{"gene":"DPYSL3","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1996,"finding":"DPYSL3/Ulip is a neuronal 64-85 kDa phosphoprotein localized in neurites, growth cones, and at the neuromuscular junction; its phosphorylation is regulated in response to nerve growth factor, indicating a functional role in neuritic outgrowth and axonal guidance.","method":"cDNA cloning, immunolocalization in neurites/growth cones/NMJ, NGF-stimulated phosphorylation assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunostaining and phosphorylation response established in single lab with multiple methods","pmids":["8551352"],"is_preprint":false},{"year":1998,"finding":"DPYSL3/Ulip4 exists in multiple differentially phosphorylated isoforms as shown by 2D immunoblot of in vitro translated protein, and its mRNA expression is regulated during development and NGF-induced differentiation of PC12 cells.","method":"2D immunoblot of in vitro translated protein, RT-PCR, PC12 NGF differentiation assay","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro translation plus multiple detection methods, single lab","pmids":["9652388"],"is_preprint":false},{"year":2005,"finding":"DPYSL3 is a calpain substrate: NMDA excitotoxicity and H2O2 oxidative stress cause calpain-mediated cleavage of DPYSL3 (62 kDa → 60 kDa doublet) in primary cortical neurons; calpain inhibitors block this cleavage, and purified calpain digestion in vitro recapitulates the cleavage product.","method":"In vitro calpain digestion, calpain inhibitor treatment in primary cortical neurons, immunoblotting","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified calpain plus pharmacological inhibitor confirmation in cells, single lab with multiple orthogonal methods","pmids":["16135096"],"is_preprint":false},{"year":2006,"finding":"NMDA-induced calpain-mediated DPYSL3 truncation requires NOS activation and ROS-dependent activation of L-type voltage-gated Ca2+ channels (L-VGCC): NOS inhibitor L-NAME and L-VGCC blocker nimodipine prevented NMDA-induced DPYSL3 truncation and cell death, while NO donor SNP triggered the same calpain-mediated truncation.","method":"Pharmacological inhibition (L-NAME, nimodipine, MK801), NO donor treatment, Ca2+ imaging, immunoblotting in primary cortical neurons","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological tools in primary neurons, single lab","pmids":["16987501"],"is_preprint":false},{"year":2007,"finding":"CRMP4b physically and functionally interacts with RhoA; siRNA knockdown of CRMP4 promotes neurite outgrowth on myelin substrates, and disruption of CRMP4b-RhoA binding with a competitive inhibitor attenuates neurite outgrowth inhibition on myelin and aggrecan. Nogo stimulation causes colocalization of CRMP4b and RhoA at growth cone actin-rich regions.","method":"Co-immunoprecipitation, siRNA knockdown, competitive peptide inhibitor, neurite outgrowth assays on inhibitory substrates, immunofluorescence colocalization","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA KD with defined phenotypic readout, competitive inhibitor rescue, colocalization; replicated across multiple approaches in same study","pmids":["17301178"],"is_preprint":false},{"year":2008,"finding":"Neurofibromin interacts with CRMP-4 (and CRMP-2) in rat brain; CDK5 is required for the interaction between neurofibromin and CRMP-2, suggesting CDK5 phosphorylation regulates these interactions.","method":"Immunoprecipitation, mass spectrometry, immunoprecipitation-immunoblot, CDK5 inhibition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from brain tissue with MS identification plus CDK5 dependency, single lab","pmids":["18313395"],"is_preprint":false},{"year":2010,"finding":"GSK3β is inactivated by myelin-associated inhibitors (MAIs) and, as a consequence, regulates phosphorylation of CRMP4 and its ability to complex with RhoA; overexpression of GSK3β attenuates myelin inhibition, and a CRMP4 antagonist attenuates the inhibitory effects of GSK3β inhibitors. This establishes GSK3β-CRMP4-RhoA as a signaling axis downstream of MAIs.","method":"Overexpression/inhibition of GSK3β, CRMP4 antagonist peptide, neurite outgrowth assay, phosphorylation analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic overexpression + pharmacological inhibition + competitive antagonist with defined phenotypic readout, single lab but multiple orthogonal approaches","pmids":["20410116"],"is_preprint":false},{"year":2010,"finding":"CRMP4 localizes to spindle microtubules during mitosis; loss of CRMP4 disrupts chromosomal alignment and mitotic progression in a GSK3-dependent phosphorylation-dependent manner, identifying CRMP4 as a physiological GSK3 substrate for mitotic progression.","method":"Immunofluorescence localization to spindle microtubules, siRNA knockdown, phosphomimetic/phospho-dead mutants, chromosomal alignment assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization to spindle plus loss-of-function and phosphorylation mutant analysis, single lab","pmids":["21179545"],"is_preprint":false},{"year":2012,"finding":"CRMP4 mediates MAG-induced inhibition of axonal outgrowth and growth cone collapse; loss of CRMP4 (Crmp4-/- DRG neurons) prevents MAG-induced inhibition and increases sensitivity to Vincristine-induced axonal degeneration; MAG-mediated axon protection against Vincristine is suppressed in CRMP4-/- neurons.","method":"Crmp4-/- mouse model, DRG neuron culture, MAG treatment, Vincristine-induced degeneration assay, axon outgrowth and growth cone collapse measurement","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotypic readout, single lab","pmids":["22583768"],"is_preprint":false},{"year":2012,"finding":"Phosphorylation of Dpysl3 (CRMP4) by Cdk5 and DYRK2 is required for proper positioning of Rohon-Beard neurons and neural crest cells during neurulation in zebrafish; phosphorylation mimics rescued the ectopic cell positioning phenotype in dpysl2/dpysl3 and cdk5/dyrk2 double morphants.","method":"Morpholino knockdown in zebrafish, phosphomimetic rescue constructs, cell transplantation analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with phosphomimetic rescue and cell transplantation, single lab with multiple approaches","pmids":["22898304"],"is_preprint":false},{"year":2013,"finding":"DPYSL3 interacts with Ezrin in pancreatic cancer cells; this interaction promotes stabilization of a focal adhesion complex (Ezrin/c-Src/FAK/Talin1) and activating phosphorylation of Ezrin and c-Src, regulating cell adhesion and migration.","method":"Co-immunoprecipitation, quantitative proteomics (MRM), functional adhesion/migration assays, phosphorylation analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MRM proteomics plus functional assays, single lab","pmids":["24339867"],"is_preprint":false},{"year":2013,"finding":"A missense variant (rs147541241:A>G) in DPYSL3/CRMP4 expressed in motor neurons reduced axonal growth and accelerated cell death compared to wild-type protein in vitro, suggesting the mutation has a gain-of-toxic-function effect on axonal growth.","method":"In vitro expression of mutant DPYSL3 in motor neuron cell culture, axon growth measurement, cell survival assay","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single expression-based assay in cultured motor neurons","pmids":["23568759"],"is_preprint":false},{"year":2014,"finding":"Crystal structures of human CRMP-4 (truncated and full-length) were determined, revealing that CRMP-4 adopts a fold similar to other CRMPs and identifying residues important for homo- and hetero-oligomerization; structures also provided insight into functionally relevant mutations of the DPYSL3 gene.","method":"X-ray crystallography (crystal structure determination with lattice-translocation disorder correction)","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of both truncated and full-length human CRMP-4 with structural comparison and functional residue identification","pmids":["24914979"],"is_preprint":false},{"year":2015,"finding":"Locus-specific CpG demethylation of the CRMP4 promoter in metastatic PC3 prostate cancer cells abolished metastasis, whereas locus-specific methylation in non-metastatic 22Rv1 cells induced metastasis; CRMP4-mediated metastasis suppression required activation of Akt/Rac1 signaling and down-regulation of MMP-9.","method":"TALE-DNA methyltransferase/demethylase-mediated locus-specific CpG modification, in vitro/in vivo migration/invasion assays, signaling pathway analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — locus-specific epigenomic editing with functional and pathway readouts, single lab","pmids":["25888628"],"is_preprint":false},{"year":2015,"finding":"CRMP4 deletion (Crmp4-/-) in mice leads to neuroprotection after spinal cord injury and reductions in inflammatory response and scar formation; CRMP4 expression is observed in inflammatory cells as well as neurons after injury, and injury increases inhibitory/toxic phosphorylated forms of CRMP4.","method":"Crmp4-/- mouse model, spinal cord transection, locomotor behavior assessment, immunohistochemistry for inflammatory markers and scar formation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple cellular and behavioral phenotypic readouts, single lab","pmids":["25652774"],"is_preprint":false},{"year":2016,"finding":"Crmp4 deletion overrides CSPG-induced inhibition of axon growth in DRG neurons in vitro; CRMP4 levels are increased in DRGs after spinal cord injury in vivo; Crmp4-/- mice exhibit axonal growth of sensory neurons and recovery of nociceptive function after spinal transection.","method":"Crmp4-/- mouse, DRG neuron culture on CSPG substrate, axon growth measurement, in vivo spinal cord injury model, nociceptive behavioral testing","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vitro and in vivo complementary assays, single lab","pmids":["26995506"],"is_preprint":false},{"year":2017,"finding":"CRMP4 negatively regulates osteoblast differentiation via inhibition of BMP2 signaling and RhoA/FAK signaling; Crmp4-/- mice display increased bone mass, mineral apposition rate, and bone formation rate; Crmp4-/- osteoblasts exhibit enhanced BMP2 signaling, increased RhoA/FAK activation, and altered cell spreading and proliferation through p27Kip1/cyclin D1.","method":"Crmp4-/- mouse model, in vitro gain/loss-of-function in stromal cells, osteoblast differentiation assays, BMP2 signaling analysis, RhoA/FAK pathway analysis, bone histomorphometry","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple in vitro and in vivo readouts and pathway analysis, single lab","pmids":["28019696"],"is_preprint":false},{"year":2018,"finding":"DPYSL3 knockdown in claudin-low breast cancer cells reduced proliferation, enhanced motility, increased EMT marker expression, caused multinucleated cell accumulation (mitotic defect) associated with vimentin microfilament collapse and increased vimentin phosphorylation; DPYSL3 suppressed EMT regulators SNAIL and TWIST and opposed PAK2-dependent migration; in turn, EMT regulators induce DPYSL3 expression (negative feedback).","method":"siRNA knockdown, cell proliferation and motility assays, immunoblot for EMT markers, microscopy for multinucleated cells and vimentin network, PAK2 inhibitor studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple orthogonal phenotypic and molecular readouts plus pathway inhibitor, single lab","pmids":["30498031"],"is_preprint":false},{"year":2018,"finding":"Calpain-2 cleaves CRMP4 into an N-terminal fragment that promotes migration and invasion in prostate cancer cells via nuclear translocation and E2F1-mediated DNMT1 expression; NF-κB RelA/p65 (with Ser276 phosphorylation) recruits DNMT1 to methylate the CRMP4 promoter, suppressing CRMP4 transcription; CRMP4 suppresses metastasis via inhibiting VEGFC through Semaphorin3B-Neuropilin2 signaling.","method":"In vitro calpain-2 cleavage assay, nuclear fractionation, siRNA/overexpression, ChIP for DNMT1 at CRMP4 promoter, VEGFC pathway analysis, cell migration/invasion assays","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and functional methods, single lab","pmids":["29601651"],"is_preprint":false},{"year":2020,"finding":"CRMP4 facilitates both Wallerian degeneration in distal axon segments (via calpain-dependent formation of harmful CRMP4 fragments) and regeneration of proximal axon segments following sciatic nerve injury; Crmp4-/- mice show impaired sensory axon regeneration and Wallerian degeneration after sciatic nerve injury.","method":"Crmp4-/- mouse model (male and female), sciatic nerve injury, in vitro DRG neuron axotomy assays, calpain fragment detection by immunoblot","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with both in vivo and in vitro readouts plus biochemical analysis of calpain fragments, single lab","pmids":["32001550"],"is_preprint":false},{"year":2021,"finding":"CRMP4 levels are increased in ALS motor neuron cell bodies but decreased in distal axons; this subcellular mislocalization is caused by increased interaction of CRMP4 with the retrograde motor protein dynein, mediating CRMP4 transport from distal axons to soma and promoting motor neuron loss; blocking the CRMP4-dynein interaction reduces motor neuron loss in C9orf72-mutant human iPSC-derived MNs and SOD1G93A ALS mice.","method":"Immunofluorescence in human ALS tissue and SOD1G93A mice, Co-immunoprecipitation for CRMP4-dynein, competitive inhibitor of CRMP4-dynein interaction, iPSC-derived motor neuron survival assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for dynein interaction, subcellular localization in patient tissue and mouse model, pharmacological rescue in both human iPSC-MNs and ALS mice, multiple orthogonal methods across multiple models","pmids":["34190355"],"is_preprint":false},{"year":2021,"finding":"CRMP4 interacts with the Semaphorin-3E tripartite receptor complex and with MAP6; CRMP4-KO mice display abnormal fornix development resembling Sema3E-KO mice; DRM domain integrity is required to transduce Sema3E signaling through Akt/GSK3; the cytoskeleton-binding domain of CRMP4 is required for Sema3E growth-promoting activity.","method":"Co-immunoprecipitation (CRMP4-MAP6, CRMP4-Sema3E receptor complex), Crmp4-/- mouse fornix anatomy, DRM fractionation, domain deletion mutants, Akt/GSK3 pathway analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs, genetic KO phenotype, DRM fractionation, domain mutant functional analysis; multiple orthogonal methods in single study","pmids":["34860155"],"is_preprint":false},{"year":2021,"finding":"CRMP4 (but not CRMP1) is involved in infrapyramidal bundle (IPB) pruning of mossy fibers in the hippocampus; genetic interaction analysis indicates CRMP2 and CRMP4 have distinct functions, with CRMP2 mediating IPB pruning via Nrp2 (semaphorin/neuropilin pathway); altered synaptic terminals of mossy fibers were observed in CRMP2 and CRMP4 mutant mice.","method":"CRMP4-/- mouse, CRMP2/CRMP4 double mutants, IPB anatomy, genetic interaction analysis with Nrp2 mutants","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and epistasis analysis, single lab","pmids":["34932871"],"is_preprint":false},{"year":2021,"finding":"CRMP4 is SUMOylated at K374 by SUMO1, SUMO2, and SUMO3; SUMO2 interacts with CRMP4 but not with K374 mutant; CRMP4 deSUMOylation promotes neurite outgrowth and strengthens its interaction with Cav1.2 L-type Ca2+ channel; CRMP4 promotes calcium influx via Cav1.2, and overexpression increases thermal pain sensitivity in rats, an effect strengthened by deSUMOylation.","method":"GST-pulldown with SUMO1/2/3, Co-IP, immunofluorescence colocalization, neurite outgrowth assay, whole-cell patch clamp, in vivo paw withdrawal latency","journal":"Journal of integrative neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST-pulldown plus Co-IP for SUMO modification, electrophysiology, and in vivo behavioral assay; multiple methods in single lab","pmids":["34645092"],"is_preprint":false},{"year":2022,"finding":"CRMP4 is required for positioning and maturation of newly generated neurons in adult hippocampal neurogenesis; in Crmp4-/- mice, DCX-positive cells are ectopically located in the granule cell layer and the ratio of calretinin-positive new neurons is increased while EdU/NeuN double-positive mature neurons are decreased, indicating CRMP4 regulates migration and maturation of adult-born neurons.","method":"Crmp4-/- mouse model, BrdU/EdU birthdating, immunostaining for DCX/calretinin/NeuN, confocal microscopy","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple neurogenesis marker analyses, single lab","pmids":["35122931"],"is_preprint":false},{"year":2022,"finding":"CRMP2 phosphorylation by Cdk5 and redundant functions of CRMP1 and CRMP4 are required for proper neuronal migration in developing cerebral cortex and hippocampus; triple mutant (CRMP1 KO; CRMP2 KI/KI; CRMP4 KO) mice show disturbed laminar positioning of cortical neurons and ectopic neurons in hippocampal regions.","method":"Triple mutant mouse model (KO/KI combinations), BrdU birthdating, in utero electroporation, cortical layer and hippocampal anatomy analysis","journal":"Cerebral cortex","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via triple mutant mice with multiple phenotypic analyses, single lab","pmids":["34297816"],"is_preprint":false},{"year":2024,"finding":"Microglia-specific CRMP4 deletion reduces microglial proliferation after LPS injection into substantia nigra and suppresses arginase-1 expression; CRMP4 is involved in LPS-induced neuroinflammation and suppresses microglial proliferation in a cell-autonomous manner.","method":"Microglia-specific Crmp4 conditional KO mouse, LPS injection model, Iba1 immunostaining, IL-10 and Arg1 expression analysis","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with defined cellular and molecular readouts, single lab","pmids":["38914219"],"is_preprint":false},{"year":2026,"finding":"CRMP4 promotes actin polymerization in ectopic endometrial stromal cells and facilitates nuclear translocation of MRTF, activating SRF and downstream target genes related to migration and invasion; CRMP4 silencing inhibits endometriosis lesion growth in vivo.","method":"siRNA/lentiviral CRMP4 KO and overexpression, free-actin quantification, immunofluorescence/MRTF nuclear translocation, SRF reporter, Transwell/wound-healing assays, in vivo mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays plus in vivo model, single lab; year 2026 as published","pmids":["41715156"],"is_preprint":false}],"current_model":"DPYSL3/CRMP4 is a cytosolic phosphoprotein and calpain/GSK3β/Cdk5 substrate that physically interacts with RhoA, dynein, MAP6, neurofibromin, Ezrin, Cav1.2, and the Sema3E receptor complex to regulate axonal growth cone dynamics, cytoskeletal (actin and microtubule) organization, mitotic chromosomal alignment via spindle microtubules, retrograde axon-to-soma death signaling (through dynein-mediated transport in ALS), adult hippocampal neurogenesis, fornix development downstream of Semaphorin-3E/Akt/GSK3 signaling, and invasive cell migration via MRTF/SRF-dependent actin polymerization; its activity is modulated by phosphorylation (GSK3β, Cdk5, DYRK2) and SUMOylation at K374, and its expression is regulated epigenetically by promoter CpG methylation and post-translationally by calpain cleavage."},"narrative":{"mechanistic_narrative":"DPYSL3 (CRMP4/Ulip) is a neuronal phosphoprotein and cytoskeletal regulator that controls axonal growth, growth cone dynamics, and cell migration by integrating extracellular guidance and inhibitory signals with actin and microtubule organization [PMID:8551352, PMID:17301178]. As a downstream effector of myelin-associated inhibitors, CRMP4 physically and functionally complexes with RhoA at actin-rich growth cone regions to transduce axon outgrowth inhibition, and disrupting the CRMP4b-RhoA interaction relieves this inhibition on myelin and chondroitin sulfate proteoglycan substrates [PMID:17301178, PMID:22583768, PMID:26995506]. This activity is gated by phosphorylation: GSK3β acts within a MAI-GSK3β-CRMP4-RhoA signaling axis, and Cdk5 and DYRK2 phosphorylate CRMP4 to govern neuronal positioning during development [PMID:20410116, PMID:22898304]. CRMP4 transduces Semaphorin-3E signaling through its association with the Sema3E receptor complex and MAP6, requiring detergent-resistant-membrane domain integrity and acting through Akt/GSK3, with Crmp4-loss producing aberrant fornix development [PMID:34860155]. Beyond guidance, CRMP4 localizes to spindle microtubules and is required for chromosomal alignment and mitotic progression in a GSK3-dependent manner [PMID:21179545]. It is also a calpain substrate, cleaved upon NMDA excitotoxic and oxidative stress in a NOS/L-VGCC-dependent manner, generating fragments that drive Wallerian degeneration and death signaling [PMID:16135096, PMID:16987501, PMID:34190355]; in ALS models CRMP4 binds the retrograde motor dynein to mislocalize from distal axons to the soma and promote motor neuron loss, which is reversed by blocking the CRMP4-dynein interaction [PMID:34190355]. In non-neuronal contexts CRMP4 regulates invasive migration: it interacts with Ezrin to stabilize a focal adhesion complex, drives MRTF/SRF-dependent actin polymerization, and its expression is controlled by promoter CpG methylation, while it negatively regulates osteoblast differentiation via BMP2 and RhoA/FAK signaling [PMID:24339867, PMID:41715156, PMID:25888628, PMID:28019696]. Its activity is further modulated by SUMOylation at K374, which weakens its interaction with the Cav1.2 L-type Ca2+ channel [PMID:34645092].","teleology":[{"year":1996,"claim":"Established CRMP4 as a neuronal phosphoprotein positioned at sites of axon growth, framing it as a candidate effector of growth and guidance signals.","evidence":"cDNA cloning with immunolocalization to neurites, growth cones, and NMJ plus NGF-stimulated phosphorylation in neuronal cells","pmids":["8551352"],"confidence":"Medium","gaps":["No molecular partners or downstream effectors identified","Functional consequence of phosphorylation undefined"]},{"year":1998,"claim":"Showed CRMP4 exists as multiple phosphorylated isoforms developmentally and during NGF-induced differentiation, reinforcing phosphoregulation as a control point.","evidence":"2D immunoblot of in vitro translated protein, RT-PCR, PC12 differentiation assay","pmids":["9652388"],"confidence":"Medium","gaps":["Kinases responsible not identified","Isoform-specific functions unresolved"]},{"year":2006,"claim":"Defined CRMP4 as a stress-regulated calpain substrate, linking excitotoxic and oxidative insults to its proteolytic processing.","evidence":"In vitro purified calpain digestion, calpain inhibitor and NOS/L-VGCC pharmacology in primary cortical neurons, immunoblotting (PMIDs 16135096, 16987501)","pmids":["16135096","16987501"],"confidence":"High","gaps":["Function of the cleavage fragments not determined here","Cleavage site not mapped"]},{"year":2010,"claim":"Identified the CRMP4b-RhoA complex as the effector arm that transduces myelin/CSPG inhibition into growth cone collapse, and placed GSK3β phosphorylation upstream of complex formation.","evidence":"Reciprocal Co-IP, siRNA knockdown, competitive peptide inhibitor and neurite outgrowth assays on inhibitory substrates, plus GSK3β manipulation (PMIDs 17301178, 20410116)","pmids":["17301178","20410116"],"confidence":"High","gaps":["Structural basis of CRMP4-RhoA binding not resolved","How phosphorylation gates the interaction at the residue level unclear"]},{"year":2010,"claim":"Extended CRMP4 function beyond neurons by showing it localizes to the mitotic spindle and is a GSK3 substrate required for chromosomal alignment.","evidence":"Immunofluorescence to spindle microtubules, siRNA knockdown, phosphomimetic/phospho-dead mutants, chromosomal alignment assays","pmids":["21179545"],"confidence":"Medium","gaps":["Spindle-binding partners not identified","Single-lab observation in cultured cells"]},{"year":2012,"claim":"Genetic and developmental work established CRMP4 as a phosphorylation-dependent determinant of neuronal positioning and MAG-mediated axon inhibition/protection.","evidence":"Crmp4-/- DRG neurons with MAG and Vincristine assays; zebrafish morpholino knockdown with Cdk5/DYRK2 phosphomimetic rescue (PMIDs 22583768, 22898304)","pmids":["22583768","22898304"],"confidence":"Medium","gaps":["Direct kinase-substrate phosphosites not all mapped","Mechanism linking phosphorylation to cytoskeletal output incomplete"]},{"year":2013,"claim":"Opened a cancer/cell-migration axis by showing CRMP4 binds Ezrin to stabilize a focal adhesion complex and that a disease-associated variant has gain-of-toxic-function in motor neurons.","evidence":"Co-IP and MRM proteomics with adhesion/migration assays in pancreatic cancer cells; in vitro expression of an rs147541241 missense variant in motor neurons (PMIDs 24339867, 23568759)","pmids":["24339867","23568759"],"confidence":"Medium","gaps":["Ezrin interaction interface not mapped","Variant pathogenicity tested only in a single cell assay"]},{"year":2014,"claim":"Provided atomic-resolution structures of human CRMP4, defining its fold and oligomerization residues and a structural framework for disease mutations.","evidence":"X-ray crystallography of truncated and full-length human CRMP-4","pmids":["24914979"],"confidence":"High","gaps":["No co-structures with partners (RhoA, dynein, Ezrin)","Structure does not capture phosphorylated or fragment states"]},{"year":2015,"claim":"Established epigenetic control of CRMP4 expression and its role as a metastasis suppressor acting through Akt/Rac1 and MMP-9.","evidence":"TALE-based locus-specific CpG methylation/demethylation with in vitro and in vivo invasion assays and pathway analysis in prostate cancer cells","pmids":["25888628"],"confidence":"Medium","gaps":["Mechanism connecting CRMP4 to Akt/Rac1 not defined","Direct vs indirect regulation of MMP-9 unresolved"]},{"year":2018,"claim":"Defined a feedback loop in which calpain-2-generated CRMP4 fragments and EMT regulators reciprocally control migration, with CRMP4 suppressing SNAIL/TWIST and PAK2-dependent motility while opposing mitotic defects.","evidence":"Calpain-2 cleavage, nuclear fractionation, ChIP for DNMT1 at the CRMP4 promoter, and siRNA knockdown with EMT/vimentin and PAK2 readouts in cancer cells (PMIDs 29601651, 30498031)","pmids":["29601651","30498031"],"confidence":"Medium","gaps":["In vivo relevance of nuclear CRMP4 fragment limited","Direct targets of the N-terminal fragment incompletely mapped"]},{"year":2017,"claim":"Demonstrated a skeletal role: CRMP4 negatively regulates osteoblast differentiation through BMP2 and RhoA/FAK signaling.","evidence":"Crmp4-/- mice with bone histomorphometry plus gain/loss-of-function osteoblast assays and pathway analysis","pmids":["28019696"],"confidence":"Medium","gaps":["Direct molecular link between CRMP4 and BMP2 receptor signaling unclear","Single-lab in vivo finding"]},{"year":2021,"claim":"Resolved a death-signaling mechanism in ALS: CRMP4 binds dynein for retrograde transport that mislocalizes it to the soma and drives motor neuron loss.","evidence":"Co-IP for CRMP4-dynein, localization in ALS patient tissue and SOD1G93A mice, and competitive inhibition rescue in C9orf72 iPSC-MNs and ALS mice","pmids":["34190355"],"confidence":"High","gaps":["Dynein adaptor/cargo selection mechanism undefined","How somatic CRMP4 accumulation triggers death not fully mechanistic"]},{"year":2021,"claim":"Placed CRMP4 in the Semaphorin-3E pathway via the Sema3E receptor complex and MAP6, requiring DRM and cytoskeleton-binding domains to signal through Akt/GSK3 for fornix development.","evidence":"Co-IPs (CRMP4-MAP6, CRMP4-Sema3E receptor), Crmp4-/- fornix anatomy, DRM fractionation, and domain-deletion functional analysis","pmids":["34860155"],"confidence":"High","gaps":["Stoichiometry within the receptor complex unknown","How DRM localization mechanistically enables signaling unresolved"]},{"year":2021,"claim":"Showed CRMP4 activity is tuned by SUMOylation at K374, which modulates its Cav1.2 interaction, neurite outgrowth, and pain sensitivity.","evidence":"GST-pulldown with SUMO1/2/3, Co-IP, electrophysiology, and in vivo paw withdrawal behavioral assay","pmids":["34645092"],"confidence":"Medium","gaps":["SUMO E3 ligase and deSUMOylase not identified","Link between Cav1.2 coupling and pain behavior indirect"]},{"year":2022,"claim":"Defined CRMP4's roles in adult hippocampal neurogenesis and, with CRMP1/CRMP2, in cortical and hippocampal neuronal migration and mossy fiber pruning, clarifying paralog redundancy and specificity.","evidence":"Crmp4-/- and CRMP1/2/4 multi-mutant mice with birthdating, marker immunostaining, in utero electroporation, and Nrp2 epistasis (PMIDs 35122931, 34297816, 34932871)","pmids":["35122931","34297816","34932871"],"confidence":"Medium","gaps":["Molecular distinction between paralog functions incomplete","Cell-intrinsic vs niche contributions not separated"]},{"year":2024,"claim":"Revealed a cell-autonomous glial role: microglial CRMP4 promotes proliferation and shapes neuroinflammatory responses.","evidence":"Microglia-specific conditional Crmp4 KO with LPS substantia nigra injection, Iba1 immunostaining, and Arg1/IL-10 analysis","pmids":["38914219"],"confidence":"Medium","gaps":["Signaling mechanism in microglia undefined","Single model and stimulus tested"]},{"year":2026,"claim":"Connected CRMP4 to a transcriptional-cytoskeletal output by showing it drives actin polymerization and MRTF/SRF activation to promote invasive migration in endometriosis.","evidence":"CRMP4 KO/overexpression, free-actin quantification, MRTF nuclear translocation, SRF reporter, migration assays, and in vivo lesion model","pmids":["41715156"],"confidence":"Medium","gaps":["Direct mechanism linking CRMP4 to actin nucleation unclear","Whether MRTF/SRF axis operates in other CRMP4 contexts untested"]},{"year":null,"claim":"How CRMP4's phosphorylation, SUMOylation, and calpain-cleavage states are integrated to switch it between growth-promoting, growth-inhibiting, and pro-death functions across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to partner choice (RhoA vs dynein vs Ezrin vs MRTF)","Structures of CRMP4 in modified or complexed states lacking","Tissue-specific regulators of CRMP4 modification largely unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,7,21,27]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,6,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental 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neurites/growth cones/NMJ, NGF-stimulated phosphorylation assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunostaining and phosphorylation response established in single lab with multiple methods\",\n      \"pmids\": [\"8551352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"DPYSL3/Ulip4 exists in multiple differentially phosphorylated isoforms as shown by 2D immunoblot of in vitro translated protein, and its mRNA expression is regulated during development and NGF-induced differentiation of PC12 cells.\",\n      \"method\": \"2D immunoblot of in vitro translated protein, RT-PCR, PC12 NGF differentiation assay\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro translation plus multiple detection methods, single lab\",\n      \"pmids\": [\"9652388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DPYSL3 is a calpain substrate: NMDA excitotoxicity and H2O2 oxidative stress cause calpain-mediated cleavage of DPYSL3 (62 kDa → 60 kDa doublet) in primary cortical neurons; calpain inhibitors block this cleavage, and purified calpain digestion in vitro recapitulates the cleavage product.\",\n      \"method\": \"In vitro calpain digestion, calpain inhibitor treatment in primary cortical neurons, immunoblotting\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified calpain plus pharmacological inhibitor confirmation in cells, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16135096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NMDA-induced calpain-mediated DPYSL3 truncation requires NOS activation and ROS-dependent activation of L-type voltage-gated Ca2+ channels (L-VGCC): NOS inhibitor L-NAME and L-VGCC blocker nimodipine prevented NMDA-induced DPYSL3 truncation and cell death, while NO donor SNP triggered the same calpain-mediated truncation.\",\n      \"method\": \"Pharmacological inhibition (L-NAME, nimodipine, MK801), NO donor treatment, Ca2+ imaging, immunoblotting in primary cortical neurons\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological tools in primary neurons, single lab\",\n      \"pmids\": [\"16987501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CRMP4b physically and functionally interacts with RhoA; siRNA knockdown of CRMP4 promotes neurite outgrowth on myelin substrates, and disruption of CRMP4b-RhoA binding with a competitive inhibitor attenuates neurite outgrowth inhibition on myelin and aggrecan. Nogo stimulation causes colocalization of CRMP4b and RhoA at growth cone actin-rich regions.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, competitive peptide inhibitor, neurite outgrowth assays on inhibitory substrates, immunofluorescence colocalization\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA KD with defined phenotypic readout, competitive inhibitor rescue, colocalization; replicated across multiple approaches in same study\",\n      \"pmids\": [\"17301178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Neurofibromin interacts with CRMP-4 (and CRMP-2) in rat brain; CDK5 is required for the interaction between neurofibromin and CRMP-2, suggesting CDK5 phosphorylation regulates these interactions.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, immunoprecipitation-immunoblot, CDK5 inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from brain tissue with MS identification plus CDK5 dependency, single lab\",\n      \"pmids\": [\"18313395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GSK3β is inactivated by myelin-associated inhibitors (MAIs) and, as a consequence, regulates phosphorylation of CRMP4 and its ability to complex with RhoA; overexpression of GSK3β attenuates myelin inhibition, and a CRMP4 antagonist attenuates the inhibitory effects of GSK3β inhibitors. This establishes GSK3β-CRMP4-RhoA as a signaling axis downstream of MAIs.\",\n      \"method\": \"Overexpression/inhibition of GSK3β, CRMP4 antagonist peptide, neurite outgrowth assay, phosphorylation analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic overexpression + pharmacological inhibition + competitive antagonist with defined phenotypic readout, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"20410116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CRMP4 localizes to spindle microtubules during mitosis; loss of CRMP4 disrupts chromosomal alignment and mitotic progression in a GSK3-dependent phosphorylation-dependent manner, identifying CRMP4 as a physiological GSK3 substrate for mitotic progression.\",\n      \"method\": \"Immunofluorescence localization to spindle microtubules, siRNA knockdown, phosphomimetic/phospho-dead mutants, chromosomal alignment assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization to spindle plus loss-of-function and phosphorylation mutant analysis, single lab\",\n      \"pmids\": [\"21179545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CRMP4 mediates MAG-induced inhibition of axonal outgrowth and growth cone collapse; loss of CRMP4 (Crmp4-/- DRG neurons) prevents MAG-induced inhibition and increases sensitivity to Vincristine-induced axonal degeneration; MAG-mediated axon protection against Vincristine is suppressed in CRMP4-/- neurons.\",\n      \"method\": \"Crmp4-/- mouse model, DRG neuron culture, MAG treatment, Vincristine-induced degeneration assay, axon outgrowth and growth cone collapse measurement\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotypic readout, single lab\",\n      \"pmids\": [\"22583768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Phosphorylation of Dpysl3 (CRMP4) by Cdk5 and DYRK2 is required for proper positioning of Rohon-Beard neurons and neural crest cells during neurulation in zebrafish; phosphorylation mimics rescued the ectopic cell positioning phenotype in dpysl2/dpysl3 and cdk5/dyrk2 double morphants.\",\n      \"method\": \"Morpholino knockdown in zebrafish, phosphomimetic rescue constructs, cell transplantation analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with phosphomimetic rescue and cell transplantation, single lab with multiple approaches\",\n      \"pmids\": [\"22898304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DPYSL3 interacts with Ezrin in pancreatic cancer cells; this interaction promotes stabilization of a focal adhesion complex (Ezrin/c-Src/FAK/Talin1) and activating phosphorylation of Ezrin and c-Src, regulating cell adhesion and migration.\",\n      \"method\": \"Co-immunoprecipitation, quantitative proteomics (MRM), functional adhesion/migration assays, phosphorylation analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MRM proteomics plus functional assays, single lab\",\n      \"pmids\": [\"24339867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A missense variant (rs147541241:A>G) in DPYSL3/CRMP4 expressed in motor neurons reduced axonal growth and accelerated cell death compared to wild-type protein in vitro, suggesting the mutation has a gain-of-toxic-function effect on axonal growth.\",\n      \"method\": \"In vitro expression of mutant DPYSL3 in motor neuron cell culture, axon growth measurement, cell survival assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single expression-based assay in cultured motor neurons\",\n      \"pmids\": [\"23568759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structures of human CRMP-4 (truncated and full-length) were determined, revealing that CRMP-4 adopts a fold similar to other CRMPs and identifying residues important for homo- and hetero-oligomerization; structures also provided insight into functionally relevant mutations of the DPYSL3 gene.\",\n      \"method\": \"X-ray crystallography (crystal structure determination with lattice-translocation disorder correction)\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of both truncated and full-length human CRMP-4 with structural comparison and functional residue identification\",\n      \"pmids\": [\"24914979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Locus-specific CpG demethylation of the CRMP4 promoter in metastatic PC3 prostate cancer cells abolished metastasis, whereas locus-specific methylation in non-metastatic 22Rv1 cells induced metastasis; CRMP4-mediated metastasis suppression required activation of Akt/Rac1 signaling and down-regulation of MMP-9.\",\n      \"method\": \"TALE-DNA methyltransferase/demethylase-mediated locus-specific CpG modification, in vitro/in vivo migration/invasion assays, signaling pathway analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — locus-specific epigenomic editing with functional and pathway readouts, single lab\",\n      \"pmids\": [\"25888628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CRMP4 deletion (Crmp4-/-) in mice leads to neuroprotection after spinal cord injury and reductions in inflammatory response and scar formation; CRMP4 expression is observed in inflammatory cells as well as neurons after injury, and injury increases inhibitory/toxic phosphorylated forms of CRMP4.\",\n      \"method\": \"Crmp4-/- mouse model, spinal cord transection, locomotor behavior assessment, immunohistochemistry for inflammatory markers and scar formation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple cellular and behavioral phenotypic readouts, single lab\",\n      \"pmids\": [\"25652774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crmp4 deletion overrides CSPG-induced inhibition of axon growth in DRG neurons in vitro; CRMP4 levels are increased in DRGs after spinal cord injury in vivo; Crmp4-/- mice exhibit axonal growth of sensory neurons and recovery of nociceptive function after spinal transection.\",\n      \"method\": \"Crmp4-/- mouse, DRG neuron culture on CSPG substrate, axon growth measurement, in vivo spinal cord injury model, nociceptive behavioral testing\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vitro and in vivo complementary assays, single lab\",\n      \"pmids\": [\"26995506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRMP4 negatively regulates osteoblast differentiation via inhibition of BMP2 signaling and RhoA/FAK signaling; Crmp4-/- mice display increased bone mass, mineral apposition rate, and bone formation rate; Crmp4-/- osteoblasts exhibit enhanced BMP2 signaling, increased RhoA/FAK activation, and altered cell spreading and proliferation through p27Kip1/cyclin D1.\",\n      \"method\": \"Crmp4-/- mouse model, in vitro gain/loss-of-function in stromal cells, osteoblast differentiation assays, BMP2 signaling analysis, RhoA/FAK pathway analysis, bone histomorphometry\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple in vitro and in vivo readouts and pathway analysis, single lab\",\n      \"pmids\": [\"28019696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DPYSL3 knockdown in claudin-low breast cancer cells reduced proliferation, enhanced motility, increased EMT marker expression, caused multinucleated cell accumulation (mitotic defect) associated with vimentin microfilament collapse and increased vimentin phosphorylation; DPYSL3 suppressed EMT regulators SNAIL and TWIST and opposed PAK2-dependent migration; in turn, EMT regulators induce DPYSL3 expression (negative feedback).\",\n      \"method\": \"siRNA knockdown, cell proliferation and motility assays, immunoblot for EMT markers, microscopy for multinucleated cells and vimentin network, PAK2 inhibitor studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple orthogonal phenotypic and molecular readouts plus pathway inhibitor, single lab\",\n      \"pmids\": [\"30498031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Calpain-2 cleaves CRMP4 into an N-terminal fragment that promotes migration and invasion in prostate cancer cells via nuclear translocation and E2F1-mediated DNMT1 expression; NF-κB RelA/p65 (with Ser276 phosphorylation) recruits DNMT1 to methylate the CRMP4 promoter, suppressing CRMP4 transcription; CRMP4 suppresses metastasis via inhibiting VEGFC through Semaphorin3B-Neuropilin2 signaling.\",\n      \"method\": \"In vitro calpain-2 cleavage assay, nuclear fractionation, siRNA/overexpression, ChIP for DNMT1 at CRMP4 promoter, VEGFC pathway analysis, cell migration/invasion assays\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and functional methods, single lab\",\n      \"pmids\": [\"29601651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRMP4 facilitates both Wallerian degeneration in distal axon segments (via calpain-dependent formation of harmful CRMP4 fragments) and regeneration of proximal axon segments following sciatic nerve injury; Crmp4-/- mice show impaired sensory axon regeneration and Wallerian degeneration after sciatic nerve injury.\",\n      \"method\": \"Crmp4-/- mouse model (male and female), sciatic nerve injury, in vitro DRG neuron axotomy assays, calpain fragment detection by immunoblot\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with both in vivo and in vitro readouts plus biochemical analysis of calpain fragments, single lab\",\n      \"pmids\": [\"32001550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRMP4 levels are increased in ALS motor neuron cell bodies but decreased in distal axons; this subcellular mislocalization is caused by increased interaction of CRMP4 with the retrograde motor protein dynein, mediating CRMP4 transport from distal axons to soma and promoting motor neuron loss; blocking the CRMP4-dynein interaction reduces motor neuron loss in C9orf72-mutant human iPSC-derived MNs and SOD1G93A ALS mice.\",\n      \"method\": \"Immunofluorescence in human ALS tissue and SOD1G93A mice, Co-immunoprecipitation for CRMP4-dynein, competitive inhibitor of CRMP4-dynein interaction, iPSC-derived motor neuron survival assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for dynein interaction, subcellular localization in patient tissue and mouse model, pharmacological rescue in both human iPSC-MNs and ALS mice, multiple orthogonal methods across multiple models\",\n      \"pmids\": [\"34190355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRMP4 interacts with the Semaphorin-3E tripartite receptor complex and with MAP6; CRMP4-KO mice display abnormal fornix development resembling Sema3E-KO mice; DRM domain integrity is required to transduce Sema3E signaling through Akt/GSK3; the cytoskeleton-binding domain of CRMP4 is required for Sema3E growth-promoting activity.\",\n      \"method\": \"Co-immunoprecipitation (CRMP4-MAP6, CRMP4-Sema3E receptor complex), Crmp4-/- mouse fornix anatomy, DRM fractionation, domain deletion mutants, Akt/GSK3 pathway analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs, genetic KO phenotype, DRM fractionation, domain mutant functional analysis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"34860155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRMP4 (but not CRMP1) is involved in infrapyramidal bundle (IPB) pruning of mossy fibers in the hippocampus; genetic interaction analysis indicates CRMP2 and CRMP4 have distinct functions, with CRMP2 mediating IPB pruning via Nrp2 (semaphorin/neuropilin pathway); altered synaptic terminals of mossy fibers were observed in CRMP2 and CRMP4 mutant mice.\",\n      \"method\": \"CRMP4-/- mouse, CRMP2/CRMP4 double mutants, IPB anatomy, genetic interaction analysis with Nrp2 mutants\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and epistasis analysis, single lab\",\n      \"pmids\": [\"34932871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRMP4 is SUMOylated at K374 by SUMO1, SUMO2, and SUMO3; SUMO2 interacts with CRMP4 but not with K374 mutant; CRMP4 deSUMOylation promotes neurite outgrowth and strengthens its interaction with Cav1.2 L-type Ca2+ channel; CRMP4 promotes calcium influx via Cav1.2, and overexpression increases thermal pain sensitivity in rats, an effect strengthened by deSUMOylation.\",\n      \"method\": \"GST-pulldown with SUMO1/2/3, Co-IP, immunofluorescence colocalization, neurite outgrowth assay, whole-cell patch clamp, in vivo paw withdrawal latency\",\n      \"journal\": \"Journal of integrative neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST-pulldown plus Co-IP for SUMO modification, electrophysiology, and in vivo behavioral assay; multiple methods in single lab\",\n      \"pmids\": [\"34645092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRMP4 is required for positioning and maturation of newly generated neurons in adult hippocampal neurogenesis; in Crmp4-/- mice, DCX-positive cells are ectopically located in the granule cell layer and the ratio of calretinin-positive new neurons is increased while EdU/NeuN double-positive mature neurons are decreased, indicating CRMP4 regulates migration and maturation of adult-born neurons.\",\n      \"method\": \"Crmp4-/- mouse model, BrdU/EdU birthdating, immunostaining for DCX/calretinin/NeuN, confocal microscopy\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple neurogenesis marker analyses, single lab\",\n      \"pmids\": [\"35122931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRMP2 phosphorylation by Cdk5 and redundant functions of CRMP1 and CRMP4 are required for proper neuronal migration in developing cerebral cortex and hippocampus; triple mutant (CRMP1 KO; CRMP2 KI/KI; CRMP4 KO) mice show disturbed laminar positioning of cortical neurons and ectopic neurons in hippocampal regions.\",\n      \"method\": \"Triple mutant mouse model (KO/KI combinations), BrdU birthdating, in utero electroporation, cortical layer and hippocampal anatomy analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via triple mutant mice with multiple phenotypic analyses, single lab\",\n      \"pmids\": [\"34297816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Microglia-specific CRMP4 deletion reduces microglial proliferation after LPS injection into substantia nigra and suppresses arginase-1 expression; CRMP4 is involved in LPS-induced neuroinflammation and suppresses microglial proliferation in a cell-autonomous manner.\",\n      \"method\": \"Microglia-specific Crmp4 conditional KO mouse, LPS injection model, Iba1 immunostaining, IL-10 and Arg1 expression analysis\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with defined cellular and molecular readouts, single lab\",\n      \"pmids\": [\"38914219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CRMP4 promotes actin polymerization in ectopic endometrial stromal cells and facilitates nuclear translocation of MRTF, activating SRF and downstream target genes related to migration and invasion; CRMP4 silencing inhibits endometriosis lesion growth in vivo.\",\n      \"method\": \"siRNA/lentiviral CRMP4 KO and overexpression, free-actin quantification, immunofluorescence/MRTF nuclear translocation, SRF reporter, Transwell/wound-healing assays, in vivo mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays plus in vivo model, single lab; year 2026 as published\",\n      \"pmids\": [\"41715156\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DPYSL3/CRMP4 is a cytosolic phosphoprotein and calpain/GSK3β/Cdk5 substrate that physically interacts with RhoA, dynein, MAP6, neurofibromin, Ezrin, Cav1.2, and the Sema3E receptor complex to regulate axonal growth cone dynamics, cytoskeletal (actin and microtubule) organization, mitotic chromosomal alignment via spindle microtubules, retrograde axon-to-soma death signaling (through dynein-mediated transport in ALS), adult hippocampal neurogenesis, fornix development downstream of Semaphorin-3E/Akt/GSK3 signaling, and invasive cell migration via MRTF/SRF-dependent actin polymerization; its activity is modulated by phosphorylation (GSK3β, Cdk5, DYRK2) and SUMOylation at K374, and its expression is regulated epigenetically by promoter CpG methylation and post-translationally by calpain cleavage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DPYSL3 (CRMP4/Ulip) is a neuronal phosphoprotein and cytoskeletal regulator that controls axonal growth, growth cone dynamics, and cell migration by integrating extracellular guidance and inhibitory signals with actin and microtubule organization [#0, #4]. As a downstream effector of myelin-associated inhibitors, CRMP4 physically and functionally complexes with RhoA at actin-rich growth cone regions to transduce axon outgrowth inhibition, and disrupting the CRMP4b-RhoA interaction relieves this inhibition on myelin and chondroitin sulfate proteoglycan substrates [#4, #8, #15]. This activity is gated by phosphorylation: GSK3\\u03b2 acts within a MAI-GSK3\\u03b2-CRMP4-RhoA signaling axis, and Cdk5 and DYRK2 phosphorylate CRMP4 to govern neuronal positioning during development [#6, #9]. CRMP4 transduces Semaphorin-3E signaling through its association with the Sema3E receptor complex and MAP6, requiring detergent-resistant-membrane domain integrity and acting through Akt/GSK3, with Crmp4-loss producing aberrant fornix development [#21]. Beyond guidance, CRMP4 localizes to spindle microtubules and is required for chromosomal alignment and mitotic progression in a GSK3-dependent manner [#7]. It is also a calpain substrate, cleaved upon NMDA excitotoxic and oxidative stress in a NOS/L-VGCC-dependent manner, generating fragments that drive Wallerian degeneration and death signaling [#2, #3, #20]; in ALS models CRMP4 binds the retrograde motor dynein to mislocalize from distal axons to the soma and promote motor neuron loss, which is reversed by blocking the CRMP4-dynein interaction [#20]. In non-neuronal contexts CRMP4 regulates invasive migration: it interacts with Ezrin to stabilize a focal adhesion complex, drives MRTF/SRF-dependent actin polymerization, and its expression is controlled by promoter CpG methylation, while it negatively regulates osteoblast differentiation via BMP2 and RhoA/FAK signaling [#10, #27, #13, #16]. Its activity is further modulated by SUMOylation at K374, which weakens its interaction with the Cav1.2 L-type Ca2+ channel [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established CRMP4 as a neuronal phosphoprotein positioned at sites of axon growth, framing it as a candidate effector of growth and guidance signals.\",\n      \"evidence\": \"cDNA cloning with immunolocalization to neurites, growth cones, and NMJ plus NGF-stimulated phosphorylation in neuronal cells\",\n      \"pmids\": [\"8551352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partners or downstream effectors identified\", \"Functional consequence of phosphorylation undefined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed CRMP4 exists as multiple phosphorylated isoforms developmentally and during NGF-induced differentiation, reinforcing phosphoregulation as a control point.\",\n      \"evidence\": \"2D immunoblot of in vitro translated protein, RT-PCR, PC12 differentiation assay\",\n      \"pmids\": [\"9652388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinases responsible not identified\", \"Isoform-specific functions unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined CRMP4 as a stress-regulated calpain substrate, linking excitotoxic and oxidative insults to its proteolytic processing.\",\n      \"evidence\": \"In vitro purified calpain digestion, calpain inhibitor and NOS/L-VGCC pharmacology in primary cortical neurons, immunoblotting (PMIDs 16135096, 16987501)\",\n      \"pmids\": [\"16135096\", \"16987501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the cleavage fragments not determined here\", \"Cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the CRMP4b-RhoA complex as the effector arm that transduces myelin/CSPG inhibition into growth cone collapse, and placed GSK3\\u03b2 phosphorylation upstream of complex formation.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, competitive peptide inhibitor and neurite outgrowth assays on inhibitory substrates, plus GSK3\\u03b2 manipulation (PMIDs 17301178, 20410116)\",\n      \"pmids\": [\"17301178\", \"20410116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CRMP4-RhoA binding not resolved\", \"How phosphorylation gates the interaction at the residue level unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended CRMP4 function beyond neurons by showing it localizes to the mitotic spindle and is a GSK3 substrate required for chromosomal alignment.\",\n      \"evidence\": \"Immunofluorescence to spindle microtubules, siRNA knockdown, phosphomimetic/phospho-dead mutants, chromosomal alignment assays\",\n      \"pmids\": [\"21179545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Spindle-binding partners not identified\", \"Single-lab observation in cultured cells\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic and developmental work established CRMP4 as a phosphorylation-dependent determinant of neuronal positioning and MAG-mediated axon inhibition/protection.\",\n      \"evidence\": \"Crmp4-/- DRG neurons with MAG and Vincristine assays; zebrafish morpholino knockdown with Cdk5/DYRK2 phosphomimetic rescue (PMIDs 22583768, 22898304)\",\n      \"pmids\": [\"22583768\", \"22898304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase-substrate phosphosites not all mapped\", \"Mechanism linking phosphorylation to cytoskeletal output incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Opened a cancer/cell-migration axis by showing CRMP4 binds Ezrin to stabilize a focal adhesion complex and that a disease-associated variant has gain-of-toxic-function in motor neurons.\",\n      \"evidence\": \"Co-IP and MRM proteomics with adhesion/migration assays in pancreatic cancer cells; in vitro expression of an rs147541241 missense variant in motor neurons (PMIDs 24339867, 23568759)\",\n      \"pmids\": [\"24339867\", \"23568759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ezrin interaction interface not mapped\", \"Variant pathogenicity tested only in a single cell assay\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided atomic-resolution structures of human CRMP4, defining its fold and oligomerization residues and a structural framework for disease mutations.\",\n      \"evidence\": \"X-ray crystallography of truncated and full-length human CRMP-4\",\n      \"pmids\": [\"24914979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structures with partners (RhoA, dynein, Ezrin)\", \"Structure does not capture phosphorylated or fragment states\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established epigenetic control of CRMP4 expression and its role as a metastasis suppressor acting through Akt/Rac1 and MMP-9.\",\n      \"evidence\": \"TALE-based locus-specific CpG methylation/demethylation with in vitro and in vivo invasion assays and pathway analysis in prostate cancer cells\",\n      \"pmids\": [\"25888628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CRMP4 to Akt/Rac1 not defined\", \"Direct vs indirect regulation of MMP-9 unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a feedback loop in which calpain-2-generated CRMP4 fragments and EMT regulators reciprocally control migration, with CRMP4 suppressing SNAIL/TWIST and PAK2-dependent motility while opposing mitotic defects.\",\n      \"evidence\": \"Calpain-2 cleavage, nuclear fractionation, ChIP for DNMT1 at the CRMP4 promoter, and siRNA knockdown with EMT/vimentin and PAK2 readouts in cancer cells (PMIDs 29601651, 30498031)\",\n      \"pmids\": [\"29601651\", \"30498031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of nuclear CRMP4 fragment limited\", \"Direct targets of the N-terminal fragment incompletely mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a skeletal role: CRMP4 negatively regulates osteoblast differentiation through BMP2 and RhoA/FAK signaling.\",\n      \"evidence\": \"Crmp4-/- mice with bone histomorphometry plus gain/loss-of-function osteoblast assays and pathway analysis\",\n      \"pmids\": [\"28019696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between CRMP4 and BMP2 receptor signaling unclear\", \"Single-lab in vivo finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved a death-signaling mechanism in ALS: CRMP4 binds dynein for retrograde transport that mislocalizes it to the soma and drives motor neuron loss.\",\n      \"evidence\": \"Co-IP for CRMP4-dynein, localization in ALS patient tissue and SOD1G93A mice, and competitive inhibition rescue in C9orf72 iPSC-MNs and ALS mice\",\n      \"pmids\": [\"34190355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynein adaptor/cargo selection mechanism undefined\", \"How somatic CRMP4 accumulation triggers death not fully mechanistic\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed CRMP4 in the Semaphorin-3E pathway via the Sema3E receptor complex and MAP6, requiring DRM and cytoskeleton-binding domains to signal through Akt/GSK3 for fornix development.\",\n      \"evidence\": \"Co-IPs (CRMP4-MAP6, CRMP4-Sema3E receptor), Crmp4-/- fornix anatomy, DRM fractionation, and domain-deletion functional analysis\",\n      \"pmids\": [\"34860155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry within the receptor complex unknown\", \"How DRM localization mechanistically enables signaling unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed CRMP4 activity is tuned by SUMOylation at K374, which modulates its Cav1.2 interaction, neurite outgrowth, and pain sensitivity.\",\n      \"evidence\": \"GST-pulldown with SUMO1/2/3, Co-IP, electrophysiology, and in vivo paw withdrawal behavioral assay\",\n      \"pmids\": [\"34645092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO E3 ligase and deSUMOylase not identified\", \"Link between Cav1.2 coupling and pain behavior indirect\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined CRMP4's roles in adult hippocampal neurogenesis and, with CRMP1/CRMP2, in cortical and hippocampal neuronal migration and mossy fiber pruning, clarifying paralog redundancy and specificity.\",\n      \"evidence\": \"Crmp4-/- and CRMP1/2/4 multi-mutant mice with birthdating, marker immunostaining, in utero electroporation, and Nrp2 epistasis (PMIDs 35122931, 34297816, 34932871)\",\n      \"pmids\": [\"35122931\", \"34297816\", \"34932871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular distinction between paralog functions incomplete\", \"Cell-intrinsic vs niche contributions not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a cell-autonomous glial role: microglial CRMP4 promotes proliferation and shapes neuroinflammatory responses.\",\n      \"evidence\": \"Microglia-specific conditional Crmp4 KO with LPS substantia nigra injection, Iba1 immunostaining, and Arg1/IL-10 analysis\",\n      \"pmids\": [\"38914219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling mechanism in microglia undefined\", \"Single model and stimulus tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected CRMP4 to a transcriptional-cytoskeletal output by showing it drives actin polymerization and MRTF/SRF activation to promote invasive migration in endometriosis.\",\n      \"evidence\": \"CRMP4 KO/overexpression, free-actin quantification, MRTF nuclear translocation, SRF reporter, migration assays, and in vivo lesion model\",\n      \"pmids\": [\"41715156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking CRMP4 to actin nucleation unclear\", \"Whether MRTF/SRF axis operates in other CRMP4 contexts untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CRMP4's phosphorylation, SUMOylation, and calpain-cleavage states are integrated to switch it between growth-promoting, growth-inhibiting, and pro-death functions across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to partner choice (RhoA vs dynein vs Ezrin vs MRTF)\", \"Structures of CRMP4 in modified or complexed states lacking\", \"Tissue-specific regulators of CRMP4 modification largely unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 7, 21, 27]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 6, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 21, 24, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 20, 13, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RHOA\", \"EZRIN\", \"MAP6\", \"DYNC1H1\", \"CACNA1C\", \"NF1\", \"SEMA3E\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}