{"gene":"UNC5C","run_date":"2026-06-10T10:51:56","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. Knockdown of DSCAM or UNC5C, or dominant-negative mutants of either, suppresses netrin-1-induced growth cone collapse. Netrin-1 increases tyrosine phosphorylation of UNC5C and promotes complex formation of DSCAM with FAK, Fyn, and PAK1. Src family kinase inhibition reduces the DSCAM-UNC5C interaction and blocks growth cone collapse.","method":"Co-immunoprecipitation, shRNA knockdown, dominant-negative overexpression, tyrosine phosphorylation assays, growth cone collapse assay in primary neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods (knockdown, dominant-negative, pharmacological inhibition), replicated across two neuronal cell types","pmids":["22685302"],"is_preprint":false},{"year":2017,"finding":"TUBB3 (polymerized β-tubulin) directly interacts with UNC5C and partially co-localizes with it in the peripheral growth cone. Netrin-1 reduces this interaction and the co-localization. UNC5C interacts with polymerized TUBB3 in microtubules as shown by in vitro co-sedimentation, and netrin-1 decreases this interaction. Knockdown of TUBB3 or UNC5C blocks netrin-1-promoted axon repulsion in vitro and causes axon projection defects in vivo. Netrin-1 differentially increases MT dynamics in the distal versus proximal growth cone during repulsion, and this effect is abolished by knockdown of UNC5C or TUBB3.","method":"Co-immunoprecipitation, in vitro co-sedimentation assay, shRNA knockdown, live-cell imaging (EB3-GFP), in vivo axon projection analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution (co-sedimentation), multiple orthogonal methods (Co-IP, live imaging, in vivo knockdown), single lab but rigorous","pmids":["28483977"],"is_preprint":false},{"year":2021,"finding":"δ-secretase (AEP/legumain) cleaves UNC5C at N467 and N547 residues, enhancing its pro-apoptotic activity and caspase-3 activation. Netrin-1 deficiency activates δ-secretase, which truncates UNC5C. Blockade of δ-secretase cleavage of UNC5C diminishes the T835M mutant's pro-apoptotic activity. Viral expression of δ-secretase-truncated UNC5C fragments in APP/PS1 mice accelerates AD pathologies and impairs learning and memory. Deletion of UNC5C from netrin-1-depleted mice attenuates AD pathologies and rescues cognitive disorders.","method":"Site-directed mutagenesis (N467, N547), in vitro cleavage assay, caspase-3 activation assay, viral gene delivery in mouse models, behavioral testing","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — cleavage site identified by mutagenesis and in vitro assay, functional rescue in vivo, single lab with multiple orthogonal methods","pmids":["33863723"],"is_preprint":false},{"year":2022,"finding":"AEP (asparagine endopeptidase) cleaves UNC5C in a Parkinson's disease context, producing intracellular fragments that facilitate dopaminergic neuronal loss. AEP-truncated UNC5C fragments promote α-synuclein aggregation and dopaminergic loss in α-SNCA transgenic mice. Netrin-1 deprivation induces AEP and caspase-3 activation, triggering UNC5C proteolytic fragmentation. Blocking UNC5C cleavage by AEP attenuates netrin-1 deprivation-elicited neuronal death and motor disorders.","method":"In vitro cleavage assay, viral overexpression of AEP-truncated UNC5C fragments, mouse behavioral assays, netrin-1 flox/flox mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo and in vitro methods in single lab, cleavage shown but specific cleavage sites not explicitly defined in abstract","pmids":["35023303"],"is_preprint":false},{"year":2014,"finding":"The T835M mutation in UNC5C increases neuronal cell death in HEK293T cells and rodent neurons, and increases susceptibility to Aβ, glutamate, and staurosporine-induced cell death. The mutation alters a conserved residue in the hinge region of UNC5C.","method":"In vitro cell death assay in HEK293T cells and primary rodent neurons, overexpression of wild-type and T835M UNC5C","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assay with multiple neurotoxic stimuli, single lab, no structural validation","pmids":["25419706"],"is_preprint":false},{"year":2025,"finding":"T835M knock-in (Unc5cKI/KI) mice develop hippocampal volume reduction, increased ventricular volume, dendritic disorganization, neuronal apoptosis (TUNEL+ and caspase 3/7 activation) by 12 months. Proteomic analysis revealed upregulation of oxidative stress pathways, increased JNK phosphorylation, and elevated NADPH oxidase. Crossing with AppNL-G-F/NL-G-F mice exacerbated these changes and increased Aβ42 levels, demonstrating that T835M increases neuronal susceptibility to amyloid pathology.","method":"Knock-in mouse model, TUNEL assay, caspase 3/7 assay, quantitative proteomics, immunohistochemistry, MRI volumetry, genetic crosses","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model with multiple orthogonal readouts (histology, proteomics, biochemistry, imaging), single lab but rigorous and comprehensive","pmids":["40468412"],"is_preprint":false},{"year":2007,"finding":"Loss of UNC5C in mice with APC1638N mutations increases intestinal tumor progression and decreases tumor cell apoptosis, establishing UNC5C as a tumor suppressor in colorectal cancer. UNC5C expression is down-regulated in human colorectal cancers primarily through promoter methylation.","method":"Double-mutant mouse model (UNC5C/APC1638N), apoptosis measurement in intestinal tumors, promoter methylation analysis","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in mouse model with defined apoptotic phenotype, replicated across human CRC cohorts and mouse models","pmids":["17967459"],"is_preprint":false},{"year":2011,"finding":"The UNC5C A628K variant significantly reduces apoptosis compared with wild-type UNC5C as measured by active caspase-3 assay in transfected HEK293T cells, and segregates with colorectal cancer in families, supporting a role for UNC5C-mediated apoptosis in tumor suppression.","method":"Transfection of HEK293T cells with A628K mutant, active caspase-3 assay, family segregation analysis","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assay with caspase-3 readout plus family segregation, single lab, single method for functional component","pmids":["21893118"],"is_preprint":false},{"year":2006,"finding":"Unc5c null mice on C57BL/6J background exhibit ventral/ipsilateral trochlear nerve misprojections and incomplete phrenic nerve innervation of the diaphragm, demonstrating that UNC5C is required for repulsive netrin-1 signaling in motor axon guidance in vivo. These phenotypes were not observed in mice lacking DCC, Neogenin1, or netrin1, placing UNC5C in a distinct signaling pathway. A major SJL-derived suppressor locus on Chromosome 17 modifies these phenotypes.","method":"Unc5c null mouse analysis, axonal tracing, genetic background experiments, genome-wide scan for modifier loci","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mouse model with specific axonal phenotype, epistatic comparison with DCC/Neogenin/netrin1 nulls, modifier locus mapping","pmids":["16723533"],"is_preprint":false},{"year":2011,"finding":"Unc5c deletion in mice disrupts long-range dorsal guidance of inferior olivary and pontine axons after crossing the midline, affects dorsal guidance of medial deep cerebellar and external cuneate axons, and causes degeneration of neurons in the external cuneate nucleus and inferior olivary nucleus. Transgenic expression of Unc5c in deep neurons and pontine neurons by the Atoh1 promoter rescues the medial deep cerebellar and pontine axon guidance defects, demonstrating cell-autonomous action.","method":"Unc5c null mouse, axonal tracing, transgenic rescue with Atoh1 promoter","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mouse model with rescue experiment demonstrating cell-autonomous function, multiple neuronal populations analyzed","pmids":["21307253"],"is_preprint":false},{"year":2014,"finding":"Unc5C expression is under direct negative transcriptional regulation by the transcription factor Ctip2, and Unc5C acts downstream of Ctip2 in controlling corticofugal axon projections. Netrin1-Unc5C interaction is involved in controlling interhemispheric projection in deep-layer callosal neurons.","method":"ChIP or transcription factor binding analysis, mouse genetic studies with Ctip2/Satb2 mutants, axon guidance assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse model, direct regulatory relationship shown, single lab","pmids":["24739528"],"is_preprint":false},{"year":2007,"finding":"RHOX5 homeodomain protein transcriptionally represses Unc5c expression in Sertoli cells in vivo, requiring a Sertoli-cell-specific cofactor. The repression is mediated through a RHOX5-responsive element in the Unc5c 5'-UTR at the transcriptional level. RHOX2, RHOX3, and human RHOXF2/PEPP2 also repress Unc5c expression, indicating conserved regulation. Unc5c mutant mice have decreased germ cell apoptosis in the testis.","method":"Transfection analysis in cell lines, deletion analysis of 5'-UTR, in vivo testis expression analysis, Unc5c mutant mouse apoptosis analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RHOX family members tested, in vivo validation, deletion analysis of regulatory element, single lab","pmids":["18077458"],"is_preprint":false},{"year":2007,"finding":"UNC5C is required for the dorsal migration of spinal accessory motor neuron (SACMN) cell bodies away from the ventral midline. In Unc5C null mice, many SACMN cell bodies fail to migrate away from the ventral midline and cluster inappropriately in the ventrolateral spinal cord. UNC5A null mice show no such phenotype.","method":"Unc5C and Unc5A null mouse analysis, SACMN cell body position analysis in embryos","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — null mouse model with specific developmental phenotype, comparison with UNC5A nulls showing specificity, single lab","pmids":["17543537"],"is_preprint":false},{"year":2025,"finding":"TRIM9, a brain-enriched E3 ubiquitin ligase, physically interacts with and co-localizes with UNC5C at the growth cone. TRIM9 is required for netrin-1-dependent changes in surface levels of UNC5C in the growth cone. Deletion of Trim9 impairs repulsive axon turning in a netrin gradient (which is UNC5C-dependent), and TRIM9 negatively regulates FAK activity in the absence of netrin-1.","method":"Co-immunoprecipitation, co-localization imaging, Trim9 knockout mouse neurons, microfluidic netrin-1 gradient, pH-mScarlet-UNC5C surface level imaging, shRNA knockdown of UNC5C","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction shown, knockout model, surface receptor imaging, multiple orthogonal methods including microfluidic gradient, peer-reviewed","pmids":["39871643"],"is_preprint":false},{"year":2024,"finding":"TRIM9 interacts with UNC5C and regulates its mobility in the plasma membrane in the absence of netrin-1. Minutes after netrin-1 addition, UNC5C surface levels drop in a TRIM9-independent fashion. Repulsive turning in a netrin gradient is blocked by UNC5C knockdown.","method":"pH-mScarlet-UNC5C surface imaging, TRIM9 knockout, shRNA knockdown, microfluidic netrin-1 gradient","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint version of PMID:39871643 with additional imaging data; findings corroborated in peer-reviewed version","pmids":["38765979"],"is_preprint":true},{"year":2019,"finding":"UNC5C directly interacts with integrin α6 in breast cancer cells. UNC5C knockdown enhances phosphorylation of FAK and SRC and increases MMP3, MMP7, MMP9, MMP10 expression via PI3K/AKT, ERK and p38 MAPK pathways. UNC5C knockdown potentiates netrin-1/integrin α6/β4 signaling and inhibits integrin-linked kinase phosphorylation at Thr-173.","method":"Co-immunoprecipitation (UNC5C-integrin α6), shRNA knockdown, overexpression in breast cancer cells, Western blot for signaling pathway components","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP for interaction, functional assays in cell lines, pathway analysis, single lab","pmids":["31789389"],"is_preprint":false},{"year":2019,"finding":"Unc5c is necessary and sufficient to guide retinal ganglion cell axons to the opposite retina (retino-retinal projection). Netrin1, an Unc5c ligand, is expressed in the ventral diencephalon in a pattern consistent with impeding the growth of Unc5c-positive retinal axons into the brain.","method":"Unc5c null mouse analysis, axonal tracing, in situ hybridization for Netrin1, comparative species analysis","journal":"Current biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — null mouse phenotype with defined axon guidance readout, expression pattern consistent with mechanism, single lab","pmids":["30905607"],"is_preprint":false},{"year":2013,"finding":"Unc5c is selectively expressed by dopamine neurons of the VTA from adolescence onwards. Unc5c haploinsufficiency leads to increased tyrosine hydroxylase expression in medial prefrontal cortex (but not nucleus accumbens) and diminished amphetamine-induced locomotion, a phenotype identical to dcc haploinsufficiency and observed only after adolescence.","method":"In situ hybridization, immunofluorescence, Western blot in unc5c heterozygous mice, behavioral testing (amphetamine-induced locomotion)","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — haploinsufficiency mouse model with specific behavioral and biochemical phenotypes, single lab","pmids":["23738838"],"is_preprint":false},{"year":2024,"finding":"Dopamine axons reach the prefrontal cortex guided by a transient gradient of Netrin-1-expressing cells, and UNC5C is expressed on dopamine axons during adolescence. Disrupting the Netrin-1 gradient reroutes dopamine axons away from their target. The timings of dopamine axon growth and UNC5C expression are phase-locked, including in a seasonal model where mesocortical dopamine development is regulated by daylength in a sexually dimorphic manner.","method":"Rodent in vivo axon tracing, Netrin-1 gradient disruption experiments, immunofluorescence, seasonal model (Siberian hamsters)","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gradient disruption with axon rerouting phenotype, multiple species, single lab","pmids":["39056276"],"is_preprint":false},{"year":2022,"finding":"UNC5C is expressed by a fraction of undifferentiated spermatogonia, and loss of Unc5c leads to accumulation of transit-amplifying progenitors, increased quiescent undifferentiated progenitors, and decline in spermatocyte I, without altering cell death rates. Netrin-1 repulses both undifferentiated and differentiating spermatogonia in vitro, suggesting UNC5C mediates adhesion/migration control in spermatogonial differentiation.","method":"Unc5crcm mutant mouse analysis, immunofluorescence, in vitro repulsion assay with Netrin-1","journal":"Stem cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with specific cellular phenotype plus in vitro repulsion assay, single lab","pmids":["35247845"],"is_preprint":false},{"year":2026,"finding":"The ZU5 domain of UNC5C binds Schisandrin A with equimolar stoichiometry driven by enthalpy change, with van der Waals forces and hydrogen bonds as main forces. Leu61 and Leu96 of ZU5 are key binding residues. Binding induces loop fluctuations and a random coil-to-α-helix transformation in ZU5.","method":"Phage display peptide library screening, fluorescence spectroscopy, isothermal titration calorimetry, molecular dynamics simulation","journal":"Bioorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biophysical binding assays with ITC and spectroscopy, but computational component prominent and single lab","pmids":["41724002"],"is_preprint":false}],"current_model":"UNC5C is a transmembrane netrin-1 dependence receptor that mediates axon repulsion by uncoupling from polymerized TUBB3 in microtubules, engages DSCAM and signaling molecules (FAK, Fyn, PAK1) via Src family kinase-dependent tyrosine phosphorylation, is regulated at the growth cone by the E3 ubiquitin ligase TRIM9, and induces apoptosis (caspase-3 activation) in the absence of netrin-1; this pro-apoptotic activity is amplified by δ-secretase/AEP cleavage at specific asparagine residues, enhanced by the AD-associated T835M mutation, and suppressed by transcription factors such as RHOX5 and Ctip2."},"narrative":{"mechanistic_narrative":"UNC5C is a transmembrane netrin-1 dependence receptor that transduces repulsive guidance cues in the developing nervous system and acts as a pro-apoptotic effector when deprived of its ligand [PMID:16723533, PMID:33863723]. In axon guidance, UNC5C is required cell-autonomously for netrin-1-dependent repulsion of multiple axon and motor-neuron populations in vivo, defining a signaling pathway distinct from DCC, Neogenin1, and netrin1 [PMID:16723533, PMID:21307253, PMID:17543537]. At the growth cone, netrin-1 stimulates a DSCAM-UNC5C complex that recruits FAK, Fyn, and PAK1 and increases UNC5C tyrosine phosphorylation through Src-family kinases to drive growth cone collapse [PMID:22685302], while UNC5C transduces repulsion by uncoupling from polymerized TUBB3 in microtubules, an event that locally remodels microtubule dynamics during turning [PMID:28483977]. Surface levels and mobility of UNC5C at the growth cone are controlled by the brain-enriched E3 ubiquitin ligase TRIM9, which also restrains FAK activity in the absence of netrin-1 [PMID:39871643]. In the absence of netrin-1, UNC5C induces caspase-3-dependent apoptosis, a function amplified by δ-secretase/AEP cleavage at N467 and N547 that generates pro-apoptotic intracellular fragments contributing to Alzheimer's-type and Parkinson's-type neurodegeneration [PMID:33863723, PMID:35023303]. This death-promoting activity underlies UNC5C's role as a tumor suppressor, where loss of UNC5C reduces tumor-cell apoptosis and accelerates intestinal tumor progression, and where UNC5C is silenced by promoter methylation in human colorectal cancer [PMID:17967459]. The Alzheimer-associated T835M variant heightens neuronal vulnerability: it increases susceptibility to Aβ, glutamate, and staurosporine in vitro [PMID:25419706] and drives hippocampal atrophy, oxidative-stress and JNK pathway activation, and neuronal apoptosis in knock-in mice, exacerbating amyloid pathology [PMID:40468412]. UNC5C expression is held in check by transcriptional repressors including RHOX5 in Sertoli cells and Ctip2 in cortical neurons [PMID:18077458, PMID:24739528].","teleology":[{"year":2006,"claim":"Established that UNC5C is genetically required for netrin-1-mediated repulsive axon guidance in vivo and operates in a pathway separable from DCC, Neogenin1, and netrin1.","evidence":"Unc5c null mouse axonal tracing with epistatic comparison to DCC/Neogenin/netrin1 nulls and modifier-locus mapping","pmids":["16723533"],"confidence":"High","gaps":["Did not resolve the molecular signaling output downstream of the receptor","Genetic background modifier on Chr17 not molecularly identified"]},{"year":2007,"claim":"Showed UNC5C is a tumor suppressor whose loss reduces apoptosis and accelerates tumor progression, linking its guidance receptor identity to programmed cell death.","evidence":"UNC5C/APC1638N double-mutant mouse with intestinal tumor apoptosis quantification and human CRC promoter methylation analysis","pmids":["17967459"],"confidence":"High","gaps":["Molecular apoptotic effector pathway not defined here","Whether loss acts purely through reduced apoptosis vs other tumor-suppressive functions unresolved"]},{"year":2007,"claim":"Identified RHOX5 as a transcriptional repressor of Unc5c in Sertoli cells, connecting receptor dosage to germ cell apoptosis.","evidence":"5'-UTR deletion analysis, transfection reporter assays, and Unc5c mutant testis apoptosis analysis","pmids":["18077458"],"confidence":"Medium","gaps":["Sertoli-specific cofactor not identified","Direct apoptotic mechanism in germ cells not dissected"]},{"year":2011,"claim":"Demonstrated cell-autonomous UNC5C function in long-range dorsal axon guidance through transgenic rescue, extending its role beyond a single neuronal population.","evidence":"Unc5c null mouse axon tracing with Atoh1-promoter transgenic rescue","pmids":["21307253"],"confidence":"High","gaps":["Ligand-receptor signaling steps not resolved","Cause of downstream neuronal degeneration unexplained"]},{"year":2011,"claim":"Linked a human UNC5C coding variant (A628K) to reduced apoptosis and familial colorectal cancer, providing genetic support for apoptosis-driven tumor suppression.","evidence":"HEK293T active caspase-3 assay of A628K mutant plus family segregation analysis","pmids":["21893118"],"confidence":"Medium","gaps":["Single functional assay for the variant","Structural basis of reduced apoptotic activity unknown"]},{"year":2012,"claim":"Defined the growth-cone signaling complex: netrin-1 drives a DSCAM-UNC5C interaction and recruitment of FAK, Fyn, and PAK1 via Src-family-kinase-dependent phosphorylation to collapse growth cones.","evidence":"Reciprocal Co-IP, shRNA knockdown, dominant-negative mutants, SFK inhibition, and growth cone collapse assays in cortical and cerebellar granule neurons","pmids":["22685302"],"confidence":"High","gaps":["Order of recruitment events not fully resolved","How phosphorylation links to cytoskeletal collapse not mechanistically traced"]},{"year":2014,"claim":"Identified the T835M variant as a hinge-region mutation that sensitizes neurons to multiple death stimuli, implicating UNC5C in Alzheimer's disease risk.","evidence":"Cell death assays in HEK293T and primary rodent neurons with WT and T835M overexpression and Aβ/glutamate/staurosporine challenge","pmids":["25419706"],"confidence":"Medium","gaps":["No structural validation of the hinge alteration","In vivo relevance not yet demonstrated at this stage"]},{"year":2014,"claim":"Placed Unc5c under direct negative transcriptional control by Ctip2 in the context of corticofugal and callosal projections.","evidence":"Transcription factor binding analysis and mouse genetic epistasis with Ctip2/Satb2 mutants","pmids":["24739528"],"confidence":"Medium","gaps":["Direct binding site not finely mapped","Quantitative contribution of Unc5c repression to projection phenotype unclear"]},{"year":2017,"claim":"Revealed the cytoskeletal mechanism of repulsion: UNC5C binds polymerized TUBB3 in microtubules and netrin-1 uncouples this interaction to remodel growth-cone microtubule dynamics.","evidence":"Co-IP, in vitro microtubule co-sedimentation, EB3-GFP live imaging, and in vivo knockdown axon analysis","pmids":["28483977"],"confidence":"High","gaps":["How ligand binding triggers receptor-microtubule uncoupling not mechanistically defined","Link between TUBB3 release and DSCAM/FAK signaling not integrated"]},{"year":2021,"claim":"Showed δ-secretase/AEP cleaves UNC5C at N467 and N547 to amplify its pro-apoptotic activity, mechanistically connecting netrin-1 loss to Alzheimer's pathology.","evidence":"Site-directed mutagenesis, in vitro cleavage and caspase-3 assays, viral fragment delivery in APP/PS1 mice, and UNC5C deletion rescue","pmids":["33863723"],"confidence":"High","gaps":["Structure of the active cleaved fragment not solved","Downstream apoptotic effectors of the fragment not enumerated"]},{"year":2022,"claim":"Extended AEP-mediated UNC5C cleavage to Parkinson's disease, where truncated fragments promote α-synuclein aggregation and dopaminergic loss.","evidence":"In vitro cleavage assays, viral expression of AEP-truncated fragments, and behavioral testing in α-SNCA transgenic and netrin-1 flox mice","pmids":["35023303"],"confidence":"Medium","gaps":["Specific cleavage sites not explicitly defined in this context","Mechanism by which fragments promote α-synuclein aggregation unresolved"]},{"year":2024,"claim":"Provided in vivo evidence that a transient Netrin-1 gradient guides UNC5C-expressing dopamine axons to the prefrontal cortex with developmentally phase-locked timing.","evidence":"Rodent axon tracing, Netrin-1 gradient disruption with axon rerouting, and a seasonal daylength model","pmids":["39056276"],"confidence":"Medium","gaps":["Receptor-level signaling during this guidance not dissected","Mechanism of sexually dimorphic regulation unknown"]},{"year":2025,"claim":"Demonstrated TRIM9 as an E3 ligase that controls UNC5C surface levels and mobility at the growth cone and restrains FAK activity basally, identifying a regulatory node for repulsive turning.","evidence":"Reciprocal Co-IP, co-localization, Trim9 knockout neurons, pH-mScarlet-UNC5C surface imaging, and microfluidic netrin-1 gradient turning assays","pmids":["39871643","38765979"],"confidence":"High","gaps":["Whether UNC5C is a direct ubiquitination substrate of TRIM9 not established","Acute netrin-1-induced surface drop is TRIM9-independent, so that effector is unknown"]},{"year":2025,"claim":"Established in vivo causality for the T835M variant by showing a knock-in mouse develops hippocampal atrophy, oxidative/JNK stress signaling, and apoptosis that worsens amyloid pathology.","evidence":"T835M knock-in mouse with TUNEL, caspase 3/7, proteomics, MRI volumetry, and crosses to AppNL-G-F mice","pmids":["40468412"],"confidence":"High","gaps":["Mechanistic link between T835M and oxidative-stress/JNK activation not resolved","Whether δ-secretase cleavage drives the in vivo phenotype not directly tested here"]},{"year":2026,"claim":"Provided the first biophysical characterization of a UNC5C domain by mapping a small-molecule binding site on the ZU5 domain.","evidence":"Phage display, fluorescence spectroscopy, ITC, and molecular dynamics of ZU5-Schisandrin A binding","pmids":["41724002"],"confidence":"Medium","gaps":["Functional consequence of ZU5 binding on receptor signaling not demonstrated","Computational component prominent; structural change not validated experimentally"]},{"year":null,"claim":"How netrin-1 binding mechanically switches UNC5C between its repulsive cytoskeletal/kinase signaling mode and its ligand-deprivation-triggered apoptotic mode at the molecular and structural level remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length structural model of the receptor in either state","Integration of TUBB3 uncoupling, DSCAM/FAK signaling, TRIM9 regulation, and AEP cleavage into one switch is incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,0,1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13,14,0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9,12,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,13,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,5,6]}],"complexes":[],"partners":["DSCAM","TUBB3","TRIM9","FAK","FYN","PAK1","ITGA6"],"other_free_text":[]}},"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 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this interaction is stimulated by netrin-1 in primary cortical neurons and cerebellar granule cells. Knockdown of DSCAM or UNC5C, or dominant-negative mutants of either, suppresses netrin-1-induced growth cone collapse. Netrin-1 increases tyrosine phosphorylation of UNC5C and promotes complex formation of DSCAM with FAK, Fyn, and PAK1. Src family kinase inhibition reduces the DSCAM-UNC5C interaction and blocks growth cone collapse.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, dominant-negative overexpression, tyrosine phosphorylation assays, growth cone collapse assay in primary neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods (knockdown, dominant-negative, pharmacological inhibition), replicated across two neuronal cell types\",\n      \"pmids\": [\"22685302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TUBB3 (polymerized β-tubulin) directly interacts with UNC5C and partially co-localizes with it in the peripheral growth cone. Netrin-1 reduces this interaction and the co-localization. UNC5C interacts with polymerized TUBB3 in microtubules as shown by in vitro co-sedimentation, and netrin-1 decreases this interaction. Knockdown of TUBB3 or UNC5C blocks netrin-1-promoted axon repulsion in vitro and causes axon projection defects in vivo. Netrin-1 differentially increases MT dynamics in the distal versus proximal growth cone during repulsion, and this effect is abolished by knockdown of UNC5C or TUBB3.\",\n      \"method\": \"Co-immunoprecipitation, in vitro co-sedimentation assay, shRNA knockdown, live-cell imaging (EB3-GFP), in vivo axon projection analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution (co-sedimentation), multiple orthogonal methods (Co-IP, live imaging, in vivo knockdown), single lab but rigorous\",\n      \"pmids\": [\"28483977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"δ-secretase (AEP/legumain) cleaves UNC5C at N467 and N547 residues, enhancing its pro-apoptotic activity and caspase-3 activation. Netrin-1 deficiency activates δ-secretase, which truncates UNC5C. Blockade of δ-secretase cleavage of UNC5C diminishes the T835M mutant's pro-apoptotic activity. Viral expression of δ-secretase-truncated UNC5C fragments in APP/PS1 mice accelerates AD pathologies and impairs learning and memory. Deletion of UNC5C from netrin-1-depleted mice attenuates AD pathologies and rescues cognitive disorders.\",\n      \"method\": \"Site-directed mutagenesis (N467, N547), in vitro cleavage assay, caspase-3 activation assay, viral gene delivery in mouse models, behavioral testing\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — cleavage site identified by mutagenesis and in vitro assay, functional rescue in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33863723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AEP (asparagine endopeptidase) cleaves UNC5C in a Parkinson's disease context, producing intracellular fragments that facilitate dopaminergic neuronal loss. AEP-truncated UNC5C fragments promote α-synuclein aggregation and dopaminergic loss in α-SNCA transgenic mice. Netrin-1 deprivation induces AEP and caspase-3 activation, triggering UNC5C proteolytic fragmentation. Blocking UNC5C cleavage by AEP attenuates netrin-1 deprivation-elicited neuronal death and motor disorders.\",\n      \"method\": \"In vitro cleavage assay, viral overexpression of AEP-truncated UNC5C fragments, mouse behavioral assays, netrin-1 flox/flox mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo and in vitro methods in single lab, cleavage shown but specific cleavage sites not explicitly defined in abstract\",\n      \"pmids\": [\"35023303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The T835M mutation in UNC5C increases neuronal cell death in HEK293T cells and rodent neurons, and increases susceptibility to Aβ, glutamate, and staurosporine-induced cell death. The mutation alters a conserved residue in the hinge region of UNC5C.\",\n      \"method\": \"In vitro cell death assay in HEK293T cells and primary rodent neurons, overexpression of wild-type and T835M UNC5C\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assay with multiple neurotoxic stimuli, single lab, no structural validation\",\n      \"pmids\": [\"25419706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"T835M knock-in (Unc5cKI/KI) mice develop hippocampal volume reduction, increased ventricular volume, dendritic disorganization, neuronal apoptosis (TUNEL+ and caspase 3/7 activation) by 12 months. Proteomic analysis revealed upregulation of oxidative stress pathways, increased JNK phosphorylation, and elevated NADPH oxidase. Crossing with AppNL-G-F/NL-G-F mice exacerbated these changes and increased Aβ42 levels, demonstrating that T835M increases neuronal susceptibility to amyloid pathology.\",\n      \"method\": \"Knock-in mouse model, TUNEL assay, caspase 3/7 assay, quantitative proteomics, immunohistochemistry, MRI volumetry, genetic crosses\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model with multiple orthogonal readouts (histology, proteomics, biochemistry, imaging), single lab but rigorous and comprehensive\",\n      \"pmids\": [\"40468412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of UNC5C in mice with APC1638N mutations increases intestinal tumor progression and decreases tumor cell apoptosis, establishing UNC5C as a tumor suppressor in colorectal cancer. UNC5C expression is down-regulated in human colorectal cancers primarily through promoter methylation.\",\n      \"method\": \"Double-mutant mouse model (UNC5C/APC1638N), apoptosis measurement in intestinal tumors, promoter methylation analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in mouse model with defined apoptotic phenotype, replicated across human CRC cohorts and mouse models\",\n      \"pmids\": [\"17967459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The UNC5C A628K variant significantly reduces apoptosis compared with wild-type UNC5C as measured by active caspase-3 assay in transfected HEK293T cells, and segregates with colorectal cancer in families, supporting a role for UNC5C-mediated apoptosis in tumor suppression.\",\n      \"method\": \"Transfection of HEK293T cells with A628K mutant, active caspase-3 assay, family segregation analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assay with caspase-3 readout plus family segregation, single lab, single method for functional component\",\n      \"pmids\": [\"21893118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Unc5c null mice on C57BL/6J background exhibit ventral/ipsilateral trochlear nerve misprojections and incomplete phrenic nerve innervation of the diaphragm, demonstrating that UNC5C is required for repulsive netrin-1 signaling in motor axon guidance in vivo. These phenotypes were not observed in mice lacking DCC, Neogenin1, or netrin1, placing UNC5C in a distinct signaling pathway. A major SJL-derived suppressor locus on Chromosome 17 modifies these phenotypes.\",\n      \"method\": \"Unc5c null mouse analysis, axonal tracing, genetic background experiments, genome-wide scan for modifier loci\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mouse model with specific axonal phenotype, epistatic comparison with DCC/Neogenin/netrin1 nulls, modifier locus mapping\",\n      \"pmids\": [\"16723533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Unc5c deletion in mice disrupts long-range dorsal guidance of inferior olivary and pontine axons after crossing the midline, affects dorsal guidance of medial deep cerebellar and external cuneate axons, and causes degeneration of neurons in the external cuneate nucleus and inferior olivary nucleus. Transgenic expression of Unc5c in deep neurons and pontine neurons by the Atoh1 promoter rescues the medial deep cerebellar and pontine axon guidance defects, demonstrating cell-autonomous action.\",\n      \"method\": \"Unc5c null mouse, axonal tracing, transgenic rescue with Atoh1 promoter\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mouse model with rescue experiment demonstrating cell-autonomous function, multiple neuronal populations analyzed\",\n      \"pmids\": [\"21307253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Unc5C expression is under direct negative transcriptional regulation by the transcription factor Ctip2, and Unc5C acts downstream of Ctip2 in controlling corticofugal axon projections. Netrin1-Unc5C interaction is involved in controlling interhemispheric projection in deep-layer callosal neurons.\",\n      \"method\": \"ChIP or transcription factor binding analysis, mouse genetic studies with Ctip2/Satb2 mutants, axon guidance assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse model, direct regulatory relationship shown, single lab\",\n      \"pmids\": [\"24739528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RHOX5 homeodomain protein transcriptionally represses Unc5c expression in Sertoli cells in vivo, requiring a Sertoli-cell-specific cofactor. The repression is mediated through a RHOX5-responsive element in the Unc5c 5'-UTR at the transcriptional level. RHOX2, RHOX3, and human RHOXF2/PEPP2 also repress Unc5c expression, indicating conserved regulation. Unc5c mutant mice have decreased germ cell apoptosis in the testis.\",\n      \"method\": \"Transfection analysis in cell lines, deletion analysis of 5'-UTR, in vivo testis expression analysis, Unc5c mutant mouse apoptosis analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RHOX family members tested, in vivo validation, deletion analysis of regulatory element, single lab\",\n      \"pmids\": [\"18077458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UNC5C is required for the dorsal migration of spinal accessory motor neuron (SACMN) cell bodies away from the ventral midline. In Unc5C null mice, many SACMN cell bodies fail to migrate away from the ventral midline and cluster inappropriately in the ventrolateral spinal cord. UNC5A null mice show no such phenotype.\",\n      \"method\": \"Unc5C and Unc5A null mouse analysis, SACMN cell body position analysis in embryos\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — null mouse model with specific developmental phenotype, comparison with UNC5A nulls showing specificity, single lab\",\n      \"pmids\": [\"17543537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM9, a brain-enriched E3 ubiquitin ligase, physically interacts with and co-localizes with UNC5C at the growth cone. TRIM9 is required for netrin-1-dependent changes in surface levels of UNC5C in the growth cone. Deletion of Trim9 impairs repulsive axon turning in a netrin gradient (which is UNC5C-dependent), and TRIM9 negatively regulates FAK activity in the absence of netrin-1.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, Trim9 knockout mouse neurons, microfluidic netrin-1 gradient, pH-mScarlet-UNC5C surface level imaging, shRNA knockdown of UNC5C\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction shown, knockout model, surface receptor imaging, multiple orthogonal methods including microfluidic gradient, peer-reviewed\",\n      \"pmids\": [\"39871643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM9 interacts with UNC5C and regulates its mobility in the plasma membrane in the absence of netrin-1. Minutes after netrin-1 addition, UNC5C surface levels drop in a TRIM9-independent fashion. Repulsive turning in a netrin gradient is blocked by UNC5C knockdown.\",\n      \"method\": \"pH-mScarlet-UNC5C surface imaging, TRIM9 knockout, shRNA knockdown, microfluidic netrin-1 gradient\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint version of PMID:39871643 with additional imaging data; findings corroborated in peer-reviewed version\",\n      \"pmids\": [\"38765979\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UNC5C directly interacts with integrin α6 in breast cancer cells. UNC5C knockdown enhances phosphorylation of FAK and SRC and increases MMP3, MMP7, MMP9, MMP10 expression via PI3K/AKT, ERK and p38 MAPK pathways. UNC5C knockdown potentiates netrin-1/integrin α6/β4 signaling and inhibits integrin-linked kinase phosphorylation at Thr-173.\",\n      \"method\": \"Co-immunoprecipitation (UNC5C-integrin α6), shRNA knockdown, overexpression in breast cancer cells, Western blot for signaling pathway components\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP for interaction, functional assays in cell lines, pathway analysis, single lab\",\n      \"pmids\": [\"31789389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Unc5c is necessary and sufficient to guide retinal ganglion cell axons to the opposite retina (retino-retinal projection). Netrin1, an Unc5c ligand, is expressed in the ventral diencephalon in a pattern consistent with impeding the growth of Unc5c-positive retinal axons into the brain.\",\n      \"method\": \"Unc5c null mouse analysis, axonal tracing, in situ hybridization for Netrin1, comparative species analysis\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — null mouse phenotype with defined axon guidance readout, expression pattern consistent with mechanism, single lab\",\n      \"pmids\": [\"30905607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Unc5c is selectively expressed by dopamine neurons of the VTA from adolescence onwards. Unc5c haploinsufficiency leads to increased tyrosine hydroxylase expression in medial prefrontal cortex (but not nucleus accumbens) and diminished amphetamine-induced locomotion, a phenotype identical to dcc haploinsufficiency and observed only after adolescence.\",\n      \"method\": \"In situ hybridization, immunofluorescence, Western blot in unc5c heterozygous mice, behavioral testing (amphetamine-induced locomotion)\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — haploinsufficiency mouse model with specific behavioral and biochemical phenotypes, single lab\",\n      \"pmids\": [\"23738838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dopamine axons reach the prefrontal cortex guided by a transient gradient of Netrin-1-expressing cells, and UNC5C is expressed on dopamine axons during adolescence. Disrupting the Netrin-1 gradient reroutes dopamine axons away from their target. The timings of dopamine axon growth and UNC5C expression are phase-locked, including in a seasonal model where mesocortical dopamine development is regulated by daylength in a sexually dimorphic manner.\",\n      \"method\": \"Rodent in vivo axon tracing, Netrin-1 gradient disruption experiments, immunofluorescence, seasonal model (Siberian hamsters)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gradient disruption with axon rerouting phenotype, multiple species, single lab\",\n      \"pmids\": [\"39056276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UNC5C is expressed by a fraction of undifferentiated spermatogonia, and loss of Unc5c leads to accumulation of transit-amplifying progenitors, increased quiescent undifferentiated progenitors, and decline in spermatocyte I, without altering cell death rates. Netrin-1 repulses both undifferentiated and differentiating spermatogonia in vitro, suggesting UNC5C mediates adhesion/migration control in spermatogonial differentiation.\",\n      \"method\": \"Unc5crcm mutant mouse analysis, immunofluorescence, in vitro repulsion assay with Netrin-1\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with specific cellular phenotype plus in vitro repulsion assay, single lab\",\n      \"pmids\": [\"35247845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The ZU5 domain of UNC5C binds Schisandrin A with equimolar stoichiometry driven by enthalpy change, with van der Waals forces and hydrogen bonds as main forces. Leu61 and Leu96 of ZU5 are key binding residues. Binding induces loop fluctuations and a random coil-to-α-helix transformation in ZU5.\",\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 / Weak — biophysical binding assays with ITC and spectroscopy, but computational component prominent and single lab\",\n      \"pmids\": [\"41724002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UNC5C is a transmembrane netrin-1 dependence receptor that mediates axon repulsion by uncoupling from polymerized TUBB3 in microtubules, engages DSCAM and signaling molecules (FAK, Fyn, PAK1) via Src family kinase-dependent tyrosine phosphorylation, is regulated at the growth cone by the E3 ubiquitin ligase TRIM9, and induces apoptosis (caspase-3 activation) in the absence of netrin-1; this pro-apoptotic activity is amplified by δ-secretase/AEP cleavage at specific asparagine residues, enhanced by the AD-associated T835M mutation, and suppressed by transcription factors such as RHOX5 and Ctip2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UNC5C is a transmembrane netrin-1 dependence receptor that transduces repulsive guidance cues in the developing nervous system and acts as a pro-apoptotic effector when deprived of its ligand [#8, #2]. In axon guidance, UNC5C is required cell-autonomously for netrin-1-dependent repulsion of multiple axon and motor-neuron populations in vivo, defining a signaling pathway distinct from DCC, Neogenin1, and netrin1 [#8, #9, #12]. At the growth cone, netrin-1 stimulates a DSCAM-UNC5C complex that recruits FAK, Fyn, and PAK1 and increases UNC5C tyrosine phosphorylation through Src-family kinases to drive growth cone collapse [#0], while UNC5C transduces repulsion by uncoupling from polymerized TUBB3 in microtubules, an event that locally remodels microtubule dynamics during turning [#1]. Surface levels and mobility of UNC5C at the growth cone are controlled by the brain-enriched E3 ubiquitin ligase TRIM9, which also restrains FAK activity in the absence of netrin-1 [#13]. In the absence of netrin-1, UNC5C induces caspase-3-dependent apoptosis, a function amplified by δ-secretase/AEP cleavage at N467 and N547 that generates pro-apoptotic intracellular fragments contributing to Alzheimer's-type and Parkinson's-type neurodegeneration [#2, #3]. This death-promoting activity underlies UNC5C's role as a tumor suppressor, where loss of UNC5C reduces tumor-cell apoptosis and accelerates intestinal tumor progression, and where UNC5C is silenced by promoter methylation in human colorectal cancer [#6]. The Alzheimer-associated T835M variant heightens neuronal vulnerability: it increases susceptibility to Aβ, glutamate, and staurosporine in vitro [#4] and drives hippocampal atrophy, oxidative-stress and JNK pathway activation, and neuronal apoptosis in knock-in mice, exacerbating amyloid pathology [#5]. UNC5C expression is held in check by transcriptional repressors including RHOX5 in Sertoli cells and Ctip2 in cortical neurons [#11, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that UNC5C is genetically required for netrin-1-mediated repulsive axon guidance in vivo and operates in a pathway separable from DCC, Neogenin1, and netrin1.\",\n      \"evidence\": \"Unc5c null mouse axonal tracing with epistatic comparison to DCC/Neogenin/netrin1 nulls and modifier-locus mapping\",\n      \"pmids\": [\"16723533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular signaling output downstream of the receptor\", \"Genetic background modifier on Chr17 not molecularly identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed UNC5C is a tumor suppressor whose loss reduces apoptosis and accelerates tumor progression, linking its guidance receptor identity to programmed cell death.\",\n      \"evidence\": \"UNC5C/APC1638N double-mutant mouse with intestinal tumor apoptosis quantification and human CRC promoter methylation analysis\",\n      \"pmids\": [\"17967459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular apoptotic effector pathway not defined here\", \"Whether loss acts purely through reduced apoptosis vs other tumor-suppressive functions unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified RHOX5 as a transcriptional repressor of Unc5c in Sertoli cells, connecting receptor dosage to germ cell apoptosis.\",\n      \"evidence\": \"5'-UTR deletion analysis, transfection reporter assays, and Unc5c mutant testis apoptosis analysis\",\n      \"pmids\": [\"18077458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sertoli-specific cofactor not identified\", \"Direct apoptotic mechanism in germ cells not dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated cell-autonomous UNC5C function in long-range dorsal axon guidance through transgenic rescue, extending its role beyond a single neuronal population.\",\n      \"evidence\": \"Unc5c null mouse axon tracing with Atoh1-promoter transgenic rescue\",\n      \"pmids\": [\"21307253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand-receptor signaling steps not resolved\", \"Cause of downstream neuronal degeneration unexplained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked a human UNC5C coding variant (A628K) to reduced apoptosis and familial colorectal cancer, providing genetic support for apoptosis-driven tumor suppression.\",\n      \"evidence\": \"HEK293T active caspase-3 assay of A628K mutant plus family segregation analysis\",\n      \"pmids\": [\"21893118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single functional assay for the variant\", \"Structural basis of reduced apoptotic activity unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the growth-cone signaling complex: netrin-1 drives a DSCAM-UNC5C interaction and recruitment of FAK, Fyn, and PAK1 via Src-family-kinase-dependent phosphorylation to collapse growth cones.\",\n      \"evidence\": \"Reciprocal Co-IP, shRNA knockdown, dominant-negative mutants, SFK inhibition, and growth cone collapse assays in cortical and cerebellar granule neurons\",\n      \"pmids\": [\"22685302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of recruitment events not fully resolved\", \"How phosphorylation links to cytoskeletal collapse not mechanistically traced\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the T835M variant as a hinge-region mutation that sensitizes neurons to multiple death stimuli, implicating UNC5C in Alzheimer's disease risk.\",\n      \"evidence\": \"Cell death assays in HEK293T and primary rodent neurons with WT and T835M overexpression and Aβ/glutamate/staurosporine challenge\",\n      \"pmids\": [\"25419706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural validation of the hinge alteration\", \"In vivo relevance not yet demonstrated at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed Unc5c under direct negative transcriptional control by Ctip2 in the context of corticofugal and callosal projections.\",\n      \"evidence\": \"Transcription factor binding analysis and mouse genetic epistasis with Ctip2/Satb2 mutants\",\n      \"pmids\": [\"24739528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding site not finely mapped\", \"Quantitative contribution of Unc5c repression to projection phenotype unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed the cytoskeletal mechanism of repulsion: UNC5C binds polymerized TUBB3 in microtubules and netrin-1 uncouples this interaction to remodel growth-cone microtubule dynamics.\",\n      \"evidence\": \"Co-IP, in vitro microtubule co-sedimentation, EB3-GFP live imaging, and in vivo knockdown axon analysis\",\n      \"pmids\": [\"28483977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ligand binding triggers receptor-microtubule uncoupling not mechanistically defined\", \"Link between TUBB3 release and DSCAM/FAK signaling not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed δ-secretase/AEP cleaves UNC5C at N467 and N547 to amplify its pro-apoptotic activity, mechanistically connecting netrin-1 loss to Alzheimer's pathology.\",\n      \"evidence\": \"Site-directed mutagenesis, in vitro cleavage and caspase-3 assays, viral fragment delivery in APP/PS1 mice, and UNC5C deletion rescue\",\n      \"pmids\": [\"33863723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the active cleaved fragment not solved\", \"Downstream apoptotic effectors of the fragment not enumerated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended AEP-mediated UNC5C cleavage to Parkinson's disease, where truncated fragments promote α-synuclein aggregation and dopaminergic loss.\",\n      \"evidence\": \"In vitro cleavage assays, viral expression of AEP-truncated fragments, and behavioral testing in α-SNCA transgenic and netrin-1 flox mice\",\n      \"pmids\": [\"35023303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cleavage sites not explicitly defined in this context\", \"Mechanism by which fragments promote α-synuclein aggregation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided in vivo evidence that a transient Netrin-1 gradient guides UNC5C-expressing dopamine axons to the prefrontal cortex with developmentally phase-locked timing.\",\n      \"evidence\": \"Rodent axon tracing, Netrin-1 gradient disruption with axon rerouting, and a seasonal daylength model\",\n      \"pmids\": [\"39056276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-level signaling during this guidance not dissected\", \"Mechanism of sexually dimorphic regulation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated TRIM9 as an E3 ligase that controls UNC5C surface levels and mobility at the growth cone and restrains FAK activity basally, identifying a regulatory node for repulsive turning.\",\n      \"evidence\": \"Reciprocal Co-IP, co-localization, Trim9 knockout neurons, pH-mScarlet-UNC5C surface imaging, and microfluidic netrin-1 gradient turning assays\",\n      \"pmids\": [\"39871643\", \"38765979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether UNC5C is a direct ubiquitination substrate of TRIM9 not established\", \"Acute netrin-1-induced surface drop is TRIM9-independent, so that effector is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established in vivo causality for the T835M variant by showing a knock-in mouse develops hippocampal atrophy, oxidative/JNK stress signaling, and apoptosis that worsens amyloid pathology.\",\n      \"evidence\": \"T835M knock-in mouse with TUNEL, caspase 3/7, proteomics, MRI volumetry, and crosses to AppNL-G-F mice\",\n      \"pmids\": [\"40468412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between T835M and oxidative-stress/JNK activation not resolved\", \"Whether δ-secretase cleavage drives the in vivo phenotype not directly tested here\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided the first biophysical characterization of a UNC5C domain by mapping a small-molecule binding site on the ZU5 domain.\",\n      \"evidence\": \"Phage display, fluorescence spectroscopy, ITC, and molecular dynamics of ZU5-Schisandrin A binding\",\n      \"pmids\": [\"41724002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ZU5 binding on receptor signaling not demonstrated\", \"Computational component prominent; structural change not validated experimentally\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How netrin-1 binding mechanically switches UNC5C between its repulsive cytoskeletal/kinase signaling mode and its ligand-deprivation-triggered apoptotic mode at the molecular and structural level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length structural model of the receptor in either state\", \"Integration of TUBB3 uncoupling, DSCAM/FAK signaling, TRIM9 regulation, and AEP cleavage into one switch is incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 0, 1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13, 14, 0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9, 12, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 13, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DSCAM\", \"TUBB3\", \"TRIM9\", \"FAK\", \"Fyn\", \"PAK1\", \"ITGA6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}