_count":6,"is_preprint":false},{"pmid":"23178624","id":"PMC_23178624","title":"Methylation of the UNC5C gene is frequently detected in hepatocellular carcinoma.","date":"2012","source":"Hepato-gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23178624","citation_count":5,"is_preprint":false},{"pmid":"37841863","id":"PMC_37841863","title":"The impact of blood MCP-1 levels on Alzheimer's disease with genetic variation of UNC5C and NAV3 loci.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37841863","citation_count":4,"is_preprint":false},{"pmid":"40830334","id":"PMC_40830334","title":"The impact of blood MCP-1 levels on Alzheimer's disease with genetic variation at the NAV3 and UNC5C loci.","date":"2025","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/40830334","citation_count":3,"is_preprint":false},{"pmid":"25902168","id":"PMC_25902168","title":"Expression and significance of netrin-1 and its receptor UNC5C in precocious puberty female rat hypothalamus.","date":"2015","source":"Asian Pacific journal of tropical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25902168","citation_count":3,"is_preprint":false},{"pmid":"35247845","id":"PMC_35247845","title":"The netrin-1 receptor UNC5C contributes to the homeostasis of undifferentiated spermatogonia in adult mice.","date":"2022","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35247845","citation_count":2,"is_preprint":false},{"pmid":"38765979","id":"PMC_38765979","title":"TRIM9 controls growth cone responses to netrin through DCC and UNC5C.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38765979","citation_count":2,"is_preprint":false},{"pmid":"39871643","id":"PMC_39871643","title":"TRIM9 Controls Growth Cone Responses to Netrin Through DCC and UNC5C.","date":"2025","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39871643","citation_count":2,"is_preprint":false},{"pmid":"40468412","id":"PMC_40468412","title":"The UNC5C T835M mutation associated with Alzheimer's disease leads to neurodegeneration involving oxidative stress and hippocampal atrophy in aged mice.","date":"2025","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/40468412","citation_count":1,"is_preprint":false},{"pmid":"36711625","id":"PMC_36711625","title":"The scheduling of adolescence with Netrin-1 and UNC5C.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711625","citation_count":1,"is_preprint":false},{"pmid":"41649849","id":"PMC_41649849","title":"LncRNA UNC5C-AS1 inhibits angiogenesis and induces endothelial apoptosis via the miR-148a-3p/EMP1 axis in preeclampsia.","date":"2026","source":"Cell adhesion & migration","url":"https://pubmed.ncbi.nlm.nih.gov/41649849","citation_count":0,"is_preprint":false},{"pmid":"41724002","id":"PMC_41724002","title":"Identification of the ZU5 domain in UNC5C as a potential receptor for Schisandrin A: experimental and computational insights.","date":"2026","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41724002","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.28.640710","title":"<i>UNC5H3</i> expression during early development in the chicken is associated with populations at the dorsal apex of the neural tube","date":"2025-03-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.28.640710","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22083,"output_tokens":5134,"usd":0.071629},"stage2":{"model":"claude-opus-4-6","input_tokens":8625,"output_tokens":3315,"usd":0.189},"total_usd":0.260629,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"DSCAM physically interacts with UNC5C, and this interaction is stimulated by netrin-1 in primary cortical neurons and cerebellar granule cells. Netrin-1 induces growth cone collapse via UNC5C/DSCAM, and this requires Src family kinase-dependent tyrosine phosphorylation of UNC5C, DSCAM, FAK, Fyn, and PAK1. DSCAM knockdown inhibits netrin-1-induced tyrosine phosphorylation of UNC5C and Fyn, placing DSCAM upstream of UNC5C-Fyn signaling.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, dominant negative overexpression, phosphorylation assays, Src family kinase inhibition, growth cone collapse assay in primary neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple orthogonal methods (KD, DN, kinase inhibition, phospho-assays), functional readout in primary neurons\",\n      \"pmids\": [\"22685302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UNC5C directly interacts with polymerized TUBB3 (neuron-specific β-tubulin) in microtubules, and netrin-1 reduces this interaction and their colocalization in growth cones. Disengagement of UNC5C from TUBB3 is required for netrin-1/UNC5C-mediated axon repulsion, and knockdown of either protein blocks repulsion and causes DRG axon projection defects in vivo. Netrin-1 increases microtubule dynamics differentially in the growth cone during repulsion.\",\n      \"method\": \"In vitro cosedimentation assay, Co-IP, shRNA knockdown, live-cell EB3-GFP imaging, in vivo DRG axon projection analysis\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro cosedimentation (biochemical reconstitution), live imaging, KD with in vivo phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"28483977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"δ-secretase (asparagine endopeptidase/AEP) cleaves UNC5C at N467 and N547 residues, enhancing its proapoptotic/caspase-3 activating activity. Netrin-1 deficiency activates δ-secretase, which truncates UNC5C; blocking this cleavage diminishes the T835M mutant's proapoptotic activity. Viral expression of δ-secretase-truncated UNC5C fragments in APP/PS1 mice accelerates AD pathologies and impairs learning/memory, while UNC5C deletion from netrin-1-depleted mice attenuates AD pathologies.\",\n      \"method\": \"In vitro cleavage assay with mutagenesis (N467/N547 sites), caspase-3 activation assay, viral expression in transgenic mice, behavioral testing, genetic deletion\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-specific mutagenesis identifying cleavage sites, in vitro assay, in vivo viral expression and genetic deletion with functional readouts\",\n      \"pmids\": [\"33863723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AEP (asparagine endopeptidase) cleaves UNC5C in Parkinson's disease, facilitating dopaminergic neuronal loss. Netrin-1 deprivation induces AEP and caspase-3 activation, triggering UNC5C proteolytic fragmentation. Blocking UNC5C cleavage by AEP attenuates neuronal death and motor disorders; overexpression of AEP-truncated UNC5C intracellular fragment elicits α-synuclein aggregation and dopaminergic loss in transgenic mice.\",\n      \"method\": \"In vitro cleavage assay, primary neuron cultures, viral overexpression in transgenic mice, behavioral motor testing, biochemical fractionation\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro cleavage, mutagenesis-implied blocking, in vivo viral expression with behavioral phenotype, replicated AEP cleavage mechanism from AD study\",\n      \"pmids\": [\"35023303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The T835M mutation in UNC5C, altering a conserved residue in the hinge region, leads to increased neuronal cell death in HEK293T cells and rodent neurons, and increases susceptibility to cell death from Aβ, glutamate, and staurosporine. This establishes T835M as a gain-of-proapoptotic-function mutation.\",\n      \"method\": \"In vitro transfection of human HEK293T cells and rodent neurons, cell death assays with multiple neurotoxic stimuli, segregation analysis in AD families\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay in multiple cell types with multiple stimuli, replicated in subsequent mouse KI study\",\n      \"pmids\": [\"25419706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UNC5C functions as a dependence receptor that induces apoptosis in the absence of its ligand netrin-1. In vivo, UNC5C inactivation in mice increases intestinal tumor progression and decreases tumor cell apoptosis, confirming tumor suppressor activity. UNC5C expression is suppressed in colorectal cancer primarily through promoter methylation.\",\n      \"method\": \"UNC5C/APC1638N double-mutant mice (genetic epistasis), apoptosis measurement in intestinal tumors, LOH and methylation analysis in human tumors\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in double-mutant mice with direct apoptosis readout, corroborated by human tumor data\",\n      \"pmids\": [\"17967459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The UNC5C variant A628K significantly reduces apoptosis (measured by active caspase-3 assay) when transfected into HEK293T cells, demonstrating a loss-of-proapoptotic-function mechanism that increases colorectal cancer risk.\",\n      \"method\": \"Transfection of HEK293T cells with wild-type vs. A628K UNC5C, active caspase-3 apoptosis assay\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay in cell line, single lab, single method\",\n      \"pmids\": [\"21893118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Unc5c is required in vivo for repulsion-based guidance of trochlear cranial nerve axons and spinal motor (phrenic nerve) axons; Unc5c null mice on C57BL/6J background show ventral/ipsilateral trochlear misprojections and incomplete phrenic nerve innervation of the diaphragm. DCC, Neogenin1, and netrin1 are dispensable for these specific guidance events, placing Unc5c as a non-redundant repulsive receptor for these axon types.\",\n      \"method\": \"Unc5c null mouse analysis, comparison with DCC/Neogenin1/netrin1 null mice (genetic epistasis), genome scan for modifier loci\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple null mutants, specific axon guidance phenotypes, in vivo\",\n      \"pmids\": [\"16723533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UNC5C is required for spinal accessory motor neuron (SACMN) migration away from the ventral midline; in UNC5C null mice, SACMN cell bodies fail to migrate dorsally and cluster inappropriately in the ventrolateral spinal cord, while UNC5A null mice have normal SACMN development.\",\n      \"method\": \"UNC5C and UNC5A null mouse analysis, cell body position analysis in spinal cord\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in vivo with specific cellular phenotype, comparison with paralog null mice\",\n      \"pmids\": [\"17543537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UNC5C is required for dorsal guidance of inferior olivary and pontine axons after crossing the midline, and for dorsal guidance of medial deep cerebellar and external cuneate axons. Transgenic re-expression of Unc5c in deep/pontine neurons via Atoh1 promoter rescues these specific defects, demonstrating cell-autonomous function of UNC5C in axon guidance.\",\n      \"method\": \"Unc5c null mice, axonal trajectory analysis, cell-autonomous rescue by Atoh1-driven transgenic Unc5c expression\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific axon guidance phenotype, cell-autonomous rescue experiment\",\n      \"pmids\": [\"21307253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DCC and Unc5C expression is under direct negative transcriptional regulation by the cortical projection neuron transcription factors Satb2 and Ctip2, respectively. Netrin1-Unc5C/DCC signaling controls interhemispheric (callosal) projections in deep-layer neurons, placing Unc5C downstream of Ctip2 in a pathway controlling corpus callosum formation.\",\n      \"method\": \"Genetic epistasis (Satb2/Ctip2 mutant mice), axon tracing, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with axon tracing, but direct transcriptional regulation validation methods not fully detailed in abstract\",\n      \"pmids\": [\"24739528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The homeodomain protein RHOX5 transcriptionally represses Unc5c expression in the testis via a responsive element in the Unc5c 5'-UTR, requiring a Sertoli cell-specific cofactor. RHOX2, RHOX3 (mouse), and RHOXF2/PEPP2 (human) also repress Unc5c, indicating conserved RHOX-dependent regulation. Unc5c mutant mice have decreased germ cell apoptosis in the testis, consistent with Rhox5 promoting germ-cell survival by suppressing Unc5c.\",\n      \"method\": \"Transfection/reporter analysis of Unc5c 5'-UTR, in vivo expression analysis in Rhox5 mutant testis, Unc5c mutant mouse germ cell apoptosis quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reporter assay + in vivo expression + KO phenotype, but transcriptional mechanism partially validated\",\n      \"pmids\": [\"18077458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Unc5c, expressed in retinal ganglion cells (RGCs), is necessary and sufficient to guide a subset of RGC axons to the opposite retina (retino-retinal projection). Netrin1 in the ventral diencephalon repels Unc5c-positive retinal axons away from the brain, directing them to the contralateral retina.\",\n      \"method\": \"Unc5c null mouse analysis, ectopic Unc5c expression, axon tracing, Netrin1 expression mapping\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with specific axon guidance phenotype in vivo\",\n      \"pmids\": [\"30905607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM9, a brain-enriched E3 ubiquitin ligase, physically interacts with UNC5C and is required for netrin-1-dependent changes in UNC5C surface levels and total levels in the growth cone. TRIM9 regulates the mobility of UNC5C in the plasma membrane and repulsive axon turning responses to netrin-1. Knockdown of UNC5C blocks repulsive turning in a netrin-1 gradient.\",\n      \"method\": \"Co-immunoprecipitation, Trim9 knockout, shRNA knockdown, pH-mScarlet-UNC5C live imaging, microfluidic netrin-1 gradient, growth cone turning assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, KO and KD with specific functional readout, live receptor imaging, multiple orthogonal methods\",\n      \"pmids\": [\"39871643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"unc5c haploinsufficiency in mice leads to increased tyrosine hydroxylase expression selectively in the medial prefrontal cortex (but not nucleus accumbens) and diminished amphetamine-induced locomotion, phenocopying dcc haploinsufficiency, suggesting DCC/UNC5C may act in a complex to regulate mesocortical dopamine development.\",\n      \"method\": \"unc5c heterozygous mice, immunofluorescence for TH and UNC5C, amphetamine behavioral testing, comparison with dcc heterozygotes\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — haploinsufficiency with specific molecular and behavioral phenotype, but DCC/UNC5C complex not directly demonstrated\",\n      \"pmids\": [\"23738838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dopamine axon growth toward the prefrontal cortex during adolescence is guided by a transient gradient of Netrin-1-expressing cells and requires UNC5C; disrupting the Netrin-1 gradient reroutes dopamine axons away from their target. UNC5C expression in dopamine neurons is phase-locked with the timing of mesocortical dopamine axon growth.\",\n      \"method\": \"Netrin-1 gradient disruption in rodent models (mice and Siberian hamsters), UNC5C expression analysis, axon tracing\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gradient disruption with axon targeting phenotype, but KO/KD of UNC5C itself not directly shown\",\n      \"pmids\": [\"39056276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The T835M knock-in mutation in UNC5C causes hippocampal volume reduction, ventricular enlargement, dendritic disorganization, neuronal apoptosis (caspase 3/7 activation, TUNEL), upregulation of oxidative stress markers (JNK phosphorylation, NADPH oxidase), and astrocyte/microglial morphological changes by 12-18 months of age. Crossing with AppNL-G-F mice exacerbates these changes and increases Aβ42 levels.\",\n      \"method\": \"T835M knock-in mouse model, MRI volumetry, TUNEL, caspase 3/7 assay, proteomics, immunohistochemistry, JNK phosphorylation assay, NADPH oxidase assay, cross with AppNL-G-F mice\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — knock-in mouse model with multiple orthogonal biochemical and histological readouts, mechanistic pathway delineation\",\n      \"pmids\": [\"40468412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UNC5C receptor loss in Unc5crcm male mice leads to accumulation of transit-amplifying progenitor spermatogonia, increase in quiescent undifferentiated progenitors, and decline in spermatocyte I numbers with age, without altering cell death rates. In vitro, Netrin-1 repulses both undifferentiated and differentiating spermatogonia, indicating UNC5C mediates repulsion to regulate spermatogonial adhesion/migration and differentiation.\",\n      \"method\": \"Unc5c mutant mice (rcm allele), histological and flow cytometric analysis of spermatogonial populations, in vitro Netrin-1 repulsion assay\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific cellular phenotype, in vitro repulsion assay, single study\",\n      \"pmids\": [\"35247845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Schisandrin A binds directly to the ZU5 domain of UNC5C with equimolar stoichiometry, driven by enthalpy change with van der Waals forces and hydrogen bonds as main interactions. Key residues Leu61 and Leu96 of ZU5 contribute the greatest binding energy, and binding follows an induced-fit mechanism involving loop fluctuations and secondary structure changes.\",\n      \"method\": \"Phage display peptide library screening, fluorescence spectroscopy, isothermal titration calorimetry, molecular dynamics simulation\",\n      \"journal\": \"Bioorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — ITC and fluorescence spectroscopy directly measure binding, but functional consequence not validated in cellular context\",\n      \"pmids\": [\"41724002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UNC5C is a transmembrane netrin-1 receptor that functions as a dependence receptor (inducing apoptosis via caspase-3 when unliganded), mediates axon repulsion through multiple mechanisms including DSCAM co-receptor engagement, Src/FAK/Fyn kinase signaling, and dissociation from polymerized TUBB3 in microtubules; it is regulated by proteolytic cleavage by δ-secretase/AEP (which enhances its neurotoxicity), by transcriptional repression via RHOX homeodomain proteins, and by the E3 ubiquitin ligase TRIM9 (which controls its surface levels and mobility); its T835M mutation causes gain-of-proapoptotic function through oxidative stress and JNK/caspase-mediated neurodegeneration, and loss-of-function (via promoter methylation or truncating mutations) confers tumor progression advantage in multiple cancers.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"UNC5C is a transmembrane netrin-1 receptor that mediates repulsive axon guidance and functions as a dependence receptor, triggering caspase-3-dependent apoptosis in the absence of ligand [PMID:17967459, PMID:25419706]. In the nervous system, UNC5C is non-redundantly required for repulsion-based guidance of cranial, spinal, cerebellar, retinal, and mesocortical dopaminergic axons, acting cell-autonomously through mechanisms involving DSCAM co-receptor engagement and Src/FAK/Fyn/PAK1 kinase signaling, dissociation from polymerized TUBB3 in growth cone microtubules, and regulation of surface levels by the E3 ubiquitin ligase TRIM9 [PMID:22685302, PMID:28483977, PMID:21307253, PMID:39871643]. The proapoptotic activity of UNC5C is amplified by δ-secretase/AEP-mediated cleavage at N467 and N547, generating neurotoxic intracellular fragments that promote Alzheimer's and Parkinson's disease-related neurodegeneration in vivo, while the T835M gain-of-function mutation causes progressive neuronal apoptosis through oxidative stress and JNK/caspase activation [PMID:33863723, PMID:35023303, PMID:40468412]. Loss of UNC5C dependence receptor function—via promoter methylation, loss-of-function mutations such as A628K, or gene inactivation—reduces tumor cell apoptosis and promotes colorectal cancer progression [PMID:17967459, PMID:21893118].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that UNC5C is non-redundantly required for repulsive guidance of specific motor axon populations resolved that DCC, Neogenin1, and Netrin1 are dispensable for these guidance events, positioning UNC5C as an independent repulsive receptor in vivo.\",\n      \"evidence\": \"Unc5c null mice compared with DCC/Neogenin1/netrin1 null mice; trochlear and phrenic nerve projection analysis\",\n      \"pmids\": [\"16723533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand for UNC5C in these guidance events not identified (netrin1 dispensable)\", \"Downstream signaling mechanism unknown at this time\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Two parallel discoveries established UNC5C's dual biological roles: as a dependence receptor whose loss promotes colorectal tumorigenesis by reducing apoptosis, and as a guidance receptor for spinal accessory motor neuron migration, with its expression regulated by RHOX homeodomain proteins in the testis to control germ cell survival.\",\n      \"evidence\": \"UNC5C/APC1638N double-mutant mice with apoptosis quantification; UNC5C null mice for SACMN migration; Rhox5 mutant testis with reporter analysis and Unc5c mutant germ cell apoptosis\",\n      \"pmids\": [\"17967459\", \"17543537\", \"18077458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of UNC5C-induced apoptosis (caspase activation pathway) not yet delineated\", \"Whether RHOX regulation of UNC5C occurs outside the testis unknown\", \"Direct binding of RHOX proteins to Unc5c regulatory elements not shown by ChIP\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cell-autonomous rescue experiments and functional variant analysis defined both the guidance and apoptotic mechanisms more precisely: UNC5C is cell-autonomously required for dorsal axon guidance of precerebellar neurons, and the A628K variant directly reduces caspase-3 activation, linking loss of proapoptotic function to colorectal cancer risk.\",\n      \"evidence\": \"Unc5c null mice with Atoh1-driven transgenic rescue for axon guidance; HEK293T transfection with A628K variant and caspase-3 assay\",\n      \"pmids\": [\"21307253\", \"21893118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how A628K impairs death domain signaling unknown\", \"Whether additional UNC5 paralogs compensate in precerebellar circuits not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of DSCAM as a co-receptor that physically associates with UNC5C and is required for netrin-1-induced growth cone collapse revealed the upstream signaling cascade (DSCAM→UNC5C→Fyn/FAK/PAK1) mediating repulsive guidance.\",\n      \"evidence\": \"Reciprocal Co-IP, shRNA knockdown, Src kinase inhibition, phosphorylation assays, growth cone collapse in primary cortical and cerebellar granule neurons\",\n      \"pmids\": [\"22685302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DSCAM-UNC5C interaction is direct or scaffold-mediated not fully resolved\", \"Structural basis of the netrin-1-stimulated interaction unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The T835M variant was identified as a gain-of-proapoptotic-function mutation in UNC5C that enhances neuronal vulnerability to multiple neurotoxic stimuli, establishing a genetic link between UNC5C and late-onset Alzheimer's disease risk.\",\n      \"evidence\": \"HEK293T and rodent neuron transfection with cell death assays under Aβ, glutamate, and staurosporine; segregation in AD families\",\n      \"pmids\": [\"25419706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which T835M enhances apoptosis (downstream pathway) not yet identified\", \"Population-level replication of AD risk association limited\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that UNC5C directly binds polymerized TUBB3 and that netrin-1 triggers their dissociation revealed a microtubule-based mechanism for repulsive turning, showing that receptor-cytoskeleton coupling is dynamically regulated during guidance.\",\n      \"evidence\": \"In vitro cosedimentation, Co-IP, EB3-GFP live imaging, shRNA knockdown, in vivo DRG axon analysis\",\n      \"pmids\": [\"28483977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which UNC5C domain mediates TUBB3 binding not mapped\", \"How TUBB3 dissociation is coordinated with DSCAM/Src signaling unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that UNC5C is necessary and sufficient for retino-retinal axon guidance, repelled by a Netrin-1 gradient in the ventral diencephalon, extended the receptor's known guidance roles to a novel projection type.\",\n      \"evidence\": \"Unc5c null mice, ectopic UNC5C expression, axon tracing, Netrin-1 expression mapping\",\n      \"pmids\": [\"30905607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether co-receptors (DSCAM, DCC) participate in retino-retinal guidance not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of δ-secretase/AEP cleavage at N467 and N547 as a mechanism that amplifies UNC5C's proapoptotic activity provided a proteolytic link between netrin-1 deficiency and neurodegeneration: AEP-generated fragments drive AD pathology in vivo.\",\n      \"evidence\": \"In vitro cleavage assay with site mutagenesis, viral expression of truncated fragments in APP/PS1 mice, UNC5C genetic deletion in netrin-1-depleted mice\",\n      \"pmids\": [\"33863723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AEP cleavage occurs at endogenous levels in human AD brain not directly shown\", \"Crystal structure of AEP-UNC5C complex unavailable\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The AEP-UNC5C cleavage mechanism was extended to Parkinson's disease, where the intracellular fragment elicits α-synuclein aggregation and dopaminergic loss, while UNC5C was also shown to regulate spermatogonial differentiation through netrin-1-mediated repulsion in the testis.\",\n      \"evidence\": \"Viral overexpression of AEP-truncated UNC5C in PD transgenic mice with behavioral testing; Unc5c rcm mutant mice with spermatogonial flow cytometry and in vitro repulsion assay\",\n      \"pmids\": [\"35023303\", \"35247845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AEP cleavage is the primary pathogenic event or secondary to other protease cascades in PD unknown\", \"Mechanism linking UNC5C to spermatogonial differentiation versus adhesion not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two advances clarified UNC5C regulation and in vivo neurodevelopmental function: TRIM9 was identified as an E3 ligase controlling UNC5C surface levels and mobility required for repulsive turning, and a transient Netrin-1 gradient was shown to guide UNC5C-expressing dopamine axons to the prefrontal cortex during adolescence.\",\n      \"evidence\": \"Co-IP, Trim9 KO, shRNA, live pH-mScarlet-UNC5C imaging in microfluidic gradient; Netrin-1 gradient disruption in rodent models with axon tracing\",\n      \"pmids\": [\"39871643\", \"39056276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM9 ubiquitinates UNC5C directly or acts through adaptor not resolved\", \"UNC5C conditional knockout in dopamine neurons not performed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The T835M knock-in mouse model delineated the in vivo degenerative cascade: oxidative stress via NADPH oxidase, JNK phosphorylation, caspase-3/7 activation, hippocampal atrophy, and exacerbation of amyloid pathology when crossed with AD mice, establishing a full mechanistic pathway from mutation to neurodegeneration.\",\n      \"evidence\": \"T835M knock-in mice, MRI volumetry, TUNEL, proteomics, JNK/caspase assays, NADPH oxidase measurement, cross with AppNL-G-F mice\",\n      \"pmids\": [\"40468412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether oxidative stress is upstream or downstream of caspase activation not resolved\", \"Therapeutic rescue of T835M phenotype not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of UNC5C death domain signaling, how AEP cleavage fragments interact with α-synuclein aggregation machinery, whether TRIM9-mediated ubiquitination is direct, and how DSCAM/TUBB3/Src pathways are integrated during growth cone repulsion.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of UNC5C intracellular domain in active/inactive state\", \"Integration of DSCAM, TUBB3, and TRIM9 regulatory arms not tested in unified system\", \"Human in vivo validation of AEP-UNC5C cleavage in neurodegeneration lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 5, 7, 9, 12, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8, 9, 10, 12, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3, 4, 5, 6, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 5, 6, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DSCAM\", \"TUBB3\", \"TRIM9\", \"NTN1\", \"FAK\", \"FYN\", \"DCC\"],\n    \"other_free_text\": []\n  }\n}\n```"}