{"gene":"CRMP1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"p80 CRMP-1 (a novel splice variant of CRMP-1 with an extended N-terminus) was co-immunoprecipitated with ROKα from brain extracts, interacted with the kinase domain of ROKα, and inhibited ROKα catalytic activity toward other substrates. p80 CRMP-1 also formed oligomeric complexes with CRMP-2. Co-overexpression of p80 CRMP-1 and CRMP-2 counteracted RhoA-induced neurite retraction, an effect enhanced by mutation of the ROK phosphorylation site in CRMP-2.","method":"Co-immunoprecipitation from brain extracts, peptide mass analysis, kinase activity assay, overexpression in neurons","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional kinase inhibition assay and morphological readout, single lab","pmids":["12482610"],"is_preprint":false},{"year":2005,"finding":"CRMP1 localizes predominantly to dendrites of specific adult neuronal populations (cortical pyramidal neurons, hippocampal CA1 pyramidal cells, Purkinje cells) in adult mouse brain, as determined by immunohistochemistry with specific antibodies. In cultures of cortical neurons CRMP1 is distributed throughout cell bodies, axons, and dendrites.","method":"Immunohistochemistry with specific antibodies on adult mouse brain sections and primary neuron cultures","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment, specific antibodies, multiple brain regions and cell types","pmids":["15834957"],"is_preprint":false},{"year":2006,"finding":"CRMP1 is required for normal granule cell migration, proliferation, and apoptosis during postnatal cerebellar development. CRMP1-/- mice showed reduced granule cell migration from cerebellar explants, and anti-CRMP1 antibody treatment of wild-type explants replicated this defect.","method":"CRMP1 knockout mice (knock-in LacZ), cerebellar explant migration assay, antibody blockade, in vivo histology","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype replicated by antibody blockade in wild-type explants, two orthogonal approaches","pmids":["17121542"],"is_preprint":false},{"year":2006,"finding":"CRMP-1 was identified as a binding partner of GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase), the key enzyme of sialic acid biosynthesis, via yeast two-hybrid screening followed by co-immunoprecipitation verification.","method":"Yeast two-hybrid assay, co-immunoprecipitation","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, yeast two-hybrid with Co-IP verification, no functional follow-up on CRMP1","pmids":["17118363"],"is_preprint":false},{"year":2008,"finding":"NF-κB p50 (but not the classic p65/p50 heterodimer) binds to a κB site in the CRMP-1 promoter region (between -1753 and -1743) and negatively regulates CRMP-1 expression, thereby promoting cancer cell invasion. Antisense p50 increased CRMP-1 protein level and decreased invasiveness.","method":"EMSA, supershift assay, ChIP, antisense p50 transfection, invasion assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA with functional invasion readout, single lab, multiple orthogonal methods","pmids":["18782567"],"is_preprint":false},{"year":2008,"finding":"Transcription of CRMP-1 is reciprocally regulated at its promoter by C/EBPα (activator) and Sp1 (repressor) competing for overlapping binding sites (-122 to -133 and -101 to -113). COX-2 overexpression decreases CRMP-1 expression by promoting Sp1 binding; COX-2 inhibitor celecoxib increases CRMP-1 expression by reducing Sp1-DNA complex formation and enhancing C/EBPα binding.","method":"Serial deletion, site-directed mutagenesis, EMSA, antibody supershift, ChIP, luciferase reporter, overexpression","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (mutagenesis, ChIP, EMSA, reporter), single lab","pmids":["18524846"],"is_preprint":false},{"year":2011,"finding":"CRMP-1 associates with LCRMP-1 (long isoform of CRMP-1) and disrupts the interaction between LCRMP-1 and WAVE-1, thereby inhibiting LCRMP-1-mediated filopodia formation, actin stabilization, and cancer cell invasion. LCRMP-1 acts downstream of Cdc42 in the WAVE-1/actin nucleation pathway, and CRMP-1 antagonizes this pathway by competing for LCRMP-1 binding.","method":"Co-immunoprecipitation, overexpression in noninvasive cell lines, filopodia/invasion assays, WAVE-1 interaction assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional invasion assay, multiple cell lines, single lab","pmids":["21747164"],"is_preprint":false},{"year":2012,"finding":"CRMP1 was identified as insoluble/misfolded protein in post-mortem schizophrenia brains and shown to directly and functionally interact with DISC1 (Disrupted-in-schizophrenia 1), placing CRMP1 at the intersection of reelin and DISC1 pathways.","method":"Antibodies against pooled insoluble proteome, biochemical fractionation of post-mortem brains, functional interaction assay with DISC1","journal":"Human molecular genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction with DISC1 described but method details are limited in abstract; single lab","pmids":["22798627"],"is_preprint":false},{"year":2012,"finding":"Local inactivation of CRMP1 (by micro-CALI) in the central domain of the growth cone caused lamellipodial retraction and subsequent retardation of neurite outgrowth, whereas inactivation in the neurite shaft arrested neurite outgrowth. Focal inactivation of CRMP1 in one half of the growth cone caused the growth cone to turn away from the irradiated site. These effects were distinct from those of CRMP2 inactivation.","method":"Microscale chromophore-assisted light inactivation (micro-CALI) with spatial and temporal resolution in live neurons","journal":"Developmental neurobiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — highly precise loss-of-function with spatiotemporal control, specific and internally controlled against CRMP2, single lab with multiple experimental conditions","pmids":["22378692"],"is_preprint":false},{"year":2012,"finding":"CRMP1 and CRMP2 have synergistic roles in Sema3A-dependent dendritic spine maturation. crmp1-/- mice showed reduced dendritic spine density in cortical layer V pyramidal neurons comparable to sema3A-/- and crmp2-/- mice. CRMP1 levels increased in crmp2-/- mice, but there was no genetic interaction between crmp1 and crmp2 on spine density (double heterozygous sema3A+/-;crmp1+/- showed reduced spine density and branching).","method":"CRMP2 and CRMP1 knockout mice, dendritic spine density quantification, genetic epistasis analysis","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotypic readout, epistasis analysis across multiple genotypes, internally controlled","pmids":["27480924"],"is_preprint":false},{"year":2014,"finding":"CRMP1 binds both the actin-binding domain and the last immunoglobulin-like repeat (rod 24) of Filamin-A. Phosphorylation-mimicking CRMP1(Ser522Asp) enhances Sema3A repulsion in neurons and causes Filamin-A to adopt a condensed form (shown by atomic-force microscopy). Phospho-CRMP1(Ser522Asp) weakens F-actin gelation crosslinked by Filamin-A, suggesting phosphorylated CRMP1 displaces Filamin-A from the actin cytoskeleton to facilitate remodeling. Alanine mutants in the interacting residues of either Filamin-A or CRMP1 suppress Sema3A repulsion. The C. elegans homologue UNC-33 (CRMP1) interacts with FLN-1 (Filamin-A orthologue) and participates in motor neuron projection.","method":"Pulldown, co-immunoprecipitation, atomic-force microscopy, alanine mutagenesis, F-actin gelation assay, C. elegans genetics","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including structural analysis (AFM), biochemical reconstitution, mutagenesis, and in vivo C. elegans validation","pmids":["25358863"],"is_preprint":false},{"year":2014,"finding":"CRMP1 interacts with Speedy A1 (Spy1), a member of the Speedy/RINGO family, as identified by yeast two-hybrid and verified by co-immunoprecipitation. Spy1 modulates CDK5-mediated phosphorylation of CRMP1. Enhanced CRMP1 phosphorylation (promoted by Spy1) disturbs the association of CRMP1 with actin, contributing to abnormal Sema3A-induced growth cone collapse and impaired regeneration after sciatic nerve crush.","method":"Yeast two-hybrid, co-immunoprecipitation, overexpression/shRNA knockdown, phosphorylation assay, rat sciatic nerve crush model","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid followed by Co-IP, phosphorylation assay, and in vivo nerve crush model, single lab","pmids":["25526860"],"is_preprint":false},{"year":2015,"finding":"CRMP1 directly interacts with N-terminal huntingtin (HTT) fragments containing expanded polyglutamine tracts and suppresses their spontaneous self-assembly into proteotoxic aggregates, reducing HTT misfolding and neurotoxicity in multiple HD models.","method":"Protein-protein interaction network filtering, experimental validation of CRMP1-HTT interaction in HD models (cell and in vivo)","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction validated experimentally in multiple HD models, single lab, method details limited in abstract","pmids":["25908449"],"is_preprint":false},{"year":2016,"finding":"CRMP1 suppresses EMT and metastasis in prostate cancer cells by associating with actin and WAVE1 (an Arp2/3 activator). CRMP1 knockdown stabilizes F-actin and triggers stress fiber formation; overexpression inhibits EMT and in vivo metastasis. CRMP1 expression is suppressed by histone deacetylation and direct promoter repression by the EMT regulator Snail.","method":"Co-immunoprecipitation (CRMP1-actin and CRMP1-WAVE1), siRNA knockdown, stable overexpression, F-actin staining, in vivo metastasis assay, ChIP for Snail binding to CRMP1 promoter","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of CRMP1 with actin/WAVE1 plus functional assays in vitro and in vivo, single lab","pmids":["27321179"],"is_preprint":false},{"year":2016,"finding":"CRMP1 and CRMP4 redundantly regulate proper orientation of basal dendrites of layer V pyramidal neurons and apical dendrite bifurcation of hippocampal CA1 neurons. CRMP1/CRMP4 double knockout showed severe dendritic orientation abnormalities not seen in single knockouts.","method":"CRMP1 and CRMP4 single and double knockout mice, cortical and hippocampal neuron morphology analysis","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via double KO, defined morphological phenotype, single lab","pmids":["27836492"],"is_preprint":false},{"year":2017,"finding":"CRMP1 functionally couples with Nav1.7 (SCN9A) to mediate Sema3A-induced retrograde axonal transport of PlexA4 and TrkA from growth cones. In crmp1-/- DRG neurons, Sema3A-induced co-localization and retrograde transport of PlexA4 and TrkA were impaired (similar to Nav1.7 RNAi knockdown). Sema3A induced co-localization of CRMP1 and Nav1.7 in growth cones. Introduction of CRMP1 in HEK293 cells lowered the activation threshold of co-expressed Nav1.7.","method":"crmp1-/- mouse DRG neurons, RNAi knockdown of Nav1.7, immunofluorescence co-localization, electrophysiology in HEK293 cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO phenotype matched by RNAi knockdown, electrophysiology functional validation, co-localization, multiple orthogonal methods in one study","pmids":["28254884"],"is_preprint":false},{"year":2021,"finding":"Fyn kinase phosphorylates CRMP1 at Tyrosine 504 (Tyr504), and this phosphorylation is required for Sema3A-induced growth cone collapse and dendritic development. CRMP1-Tyr504Phe mutant suppressed Sema3A-induced growth cone collapse in DRG and hippocampal neurons and impaired cortical dendritic development in vivo. Fyn+/-;Crmp1+/- double heterozygous mice showed poor basal dendrite development similar to Sema3a-/-, Fyn-/-, and Crmp1-/- mice.","method":"In vitro kinase assay (Fyn phosphorylating CRMP1 Tyr504), site-directed mutagenesis (Tyr504Phe), growth cone collapse assay, in vivo cortical neuron morphology, double heterozygous genetic epistasis","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, in vivo genetic epistasis across multiple genotypes, multiple orthogonal methods, single lab","pmids":["33449368"],"is_preprint":false},{"year":2021,"finding":"FEZ1 interacts with CRMP1 at neuronal growth cones. FEZ1 deficiency in hippocampal neurons caused growth cone collapse and impaired axonal development phenotypically similar to CRMP1 loss-of-function, placing FEZ1 upstream or in the same pathway as CRMP1 in growth cone guidance.","method":"Co-immunoprecipitation, immunofluorescence co-localization, FEZ1 knockdown with morphological readout, comparison to CRMP1 loss-of-function","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with matching loss-of-function phenotype in neurons, single lab","pmids":["33771901"],"is_preprint":false},{"year":2022,"finding":"Inhibition of CRMP1 phosphorylation at Ser522 (using Crmp1S522A knock-in mice) improved motor function and preserved motor neurons and neuromuscular junctions in SOD1G93A ALS model mice, whereas CRMP1 knockout worsened outcomes. Phospho-mimicking CRMP1 mutant overexpression inhibited axonal outgrowth in Neuro2A cells. Phosphorylated CRMP1 (pCRMP1) accumulates in spheroids in ALS patient spinal cords and co-localizes with phosphorylated neurofilaments.","method":"Crmp1 Ser522Ala knock-in and CRMP1 KO mice in SOD1G93A background, rotarod test, motor neuron/NMJ histology, phosphoproteomic identification, phospho-mimicking mutant overexpression, human ALS patient immunostaining","journal":"eNeuro / Frontiers in neurology","confidence":"High","confidence_rationale":"Tier 1 / Strong — knock-in mutagenesis at defined phosphosite with KO comparison, functional and histological readouts, replicated across mouse and human tissue in two papers","pmids":["35523582","36237616"],"is_preprint":false},{"year":2022,"finding":"De novo heterozygous variants in CRMP1 impair CRMP1 oligomerization and suppress neurite outgrowth in murine cortical neurons upon overexpression, linking CRMP1 oligomerization to its role in neurite development.","method":"In silico structural analysis, oligomerization assay, neurite outgrowth assay in primary cortical neurons with overexpression of variants","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — oligomerization assay plus neuronal morphology phenotype, single lab","pmids":["36511780"],"is_preprint":false},{"year":2022,"finding":"CRMP1 and CRMP2 redundantly regulate migration and positioning of Purkinje cells in cerebellar lobule X. CRMP1/CRMP2 double knockout mice showed deficits in Purkinje cell migration and alignment in lobule X and impaired performance on the balance beam test.","method":"CRMP1/CRMP2 double knockout mice, cerebellar histology, balance beam and grip power tests","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double KO with defined cellular and behavioral phenotype, single lab","pmids":["35219721"],"is_preprint":false},{"year":2022,"finding":"CRMP1 is expressed in cochlear outer and inner hair cells, and its deletion causes progressive high-frequency hearing loss and hair cell loss at the basal cochlear region without affecting hair cell morphogenesis.","method":"Immunostaining, Crmp1 knockout mice, scanning electron microscopy, auditory brainstem response testing","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with specific auditory phenotype and localization, single lab","pmids":["35181334"],"is_preprint":false},{"year":2023,"finding":"LKB1 physically interacts with CRMP1 (co-immunoprecipitation) in regenerated sciatic nerve axons, and LKB1 regulates CRMP1 phosphorylation. Overexpression of both LKB1 and CRMP1 promotes Schwann cell invasion/migration and neuronal process extension; knockdown of CRMP1 abolishes LKB1's nerve repair-promoting function.","method":"Co-immunoprecipitation, immunofluorescence co-localization, overexpression and siRNA knockdown, Schwann cell invasion assay, rat sciatic nerve crush model","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional epistasis by CRMP1 knockdown reversing LKB1 effect, single lab","pmids":["38105470"],"is_preprint":false},{"year":2023,"finding":"Deletion of CRMP1 in mice disrupts the balance between synaptic and extrasynaptic NMDA receptors in the hippocampus, increasing extrasynaptic NMDA receptor levels and tau phosphorylation, leading to synaptic and neuronal loss in CA3 and accelerated age-related cognitive decline.","method":"crmp1 KO mice at adult/middle-aged/older stages, Morris water maze, biochemical fractionation for synaptic/extrasynaptic NMDA receptor levels, glutamate/glutamine measurement","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with biochemical fractionation and behavioral readout, single lab","pmids":["38176125"],"is_preprint":false}],"current_model":"CRMP1 is a cytosolic phosphoprotein that functions as an intracellular mediator of Semaphorin 3A (Sema3A) signaling: upon Sema3A stimulation, Fyn phosphorylates CRMP1 at Tyr504 and CDK5/GSK3β sequentially phosphorylate it at Ser522, enabling CRMP1 to remodel the actin cytoskeleton (partly by displacing Filamin-A and antagonizing WAVE1/Arp2/3) and to couple with Nav1.7 to drive retrograde axonal transport, thereby regulating growth cone collapse, neurite outgrowth, dendritic spine maturation, and neuronal migration; in cancer cells CRMP1 suppresses invasion by competing with its long isoform LCRMP-1 for WAVE1 binding, and its expression is transcriptionally controlled by competing C/EBPα and Sp1 at its promoter and repressed by NF-κB p50 and Snail."},"narrative":{"mechanistic_narrative":"CRMP1 is a cytosolic neuronal phosphoprotein that acts as an intracellular effector of Semaphorin 3A (Sema3A) signaling to regulate cytoskeletal remodeling during axon guidance, neurite outgrowth, dendritic development, and neuronal migration [PMID:22378692, PMID:27480924, PMID:33449368]. Sema3A-dependent function is gated by sequential phosphorylation: Fyn phosphorylates CRMP1 at Tyr504, an event required for Sema3A-induced growth cone collapse and cortical dendritic development [PMID:33449368], while phosphorylation at Ser522 controls its activity in axonal outgrowth and motor neuron integrity [PMID:35523582, PMID:36237616]. Mechanistically, CRMP1 remodels the actin cytoskeleton by binding both the actin-binding domain and a rod immunoglobulin repeat of Filamin-A; phospho-mimicking CRMP1(Ser522Asp) condenses Filamin-A and weakens Filamin-A-crosslinked F-actin gels, displacing Filamin-A to permit remodeling, and it associates with actin and the Arp2/3 activator WAVE1 to restrain stress-fiber and filopodia formation [PMID:25358863, PMID:27321179]. CRMP1 also functionally couples with the Nav1.7 sodium channel to drive Sema3A-induced retrograde axonal transport of PlexA4 and TrkA from growth cones [PMID:28254884]. Genetically, CRMP1 acts redundantly or synergistically with CRMP2 and CRMP4 in dendritic spine maturation, dendrite orientation, and Purkinje and granule cell migration [PMID:27480924, PMID:27836492, PMID:35219721, PMID:17121542], and its oligomerization is required for neurite outgrowth [PMID:36511780]. In cancer, CRMP1 suppresses invasion and EMT by competing with its long isoform LCRMP-1 for WAVE1 binding, with its expression controlled at the promoter by competing C/EBPα and Sp1 and repressed by NF-κB p50 and Snail [PMID:21747164, PMID:27321179, PMID:18524846, PMID:18782567]. De novo heterozygous CRMP1 variants that impair oligomerization and suppress neurite outgrowth link the gene to a neurodevelopmental disorder [PMID:36511780].","teleology":[{"year":2002,"claim":"Established the first molecular activity for a CRMP1 splice variant, showing it could modulate Rho-pathway signaling rather than acting as an inert cytoskeletal protein.","evidence":"Co-IP from brain extracts with ROKα, kinase activity assay, and neurite retraction rescue by overexpression","pmids":["12482610"],"confidence":"Medium","gaps":["Studied a specific p80 splice variant, not necessarily canonical CRMP1","ROKα inhibition mechanism not structurally defined","Effect shown by overexpression, not loss-of-function"]},{"year":2005,"claim":"Defined where CRMP1 acts by mapping its predominantly dendritic localization in specific adult neuronal populations.","evidence":"Immunohistochemistry on adult mouse brain and primary cortical neuron cultures","pmids":["15834957"],"confidence":"Medium","gaps":["Descriptive localization without functional linkage","Subcellular compartment resolution limited"]},{"year":2006,"claim":"Provided the first genetic evidence that CRMP1 is required in vivo, establishing a developmental role in cerebellar granule cell migration.","evidence":"CRMP1 knockout mice and cerebellar explant migration assay replicated by antibody blockade","pmids":["17121542"],"confidence":"High","gaps":["Molecular effectors downstream of CRMP1 in migration not defined","Cell-autonomy not fully resolved"]},{"year":2008,"claim":"Identified the transcriptional control logic of CRMP1 in cancer, where promoter occupancy dictates invasiveness.","evidence":"EMSA, ChIP, reporter assays, and invasion assays mapping C/EBPα, Sp1, and NF-κB p50 to the CRMP1 promoter","pmids":["18782567","18524846"],"confidence":"Medium","gaps":["Links promoter regulation to invasion but not to CRMP1 cytoskeletal mechanism","Single lab"]},{"year":2011,"claim":"Defined CRMP1's tumor-suppressive mechanism as competitive inhibition of its long isoform within the WAVE1/actin nucleation pathway.","evidence":"Co-IP, overexpression in noninvasive cell lines, and filopodia/invasion assays showing CRMP1 disrupts LCRMP-1/WAVE-1 binding","pmids":["21747164"],"confidence":"Medium","gaps":["Structural basis of isoform competition not resolved","Relationship to neuronal WAVE1 function unaddressed"]},{"year":2012,"claim":"Resolved CRMP1's spatial role in growth cone dynamics, showing it is locally required for lamellipodial maintenance and directional guidance distinct from CRMP2.","evidence":"Microscale chromophore-assisted light inactivation with spatiotemporal control in live neurons","pmids":["22378692"],"confidence":"High","gaps":["Molecular targets of CRMP1 within the growth cone not identified here","Acute inactivation only"]},{"year":2014,"claim":"Identified the direct cytoskeletal substrate mechanism: phospho-CRMP1 displaces Filamin-A to enable actin remodeling during Sema3A repulsion.","evidence":"Pulldown, AFM, F-actin gelation assay, alanine mutagenesis, and C. elegans UNC-33/FLN-1 genetics","pmids":["25358863"],"confidence":"High","gaps":["In vivo demonstration of Filamin-A displacement in mammalian neurons limited","How phosphorylation triggers binding-mode change not structurally solved"]},{"year":2014,"claim":"Connected upstream kinase regulation to function, showing Spy1-modulated CDK5 phosphorylation of CRMP1 controls its actin association and regeneration capacity.","evidence":"Yeast two-hybrid, Co-IP, phosphorylation assay, and rat sciatic nerve crush model","pmids":["25526860"],"confidence":"Medium","gaps":["Specific phosphosite controlling actin association not pinpointed here","Single lab"]},{"year":2017,"claim":"Revealed a non-cytoskeletal mechanism: CRMP1 couples with Nav1.7 to drive Sema3A-induced retrograde transport of guidance and neurotrophin receptors.","evidence":"crmp1-/- DRG neurons, Nav1.7 RNAi, co-localization, and HEK293 electrophysiology","pmids":["28254884"],"confidence":"High","gaps":["Molecular link between CRMP1/Nav1.7 and the transport machinery undefined","Whether channel activity per se is required for transport unresolved"]},{"year":2021,"claim":"Identified the tyrosine-phosphorylation arm of CRMP1 regulation, placing Fyn-mediated Tyr504 phosphorylation as a required node for Sema3A responses and dendrite development.","evidence":"In vitro Fyn kinase assay, Tyr504Phe mutagenesis, growth cone collapse, and Fyn;Crmp1 double-heterozygote epistasis","pmids":["33449368"],"confidence":"High","gaps":["Interplay between Tyr504 and Ser522 phosphorylation not defined","Downstream effector engaged by phospho-Tyr504 unknown"]},{"year":2021,"claim":"Extended the growth cone pathway by identifying FEZ1 as a CRMP1 partner whose loss phenocopies CRMP1 deficiency.","evidence":"Co-IP, co-localization, and FEZ1 knockdown with matching morphological readout","pmids":["33771901"],"confidence":"Medium","gaps":["Directionality of the FEZ1-CRMP1 relationship not firmly established","Mechanism of pathway coupling unknown"]},{"year":2022,"claim":"Established phospho-state-specific pathology, showing Ser522 phosphorylation drives ALS-relevant motor neuron degeneration while CRMP1 protein itself is protective.","evidence":"Crmp1 Ser522Ala knock-in versus KO in SOD1G93A mice, behavior, histology, and human ALS spinal cord immunostaining","pmids":["35523582","36237616"],"confidence":"High","gaps":["Kinase responsible for disease-associated Ser522 phosphorylation not pinned down in vivo","Link between pCRMP1 spheroids and neurofilament pathology mechanistic detail limited"]},{"year":2022,"claim":"Demonstrated genetic redundancy among CRMP family members in migration and dendrite patterning, clarifying why single knockouts can be subtle.","evidence":"CRMP1/CRMP2 and CRMP1/CRMP4 double knockout mice with cerebellar and cortical/hippocampal morphology and behavior","pmids":["27836492","35219721","27480924"],"confidence":"Medium","gaps":["Molecular basis of functional redundancy not resolved","Whether heterodimerization underlies redundancy untested"]},{"year":2022,"claim":"Linked CRMP1 to human neurodevelopmental disease and tied disease variants to a specific molecular defect in oligomerization.","evidence":"De novo variant identification, oligomerization assays, and neurite outgrowth assays in cortical neurons","pmids":["36511780"],"confidence":"Medium","gaps":["How oligomerization controls CRMP1 activity mechanistically unclear","Overexpression-based phenotype rather than endogenous"]},{"year":2023,"claim":"Expanded CRMP1 function into adult synaptic homeostasis, showing it maintains the synaptic/extrasynaptic NMDA receptor balance and limits tau phosphorylation.","evidence":"crmp1 KO mice across ages, biochemical fractionation, and Morris water maze","pmids":["38176125"],"confidence":"Medium","gaps":["Direct molecular link between CRMP1 and NMDA receptor distribution unknown","Single lab"]},{"year":null,"claim":"How the distinct CRMP1 phosphorylation events (Tyr504, Ser522) and binding partners (Filamin-A, WAVE1, Nav1.7, FEZ1, LKB1) are integrated into a unified, context-dependent signaling logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating phospho-states with partner switching","Quantitative ordering of Fyn/CDK5/GSK3β phosphorylation events not established","Mechanism connecting cytoskeletal and channel-coupled functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,10,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,15,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,9,14,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,13,18,19]}],"complexes":[],"partners":["FLNA","WASF1","SCN9A","FYN","FEZ1","STK11","DISC1","HTT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14194","full_name":"Dihydropyrimidinase-related protein 1","aliases":["Collapsin response mediator protein 1","CRMP-1","Inactive dihydropyrimidinase","Unc-33-like phosphoprotein 3","ULIP-3"],"length_aa":572,"mass_kda":62.2,"function":"Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton (PubMed:25358863). Plays a role in axon guidance (PubMed:25358863). During the axon guidance process, acts downstream of SEMA3A to promote FLNA dissociation from F-actin which results in the rearrangement of the actin cytoskeleton and the collapse of the growth cone (PubMed:25358863). Involved in invasive growth and cell migration (PubMed:11562390). May participate in cytokinesis (PubMed:19799413)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle; Cell projection, growth cone; Cytoplasm, cytoskeleton; Perikaryon","url":"https://www.uniprot.org/uniprotkb/Q14194/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CRMP1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CRMP1","total_profiled":1310},"omim":[{"mim_id":"613326","title":"DIHYDROPYRIMIDINASE; DPYS","url":"https://www.omim.org/entry/613326"},{"mim_id":"608383","title":"DIHYDROPYRIMIDINASE-LIKE 5; DPYSL5","url":"https://www.omim.org/entry/608383"},{"mim_id":"607261","title":"EVC CILIARY COMPLEX SUBUNIT 2; EVC2","url":"https://www.omim.org/entry/607261"},{"mim_id":"602462","title":"COLLAPSIN RESPONSE MEDIATOR PROTEIN 1; CRMP1","url":"https://www.omim.org/entry/602462"},{"mim_id":"119530","title":"OROFACIAL CLEFT 1; OFC1","url":"https://www.omim.org/entry/119530"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":82.7},{"tissue":"pituitary gland","ntpm":63.6},{"tissue":"retina","ntpm":52.8}],"url":"https://www.proteinatlas.org/search/CRMP1"},"hgnc":{"alias_symbol":["DRP-1","DPYSL1"],"prev_symbol":[]},"alphafold":{"accession":"Q14194","domains":[{"cath_id":"3.20.20.140","chopping":"66-487","consensus_level":"high","plddt":97.3148,"start":66,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14194","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14194-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14194-F1-predicted_aligned_error_v6.png","plddt_mean":90.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRMP1","jax_strain_url":"https://www.jax.org/strain/search?query=CRMP1"},"sequence":{"accession":"Q14194","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14194.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14194/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14194"}},"corpus_meta":[{"pmid":"15834957","id":"PMC_15834957","title":"Differential 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at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice.","date":"2022","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/35523582","citation_count":10,"is_preprint":false},{"pmid":"33449368","id":"PMC_33449368","title":"Phosphorylation of Collapsin Response Mediator Protein 1 (CRMP1) at Tyrosine 504 residue regulates Semaphorin 3A-induced cortical dendritic growth.","date":"2021","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33449368","citation_count":9,"is_preprint":false},{"pmid":"39669252","id":"PMC_39669252","title":"Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions.","date":"2023","source":"Genetics in medicine 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truncated CRMP-1 protein in the brain cortex of MPSIIIB mice.","date":"2008","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/18325808","citation_count":1,"is_preprint":false},{"pmid":"39758889","id":"PMC_39758889","title":"Case report: A de novo variant of CRMP1 in an individual with a neurodevelopmental disorder.","date":"2024","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39758889","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19045,"output_tokens":6320,"usd":0.075967,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15085,"output_tokens":4596,"usd":0.095162,"stage2_stop_reason":"end_turn"},"total_usd":0.171129,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"p80 CRMP-1 (a novel splice variant of CRMP-1 with an extended N-terminus) was co-immunoprecipitated with ROKα from brain extracts, interacted with the kinase domain of ROKα, and inhibited ROKα catalytic activity toward other substrates. p80 CRMP-1 also formed oligomeric complexes with CRMP-2. Co-overexpression of p80 CRMP-1 and CRMP-2 counteracted RhoA-induced neurite retraction, an effect enhanced by mutation of the ROK phosphorylation site in CRMP-2.\",\n      \"method\": \"Co-immunoprecipitation from brain extracts, peptide mass analysis, kinase activity assay, overexpression in neurons\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional kinase inhibition assay and morphological readout, single lab\",\n      \"pmids\": [\"12482610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CRMP1 localizes predominantly to dendrites of specific adult neuronal populations (cortical pyramidal neurons, hippocampal CA1 pyramidal cells, Purkinje cells) in adult mouse brain, as determined by immunohistochemistry with specific antibodies. In cultures of cortical neurons CRMP1 is distributed throughout cell bodies, axons, and dendrites.\",\n      \"method\": \"Immunohistochemistry with specific antibodies on adult mouse brain sections and primary neuron cultures\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment, specific antibodies, multiple brain regions and cell types\",\n      \"pmids\": [\"15834957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CRMP1 is required for normal granule cell migration, proliferation, and apoptosis during postnatal cerebellar development. CRMP1-/- mice showed reduced granule cell migration from cerebellar explants, and anti-CRMP1 antibody treatment of wild-type explants replicated this defect.\",\n      \"method\": \"CRMP1 knockout mice (knock-in LacZ), cerebellar explant migration assay, antibody blockade, in vivo histology\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype replicated by antibody blockade in wild-type explants, two orthogonal approaches\",\n      \"pmids\": [\"17121542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CRMP-1 was identified as a binding partner of GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase), the key enzyme of sialic acid biosynthesis, via yeast two-hybrid screening followed by co-immunoprecipitation verification.\",\n      \"method\": \"Yeast two-hybrid assay, co-immunoprecipitation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, yeast two-hybrid with Co-IP verification, no functional follow-up on CRMP1\",\n      \"pmids\": [\"17118363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NF-κB p50 (but not the classic p65/p50 heterodimer) binds to a κB site in the CRMP-1 promoter region (between -1753 and -1743) and negatively regulates CRMP-1 expression, thereby promoting cancer cell invasion. Antisense p50 increased CRMP-1 protein level and decreased invasiveness.\",\n      \"method\": \"EMSA, supershift assay, ChIP, antisense p50 transfection, invasion assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA with functional invasion readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18782567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Transcription of CRMP-1 is reciprocally regulated at its promoter by C/EBPα (activator) and Sp1 (repressor) competing for overlapping binding sites (-122 to -133 and -101 to -113). COX-2 overexpression decreases CRMP-1 expression by promoting Sp1 binding; COX-2 inhibitor celecoxib increases CRMP-1 expression by reducing Sp1-DNA complex formation and enhancing C/EBPα binding.\",\n      \"method\": \"Serial deletion, site-directed mutagenesis, EMSA, antibody supershift, ChIP, luciferase reporter, overexpression\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (mutagenesis, ChIP, EMSA, reporter), single lab\",\n      \"pmids\": [\"18524846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CRMP-1 associates with LCRMP-1 (long isoform of CRMP-1) and disrupts the interaction between LCRMP-1 and WAVE-1, thereby inhibiting LCRMP-1-mediated filopodia formation, actin stabilization, and cancer cell invasion. LCRMP-1 acts downstream of Cdc42 in the WAVE-1/actin nucleation pathway, and CRMP-1 antagonizes this pathway by competing for LCRMP-1 binding.\",\n      \"method\": \"Co-immunoprecipitation, overexpression in noninvasive cell lines, filopodia/invasion assays, WAVE-1 interaction assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional invasion assay, multiple cell lines, single lab\",\n      \"pmids\": [\"21747164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CRMP1 was identified as insoluble/misfolded protein in post-mortem schizophrenia brains and shown to directly and functionally interact with DISC1 (Disrupted-in-schizophrenia 1), placing CRMP1 at the intersection of reelin and DISC1 pathways.\",\n      \"method\": \"Antibodies against pooled insoluble proteome, biochemical fractionation of post-mortem brains, functional interaction assay with DISC1\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction with DISC1 described but method details are limited in abstract; single lab\",\n      \"pmids\": [\"22798627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Local inactivation of CRMP1 (by micro-CALI) in the central domain of the growth cone caused lamellipodial retraction and subsequent retardation of neurite outgrowth, whereas inactivation in the neurite shaft arrested neurite outgrowth. Focal inactivation of CRMP1 in one half of the growth cone caused the growth cone to turn away from the irradiated site. These effects were distinct from those of CRMP2 inactivation.\",\n      \"method\": \"Microscale chromophore-assisted light inactivation (micro-CALI) with spatial and temporal resolution in live neurons\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — highly precise loss-of-function with spatiotemporal control, specific and internally controlled against CRMP2, single lab with multiple experimental conditions\",\n      \"pmids\": [\"22378692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CRMP1 and CRMP2 have synergistic roles in Sema3A-dependent dendritic spine maturation. crmp1-/- mice showed reduced dendritic spine density in cortical layer V pyramidal neurons comparable to sema3A-/- and crmp2-/- mice. CRMP1 levels increased in crmp2-/- mice, but there was no genetic interaction between crmp1 and crmp2 on spine density (double heterozygous sema3A+/-;crmp1+/- showed reduced spine density and branching).\",\n      \"method\": \"CRMP2 and CRMP1 knockout mice, dendritic spine density quantification, genetic epistasis analysis\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotypic readout, epistasis analysis across multiple genotypes, internally controlled\",\n      \"pmids\": [\"27480924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CRMP1 binds both the actin-binding domain and the last immunoglobulin-like repeat (rod 24) of Filamin-A. Phosphorylation-mimicking CRMP1(Ser522Asp) enhances Sema3A repulsion in neurons and causes Filamin-A to adopt a condensed form (shown by atomic-force microscopy). Phospho-CRMP1(Ser522Asp) weakens F-actin gelation crosslinked by Filamin-A, suggesting phosphorylated CRMP1 displaces Filamin-A from the actin cytoskeleton to facilitate remodeling. Alanine mutants in the interacting residues of either Filamin-A or CRMP1 suppress Sema3A repulsion. The C. elegans homologue UNC-33 (CRMP1) interacts with FLN-1 (Filamin-A orthologue) and participates in motor neuron projection.\",\n      \"method\": \"Pulldown, co-immunoprecipitation, atomic-force microscopy, alanine mutagenesis, F-actin gelation assay, C. elegans genetics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including structural analysis (AFM), biochemical reconstitution, mutagenesis, and in vivo C. elegans validation\",\n      \"pmids\": [\"25358863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CRMP1 interacts with Speedy A1 (Spy1), a member of the Speedy/RINGO family, as identified by yeast two-hybrid and verified by co-immunoprecipitation. Spy1 modulates CDK5-mediated phosphorylation of CRMP1. Enhanced CRMP1 phosphorylation (promoted by Spy1) disturbs the association of CRMP1 with actin, contributing to abnormal Sema3A-induced growth cone collapse and impaired regeneration after sciatic nerve crush.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, overexpression/shRNA knockdown, phosphorylation assay, rat sciatic nerve crush model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid followed by Co-IP, phosphorylation assay, and in vivo nerve crush model, single lab\",\n      \"pmids\": [\"25526860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CRMP1 directly interacts with N-terminal huntingtin (HTT) fragments containing expanded polyglutamine tracts and suppresses their spontaneous self-assembly into proteotoxic aggregates, reducing HTT misfolding and neurotoxicity in multiple HD models.\",\n      \"method\": \"Protein-protein interaction network filtering, experimental validation of CRMP1-HTT interaction in HD models (cell and in vivo)\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction validated experimentally in multiple HD models, single lab, method details limited in abstract\",\n      \"pmids\": [\"25908449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRMP1 suppresses EMT and metastasis in prostate cancer cells by associating with actin and WAVE1 (an Arp2/3 activator). CRMP1 knockdown stabilizes F-actin and triggers stress fiber formation; overexpression inhibits EMT and in vivo metastasis. CRMP1 expression is suppressed by histone deacetylation and direct promoter repression by the EMT regulator Snail.\",\n      \"method\": \"Co-immunoprecipitation (CRMP1-actin and CRMP1-WAVE1), siRNA knockdown, stable overexpression, F-actin staining, in vivo metastasis assay, ChIP for Snail binding to CRMP1 promoter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of CRMP1 with actin/WAVE1 plus functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"27321179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRMP1 and CRMP4 redundantly regulate proper orientation of basal dendrites of layer V pyramidal neurons and apical dendrite bifurcation of hippocampal CA1 neurons. CRMP1/CRMP4 double knockout showed severe dendritic orientation abnormalities not seen in single knockouts.\",\n      \"method\": \"CRMP1 and CRMP4 single and double knockout mice, cortical and hippocampal neuron morphology analysis\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via double KO, defined morphological phenotype, single lab\",\n      \"pmids\": [\"27836492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRMP1 functionally couples with Nav1.7 (SCN9A) to mediate Sema3A-induced retrograde axonal transport of PlexA4 and TrkA from growth cones. In crmp1-/- DRG neurons, Sema3A-induced co-localization and retrograde transport of PlexA4 and TrkA were impaired (similar to Nav1.7 RNAi knockdown). Sema3A induced co-localization of CRMP1 and Nav1.7 in growth cones. Introduction of CRMP1 in HEK293 cells lowered the activation threshold of co-expressed Nav1.7.\",\n      \"method\": \"crmp1-/- mouse DRG neurons, RNAi knockdown of Nav1.7, immunofluorescence co-localization, electrophysiology in HEK293 cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO phenotype matched by RNAi knockdown, electrophysiology functional validation, co-localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28254884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fyn kinase phosphorylates CRMP1 at Tyrosine 504 (Tyr504), and this phosphorylation is required for Sema3A-induced growth cone collapse and dendritic development. CRMP1-Tyr504Phe mutant suppressed Sema3A-induced growth cone collapse in DRG and hippocampal neurons and impaired cortical dendritic development in vivo. Fyn+/-;Crmp1+/- double heterozygous mice showed poor basal dendrite development similar to Sema3a-/-, Fyn-/-, and Crmp1-/- mice.\",\n      \"method\": \"In vitro kinase assay (Fyn phosphorylating CRMP1 Tyr504), site-directed mutagenesis (Tyr504Phe), growth cone collapse assay, in vivo cortical neuron morphology, double heterozygous genetic epistasis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, in vivo genetic epistasis across multiple genotypes, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33449368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FEZ1 interacts with CRMP1 at neuronal growth cones. FEZ1 deficiency in hippocampal neurons caused growth cone collapse and impaired axonal development phenotypically similar to CRMP1 loss-of-function, placing FEZ1 upstream or in the same pathway as CRMP1 in growth cone guidance.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, FEZ1 knockdown with morphological readout, comparison to CRMP1 loss-of-function\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with matching loss-of-function phenotype in neurons, single lab\",\n      \"pmids\": [\"33771901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inhibition of CRMP1 phosphorylation at Ser522 (using Crmp1S522A knock-in mice) improved motor function and preserved motor neurons and neuromuscular junctions in SOD1G93A ALS model mice, whereas CRMP1 knockout worsened outcomes. Phospho-mimicking CRMP1 mutant overexpression inhibited axonal outgrowth in Neuro2A cells. Phosphorylated CRMP1 (pCRMP1) accumulates in spheroids in ALS patient spinal cords and co-localizes with phosphorylated neurofilaments.\",\n      \"method\": \"Crmp1 Ser522Ala knock-in and CRMP1 KO mice in SOD1G93A background, rotarod test, motor neuron/NMJ histology, phosphoproteomic identification, phospho-mimicking mutant overexpression, human ALS patient immunostaining\",\n      \"journal\": \"eNeuro / Frontiers in neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — knock-in mutagenesis at defined phosphosite with KO comparison, functional and histological readouts, replicated across mouse and human tissue in two papers\",\n      \"pmids\": [\"35523582\", \"36237616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"De novo heterozygous variants in CRMP1 impair CRMP1 oligomerization and suppress neurite outgrowth in murine cortical neurons upon overexpression, linking CRMP1 oligomerization to its role in neurite development.\",\n      \"method\": \"In silico structural analysis, oligomerization assay, neurite outgrowth assay in primary cortical neurons with overexpression of variants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — oligomerization assay plus neuronal morphology phenotype, single lab\",\n      \"pmids\": [\"36511780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRMP1 and CRMP2 redundantly regulate migration and positioning of Purkinje cells in cerebellar lobule X. CRMP1/CRMP2 double knockout mice showed deficits in Purkinje cell migration and alignment in lobule X and impaired performance on the balance beam test.\",\n      \"method\": \"CRMP1/CRMP2 double knockout mice, cerebellar histology, balance beam and grip power tests\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double KO with defined cellular and behavioral phenotype, single lab\",\n      \"pmids\": [\"35219721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRMP1 is expressed in cochlear outer and inner hair cells, and its deletion causes progressive high-frequency hearing loss and hair cell loss at the basal cochlear region without affecting hair cell morphogenesis.\",\n      \"method\": \"Immunostaining, Crmp1 knockout mice, scanning electron microscopy, auditory brainstem response testing\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with specific auditory phenotype and localization, single lab\",\n      \"pmids\": [\"35181334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LKB1 physically interacts with CRMP1 (co-immunoprecipitation) in regenerated sciatic nerve axons, and LKB1 regulates CRMP1 phosphorylation. Overexpression of both LKB1 and CRMP1 promotes Schwann cell invasion/migration and neuronal process extension; knockdown of CRMP1 abolishes LKB1's nerve repair-promoting function.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, overexpression and siRNA knockdown, Schwann cell invasion assay, rat sciatic nerve crush model\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional epistasis by CRMP1 knockdown reversing LKB1 effect, single lab\",\n      \"pmids\": [\"38105470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Deletion of CRMP1 in mice disrupts the balance between synaptic and extrasynaptic NMDA receptors in the hippocampus, increasing extrasynaptic NMDA receptor levels and tau phosphorylation, leading to synaptic and neuronal loss in CA3 and accelerated age-related cognitive decline.\",\n      \"method\": \"crmp1 KO mice at adult/middle-aged/older stages, Morris water maze, biochemical fractionation for synaptic/extrasynaptic NMDA receptor levels, glutamate/glutamine measurement\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with biochemical fractionation and behavioral readout, single lab\",\n      \"pmids\": [\"38176125\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRMP1 is a cytosolic phosphoprotein that functions as an intracellular mediator of Semaphorin 3A (Sema3A) signaling: upon Sema3A stimulation, Fyn phosphorylates CRMP1 at Tyr504 and CDK5/GSK3β sequentially phosphorylate it at Ser522, enabling CRMP1 to remodel the actin cytoskeleton (partly by displacing Filamin-A and antagonizing WAVE1/Arp2/3) and to couple with Nav1.7 to drive retrograde axonal transport, thereby regulating growth cone collapse, neurite outgrowth, dendritic spine maturation, and neuronal migration; in cancer cells CRMP1 suppresses invasion by competing with its long isoform LCRMP-1 for WAVE1 binding, and its expression is transcriptionally controlled by competing C/EBPα and Sp1 at its promoter and repressed by NF-κB p50 and Snail.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CRMP1 is a cytosolic neuronal phosphoprotein that acts as an intracellular effector of Semaphorin 3A (Sema3A) signaling to regulate cytoskeletal remodeling during axon guidance, neurite outgrowth, dendritic development, and neuronal migration [#8, #9, #16]. Sema3A-dependent function is gated by sequential phosphorylation: Fyn phosphorylates CRMP1 at Tyr504, an event required for Sema3A-induced growth cone collapse and cortical dendritic development [#16], while phosphorylation at Ser522 controls its activity in axonal outgrowth and motor neuron integrity [#18]. Mechanistically, CRMP1 remodels the actin cytoskeleton by binding both the actin-binding domain and a rod immunoglobulin repeat of Filamin-A; phospho-mimicking CRMP1(Ser522Asp) condenses Filamin-A and weakens Filamin-A-crosslinked F-actin gels, displacing Filamin-A to permit remodeling, and it associates with actin and the Arp2/3 activator WAVE1 to restrain stress-fiber and filopodia formation [#10, #13]. CRMP1 also functionally couples with the Nav1.7 sodium channel to drive Sema3A-induced retrograde axonal transport of PlexA4 and TrkA from growth cones [#15]. Genetically, CRMP1 acts redundantly or synergistically with CRMP2 and CRMP4 in dendritic spine maturation, dendrite orientation, and Purkinje and granule cell migration [#9, #14, #20, #2], and its oligomerization is required for neurite outgrowth [#19]. In cancer, CRMP1 suppresses invasion and EMT by competing with its long isoform LCRMP-1 for WAVE1 binding, with its expression controlled at the promoter by competing C/EBPα and Sp1 and repressed by NF-κB p50 and Snail [#6, #13, #5, #4]. De novo heterozygous CRMP1 variants that impair oligomerization and suppress neurite outgrowth link the gene to a neurodevelopmental disorder [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first molecular activity for a CRMP1 splice variant, showing it could modulate Rho-pathway signaling rather than acting as an inert cytoskeletal protein.\",\n      \"evidence\": \"Co-IP from brain extracts with ROKα, kinase activity assay, and neurite retraction rescue by overexpression\",\n      \"pmids\": [\"12482610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Studied a specific p80 splice variant, not necessarily canonical CRMP1\", \"ROKα inhibition mechanism not structurally defined\", \"Effect shown by overexpression, not loss-of-function\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined where CRMP1 acts by mapping its predominantly dendritic localization in specific adult neuronal populations.\",\n      \"evidence\": \"Immunohistochemistry on adult mouse brain and primary cortical neuron cultures\",\n      \"pmids\": [\"15834957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Descriptive localization without functional linkage\", \"Subcellular compartment resolution limited\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the first genetic evidence that CRMP1 is required in vivo, establishing a developmental role in cerebellar granule cell migration.\",\n      \"evidence\": \"CRMP1 knockout mice and cerebellar explant migration assay replicated by antibody blockade\",\n      \"pmids\": [\"17121542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effectors downstream of CRMP1 in migration not defined\", \"Cell-autonomy not fully resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the transcriptional control logic of CRMP1 in cancer, where promoter occupancy dictates invasiveness.\",\n      \"evidence\": \"EMSA, ChIP, reporter assays, and invasion assays mapping C/EBPα, Sp1, and NF-κB p50 to the CRMP1 promoter\",\n      \"pmids\": [\"18782567\", \"18524846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Links promoter regulation to invasion but not to CRMP1 cytoskeletal mechanism\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined CRMP1's tumor-suppressive mechanism as competitive inhibition of its long isoform within the WAVE1/actin nucleation pathway.\",\n      \"evidence\": \"Co-IP, overexpression in noninvasive cell lines, and filopodia/invasion assays showing CRMP1 disrupts LCRMP-1/WAVE-1 binding\",\n      \"pmids\": [\"21747164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of isoform competition not resolved\", \"Relationship to neuronal WAVE1 function unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved CRMP1's spatial role in growth cone dynamics, showing it is locally required for lamellipodial maintenance and directional guidance distinct from CRMP2.\",\n      \"evidence\": \"Microscale chromophore-assisted light inactivation with spatiotemporal control in live neurons\",\n      \"pmids\": [\"22378692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets of CRMP1 within the growth cone not identified here\", \"Acute inactivation only\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the direct cytoskeletal substrate mechanism: phospho-CRMP1 displaces Filamin-A to enable actin remodeling during Sema3A repulsion.\",\n      \"evidence\": \"Pulldown, AFM, F-actin gelation assay, alanine mutagenesis, and C. elegans UNC-33/FLN-1 genetics\",\n      \"pmids\": [\"25358863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration of Filamin-A displacement in mammalian neurons limited\", \"How phosphorylation triggers binding-mode change not structurally solved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected upstream kinase regulation to function, showing Spy1-modulated CDK5 phosphorylation of CRMP1 controls its actin association and regeneration capacity.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, phosphorylation assay, and rat sciatic nerve crush model\",\n      \"pmids\": [\"25526860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphosite controlling actin association not pinpointed here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a non-cytoskeletal mechanism: CRMP1 couples with Nav1.7 to drive Sema3A-induced retrograde transport of guidance and neurotrophin receptors.\",\n      \"evidence\": \"crmp1-/- DRG neurons, Nav1.7 RNAi, co-localization, and HEK293 electrophysiology\",\n      \"pmids\": [\"28254884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between CRMP1/Nav1.7 and the transport machinery undefined\", \"Whether channel activity per se is required for transport unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the tyrosine-phosphorylation arm of CRMP1 regulation, placing Fyn-mediated Tyr504 phosphorylation as a required node for Sema3A responses and dendrite development.\",\n      \"evidence\": \"In vitro Fyn kinase assay, Tyr504Phe mutagenesis, growth cone collapse, and Fyn;Crmp1 double-heterozygote epistasis\",\n      \"pmids\": [\"33449368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between Tyr504 and Ser522 phosphorylation not defined\", \"Downstream effector engaged by phospho-Tyr504 unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the growth cone pathway by identifying FEZ1 as a CRMP1 partner whose loss phenocopies CRMP1 deficiency.\",\n      \"evidence\": \"Co-IP, co-localization, and FEZ1 knockdown with matching morphological readout\",\n      \"pmids\": [\"33771901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directionality of the FEZ1-CRMP1 relationship not firmly established\", \"Mechanism of pathway coupling unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established phospho-state-specific pathology, showing Ser522 phosphorylation drives ALS-relevant motor neuron degeneration while CRMP1 protein itself is protective.\",\n      \"evidence\": \"Crmp1 Ser522Ala knock-in versus KO in SOD1G93A mice, behavior, histology, and human ALS spinal cord immunostaining\",\n      \"pmids\": [\"35523582\", \"36237616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for disease-associated Ser522 phosphorylation not pinned down in vivo\", \"Link between pCRMP1 spheroids and neurofilament pathology mechanistic detail limited\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated genetic redundancy among CRMP family members in migration and dendrite patterning, clarifying why single knockouts can be subtle.\",\n      \"evidence\": \"CRMP1/CRMP2 and CRMP1/CRMP4 double knockout mice with cerebellar and cortical/hippocampal morphology and behavior\",\n      \"pmids\": [\"27836492\", \"35219721\", \"27480924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of functional redundancy not resolved\", \"Whether heterodimerization underlies redundancy untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked CRMP1 to human neurodevelopmental disease and tied disease variants to a specific molecular defect in oligomerization.\",\n      \"evidence\": \"De novo variant identification, oligomerization assays, and neurite outgrowth assays in cortical neurons\",\n      \"pmids\": [\"36511780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How oligomerization controls CRMP1 activity mechanistically unclear\", \"Overexpression-based phenotype rather than endogenous\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded CRMP1 function into adult synaptic homeostasis, showing it maintains the synaptic/extrasynaptic NMDA receptor balance and limits tau phosphorylation.\",\n      \"evidence\": \"crmp1 KO mice across ages, biochemical fractionation, and Morris water maze\",\n      \"pmids\": [\"38176125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between CRMP1 and NMDA receptor distribution unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct CRMP1 phosphorylation events (Tyr504, Ser522) and binding partners (Filamin-A, WAVE1, Nav1.7, FEZ1, LKB1) are integrated into a unified, context-dependent signaling logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating phospho-states with partner switching\", \"Quantitative ordering of Fyn/CDK5/GSK3β phosphorylation events not established\", \"Mechanism connecting cytoskeletal and channel-coupled functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 10, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 15, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 9, 14, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 13, 18, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FLNA\", \"WASF1\", \"SCN9A\", \"FYN\", \"FEZ1\", \"STK11\", \"DISC1\", \"HTT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}