Affinage

DSCAM

Cell adhesion molecule DSCAM · UniProt O60469

Length
2012 aa
Mass
222.3 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DSCAM is a transmembrane immunoglobulin-superfamily cell-adhesion molecule that organizes neuronal connectivity through isoform-specific homophilic recognition and contact-dependent repulsion (PMID:10925149, PMID:17721508, PMID:17482551, PMID:17481394, PMID:17481395). In Drosophila, vast ectodomain diversity generates structurally unique receptors whose antiparallel D2/D3 horseshoe pairing confers homophilic binding specificity; this diversity is required for precise axon branch segregation, dendrite self-avoidance, and circuit assembly, with neighboring neurons needing distinct isoforms while the specific identity in any one neuron is irrelevant (PMID:11856530, PMID:16678102, PMID:17721508, PMID:17482551, PMID:17481394, PMID:17481395, PMID:17851526). Vertebrate DSCAM and DSCAML1 likewise mediate isoneuronal and heteroneuronal self-avoidance to preserve dendritic spacing and mosaic patterning in the retina through cell-autonomous homophilic binding, in part by masking cadherin-mediated adhesion (PMID:18216854, PMID:18216855, PMID:19945391, PMID:22063212, PMID:30297418). DSCAM signals into the cytoskeleton via Pak1 — directly in vertebrates and through the Dock adaptor and the sorting nexin DSH3PX1 in flies — engaging Wasp/actin machinery, JNK/p38 MAP kinases, and Abl kinase to control arbor morphology (PMID:10892653, PMID:11546816, PMID:15169762, PMID:25988807). DSCAM also acts as a netrin-1 receptor on commissural axons, binding netrin-1 and signaling through Fyn and Pak1 and associating with UNC5C to mediate growth cone collapse, although a mouse null shows netrin-1 commissural guidance can proceed without DSCAM (PMID:18585357, PMID:19196994, PMID:22685302, PMID:22238077). Distinct domains drive distinct outputs: the extracellular domain binds neuroligin-1 to block the neuroligin-1–neurexin1β interaction and restrain premature spine maturation and glutamatergic transmission (PMID:34848499), the protein suppresses a RapGEF2–Rap1–N-cadherin cascade to permit neuronal delamination (PMID:32917586), and the intracellular domain is released by γ-secretase and imported to the nucleus via IPO5 to regulate genes controlling differentiation and synapse formation (PMID:30745319). DSCAM dosage is mechanistically tied to disease: a hyperactive DSCAM/PAK1 pathway impairs neurogenesis in Down syndrome models, and DSCAM loss or mutation reduces NMDA-receptor function and produces autism-like phenotypes (PMID:33945512, PMID:34253863, PMID:34848499).

Mechanistic history

Synthesis pass · year-by-year structured walk · 35 steps
  1. 2000 High

    Established that Dscam couples to intracellular signaling and acts in axon pathfinding, defining its first molecular pathway.

    Evidence Affinity purification and direct binding plus genetic epistasis in Drosophila (Dscam–Dock–Pak)

    PMID:10892653

    Open questions at the time
    • Did not establish the ligand triggering Dscam signaling
    • Vertebrate relevance of the Dock requirement untested at this point
  2. 2000 Medium

    Showed human DSCAM is a homophilic adhesion molecule, defining its core biochemical adhesive activity.

    Evidence Cell aggregation assay with transfected L cells and Western blot

    PMID:10925149

    Open questions at the time
    • Single-lab aggregation assay without structural basis
    • Did not address isoform specificity
  3. 2002 Medium

    Connected Dscam to actin polymerization and receptor trafficking machinery, extending the cytoplasmic signaling output.

    Evidence Co-IP and domain mapping from S2 cells linking Dscam–Dock to DSH3PX1, Wasp, and AP-50

    PMID:11546816

    Open questions at the time
    • Interactions shown in S2 cells, not in neurons
    • Functional consequence for axon guidance not directly tested
  4. 2002 High

    Defined Dscam's in vivo role in axon branch segregation, linking the molecule to circuit-level wiring control.

    Evidence Genetic mosaic single-axon analysis in Drosophila mushroom body neurons

    PMID:11856530

    Open questions at the time
    • Did not explain how diversity contributes to segregation
    • Molecular trigger for segregation unresolved
  5. 2003 High

    Showed Dscam directs ORN axon targeting to specific glomeruli, generalizing its wiring role to sensory map formation.

    Evidence Loss-of-function genetics and immunolocalization in the Drosophila antennal lobe

    PMID:12546818

    Open questions at the time
    • Did not resolve isoform contribution to targeting specificity
  6. 2004 Medium

    Demonstrated that juxtamembrane isoform choice partitions Dscam between axons and dendrites, linking alternative splicing to subcellular function.

    Evidence Transgene rescue and GFP-tagged isoform localization in mushroom body neurons

    PMID:15339648

    Open questions at the time
    • Mechanism of differential targeting not defined
    • Single-lab localization data
  7. 2004 Medium

    Established that human DSCAM directly activates Pak1 and MAP kinases without the Dock adaptor, distinguishing vertebrate from fly signaling.

    Evidence Co-IP, in vitro kinase assay, and cell morphology assay

    PMID:15169762

    Open questions at the time
    • In vivo neuronal relevance of JNK/p38 activation untested
    • Upstream activating ligand not identified
  8. 2006 High

    Proved that a large number of unique isoforms is functionally required for precise connectivity, validating the diversity hypothesis.

    Evidence Homologous recombination to reduce isoform diversity with single-isoform rescue in mechanosensory neurons

    PMID:16678102

    Open questions at the time
    • Did not provide the structural basis for isoform-specific recognition
  9. 2007 High

    Provided the structural mechanism of isoform-specific homophilic binding, explaining how diversity encodes self-recognition.

    Evidence X-ray crystallography of two isoforms plus structure-guided mutagenesis and peptide swapping

    PMID:17721508

    Open questions at the time
    • Did not address how binding is converted into repulsion at the cytoplasmic side
  10. 2007 High

    Defined dendrite self-avoidance as the cellular logic of Dscam diversity and localized the repulsive conversion to the cytoplasmic tail.

    Evidence Loss-of-function, single-isoform rescue, and live dendrite imaging in da sensory neurons; concurrent single-isoform knock-in

    PMID:17481394 PMID:17481395 PMID:17482551 PMID:17851526

    Open questions at the time
    • The cytoplasmic effectors converting recognition to repulsion not fully mapped
  11. 2007 Medium

    Showed endodomain/juxtamembrane variants assign Dscam to dendritic versus axonal morphogenesis, refining isoform-specific cellular roles.

    Evidence microRNA-based RNAi of isoform subsets with transgenic rescue and subcellular localization

    PMID:17581959

    Open questions at the time
    • Trafficking machinery directing isoform sorting not identified
  12. 2008 High

    Identified DSCAM as a netrin-1 receptor capable of DCC-independent axon guidance, extending its role beyond homophilic adhesion.

    Evidence Binding assay, siRNA knockdown, and Xenopus turning/overexpression assays on commissural axons

    PMID:18585357

    Open questions at the time
    • Whether DSCAM is required for guidance in mammals in vivo left open
    • Signaling pathway downstream of netrin–DSCAM not detailed here
  13. 2008 High

    Established that vertebrate Dscam/DscamL direct lamina-specific synaptic arborization via homophilic adhesion, conserving the adhesion role in vertebrate circuits.

    Evidence In vivo loss/gain-of-function, homophilic adhesion assay, and IPL lamination analysis in chick

    PMID:18216854

    Open questions at the time
    • Relationship between adhesion-driven lamination and self-avoidance not reconciled
  14. 2008 High

    Demonstrated mammalian DSCAM mediates self-avoidance and mosaic spacing, transferring the fly self-avoidance concept to vertebrates.

    Evidence Spontaneous mouse mutation analysis and anatomical phenotyping of amacrine cells

    PMID:18216855

    Open questions at the time
    • Mammalian DSCAM lacks fly-scale diversity, leaving the recognition mechanism unexplained
  15. 2008 Medium

    Confirmed in flies that Dscam binds Netrin and acts as an attractive midline-crossing receptor redundantly with a paralog.

    Evidence Cell overlay binding, dose-sensitive genetic interactions, and overexpression-induced ectopic crossing

    PMID:18948420

    Open questions at the time
    • Single-lab; signaling downstream of Dscam–Netrin not dissected
  16. 2009 High

    Showed vertebrate DSCAM transduces netrin-1 via Fyn and Pak1 to drive axon outgrowth and turning in vivo, defining the netrin–DSCAM signaling module.

    Evidence Co-IP, siRNA knockdown, in vitro turning, and in ovo knockdown

    PMID:19196994

    Open questions at the time
    • In ovo/in vitro findings later contested by mouse null
    • Direct enzymatic activation mechanism of Fyn/Pak1 not fully resolved
  17. 2009 Medium

    Linked endodomain exon-19 inclusion to stage-specific morphogenesis, showing splicing tunes Dscam potency across development.

    Evidence Stage-specific RNAi with transgenic rescue and tagged-isoform localization

    PMID:19211897

    Open questions at the time
    • Molecular basis of differential neurite targeting unresolved
  18. 2009 High

    Connected DSCAM to a physiological circuit function, showing it is required for synchronizing respiratory rhythm-generating neurons.

    Evidence Knockout mice, plethysmography, and voltage-sensitive dye imaging of medullary neurons

    PMID:19261893

    Open questions at the time
    • Cellular mechanism linking self-avoidance/adhesion to neuronal synchrony not defined
  19. 2009 High

    Showed self-avoidance and synaptic specificity are genetically separable DSCAM/DSCAML1 functions in the mammalian retina.

    Evidence Knockout mouse anatomy and electrophysiology across multiple retinal cell types

    PMID:19945391

    Open questions at the time
    • Molecular distinction between the two functions unresolved
  20. 2010 High

    Revealed Dscam-mediated repulsion enforces invariant postsynaptic partner combinations at synapses, extending repulsion to synaptic partner selection.

    Evidence Dscam1;Dscam2 double mutant analysis with electron microscopy of tetrad synapses

    PMID:20826308

    Open questions at the time
    • How redundant Dscams partition partner exclusion not detailed
  21. 2010 Medium

    Showed DSCAM mRNA is dendritically transported with CPEB1 and locally translated upon NMDA stimulation, adding post-transcriptional regulation defective in a Down syndrome model.

    Evidence In situ hybridization, mRNP Co-IP, metabolic labeling, and overexpression in hippocampal neurons

    PMID:20926679

    Open questions at the time
    • Functional consequence of local translation for connectivity untested
    • Single-lab
  22. 2012 High

    Defined a netrin-1-stimulated DSCAM–UNC5C complex driving growth cone collapse, broadening DSCAM's role to repulsive netrin signaling.

    Evidence Reciprocal Co-IP, shRNA knockdown, growth cone collapse assay, and Src-dependent phosphorylation analysis

    PMID:22685302

    Open questions at the time
    • How the same receptor mediates both attraction and collapse not resolved
  23. 2012 Medium

    Genetic null in mouse showed DSCAM is dispensable for netrin-1 commissural guidance, contradicting siRNA-based requirement claims.

    Evidence DSCAM-null mouse genetics with in vitro outgrowth and receptor expression analysis

    PMID:22238077

    Open questions at the time
    • Discrepancy with knockdown studies unresolved
    • Context where DSCAM netrin function is required not defined
  24. 2012 High

    Established DSCAM acts cell-autonomously through same-type homophilic binding for retinal spacing, confirming the homophilic self-avoidance mechanism in vivo.

    Evidence Conditional knockout and chimeric retina analysis

    PMID:22063212

    Open questions at the time
    • Downstream repulsive effectors in mammals not identified
  25. 2012 Medium

    Connected DSCAM to cortical spine maturation, showing DSCAM levels shape dendritic branching and spine morphology.

    Evidence Subcellular fractionation, Golgi staining, and in vivo del17 mutant spine quantification

    PMID:23175819

    Open questions at the time
    • Molecular pathway controlling spine maturation not defined here
    • Single-lab
  26. 2015 Medium

    Placed Abl kinase downstream of Dscam in presynaptic arbor size control, identifying a dose-sensitive effector pathway.

    Evidence Genetic epistasis and pharmacological Abl inhibition in Drosophila

    PMID:25988807

    Open questions at the time
    • Direct biochemical link between Dscam and Abl not shown
    • Single-lab
  27. 2015 Medium

    Identified TBCD as a Dscam ICD partner coupling the receptor to microtubule organization for dendritic targeting.

    Evidence Co-IP of Dscam ICD–TBCD, genetic epistasis, and single-cell clone analysis

    PMID:25653356

    Open questions at the time
    • Mechanism by which TBCD-microtubule coupling directs targeting unresolved
    • Single-lab
  28. 2016 High

    Showed different Dscam proteins can act adhesively rather than repulsively in closely related neurons, revealing context-dependent output modes.

    Evidence Live imaging, genetic mosaics, and double mutant analysis of L4 dendritic targeting

    PMID:26844831

    Open questions at the time
    • What switches Dscam between adhesion and repulsion not defined
  29. 2018 Medium

    Proposed mammalian DSCAM drives self-avoidance by masking cadherin adhesion, offering a diversity-independent mechanism for vertebrates.

    Evidence In vivo genetics, in vitro adhesion assay, and double mutant analysis with cadherins

    PMID:30297418

    Open questions at the time
    • Molecular basis of cadherin masking not structurally defined
    • Single-lab
  30. 2019 High

    Revealed regulated intramembrane proteolysis of DSCAM: the ICD is released by γ-secretase and imported via IPO5 to control gene expression and synapse number.

    Evidence ORFeome screen, ICD–IPO5 Co-IP, γ-secretase inhibition, RNA-seq, and gain-of-function in neurons

    PMID:30745319

    Open questions at the time
    • Direct nuclear DNA/transcription targets of the ICD not identified
    • Trigger for cleavage in vivo unclear
  31. 2019 Medium

    Showed neuronal sphingolipids are required for correct axonal sorting of Dscam isoforms, linking membrane lipid composition to receptor localization.

    Evidence Forward genetic screen with SPT loss/gain-of-function and Dscam localization imaging

    PMID:30778062

    Open questions at the time
    • Direct biophysical mechanism of lipid-dependent sorting unresolved
    • Single-lab
  32. 2020 High

    Defined a non-adhesion role: DSCAM suppresses a RapGEF2–Rap1–N-cadherin cascade to permit neuronal delamination during midbrain development.

    Evidence Cre-loxP labeling, shRNA knockdown, DSCAM–RapGEF2 Co-IP, and epistasis with N-cadherin imaging

    PMID:32917586

    Open questions at the time
    • How DSCAM engagement is spatially restricted to apical endfeet not fully defined
  33. 2021 High

    Identified the DSCAM ectodomain–neuroligin-1 interaction as a brake on premature spine maturation, linking DSCAM to synaptic adhesion competition and autism-like phenotypes.

    Evidence DSCAM–NLGN1 Co-IP, ectodomain rescue, spine morphology, electrophysiology, and behavior

    PMID:34848499

    Open questions at the time
    • Structural basis for blocking the NLGN1–neurexin1β interaction not resolved
  34. 2021 High

    Linked DSCAM/PAK1 hyperactivation to impaired neurogenesis in Down syndrome, establishing dosage-dependent pathology reversible by pathway suppression.

    Evidence iPSC-derived cerebral organoids, scRNA-seq, CRISPR/CRISPRi, and small-molecule PAK1 inhibition

    PMID:33945512

    Open questions at the time
    • How PAK1 hyperactivation mechanistically blocks neurogenesis not fully defined
  35. 2021 High

    Connected DSCAM to NMDA-receptor function, showing patient DSCAM mutations reduce NMDA-R currents via ERK-dependent subunit expression.

    Evidence ASD patient iPSC neurons, WT/truncated DSCAM rescue, electrophysiology, RNA-seq, and shRNA knockdown

    PMID:34253863

    Open questions at the time
    • Direct physical coupling of DSCAM to NMDA-R subunits not established
    • Mechanism linking DSCAM to ERK signaling not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single receptor integrates homophilic adhesion/repulsion, netrin signaling, cadherin masking, RapGEF2 regulation, and ICD nuclear signaling into context-specific outputs remains unresolved.
  • No unifying model for how DSCAM switches between adhesive, repulsive, and signaling modes
  • Vertebrate self-avoidance mechanism without isoform diversity incompletely defined
  • Direct transcriptional targets of the nuclear ICD unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 6 GO:0001618 virus receptor activity 3 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3 R-HSA-1500931 Cell-Cell communication 2
Partners
DOCKFYNIPO5NLGN1PAK1RAPGEF2TBCDUNC5C

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Drosophila Dscam binds directly to both the SH2 and SH3 domains of the adaptor protein Dock, and genetic studies showed that Dscam, Dock, and Pak act together to direct axon pathfinding of Bolwig's nerve to an intermediate target in the embryo. Affinity purification, direct binding assay, genetic epistasis Cell High 10892653
2000 Human DSCAM mediates cation-independent homophilic cell–cell adhesion; transfected mouse fibroblast L cells expressing DSCAM formed aggregates specifically with other DSCAM-expressing cells. Cell transfection, Western blot, cell aggregation assay Brain research. Molecular brain research Medium 10925149
2001 DSH3PX1 (sorting nexin) co-immunoprecipitates with Dock and Dscam from S2 cell extracts and connects Dscam to Wasp (actin polymerization machinery) and the clathrin adaptor AP-50, linking Dscam to cytoskeletal rearrangements and receptor trafficking. Affinity purification from S2 cells, co-immunoprecipitation, in vitro binding domain mapping The Journal of biological chemistry Medium 11546816
2002 Drosophila Dscam controls axon branch segregation and suppresses ectopic bifurcation in mushroom body neurons; loss of Dscam causes additional branches that randomly segregate among targets. Genetic mosaic screen, single axon analysis, loss-of-function Neuron High 11856530
2003 Dscam is required for specific olfactory receptor neuron axon targeting to correct glomeruli in the Drosophila antennal lobe; Dscam protein is localized to developing ORN axons. Loss-of-function genetics, immunolocalization, axon targeting analysis Neuron High 12546818
2004 The transmembrane/juxtamembrane domain encoded by exon 17.2 targets Dscam to axons and is required for axon bifurcation/segregation in mushroom body neurons, while exon 17.1-containing Dscam is targeted to dendrites. Transgene rescue experiments, GFP-tagged isoform localization, loss-of-function analysis Neuron Medium 15339648
2004 Human DSCAM directly binds Pak1 and stimulates Pak1 phosphorylation and kinase activity; DSCAM also activates JNK and p38 MAP kinases. Unlike Drosophila, human DSCAM interacts with Pak1 directly without requiring the Dock adaptor. Co-immunoprecipitation, in vitro kinase assay, cell morphology assay The Journal of biological chemistry Medium 15169762
2006 Reduction of Dscam isoform diversity to 22,176 isoforms (from maximum 38,016) causes specific connectivity defects in mechanosensory neurons, demonstrating that a large number of structurally unique receptor isoforms is required for precise neuronal connectivity. Homologous recombination to reduce diversity, genetic rescue with single isoforms, loss-of-function analysis Cell High 16678102
2007 Crystal structures of two Dscam isoforms reveal a horseshoe configuration of domains D1–D4; homophilic dimerization involves antiparallel pairing of variable domain D2 with D2 and D3 with D3. Structure-guided mutagenesis and peptide swapping confirmed that epitope I (variable residues of D2/D3) confers isoform-specific homophilic binding specificity. X-ray crystallography, structure-guided mutagenesis, peptide segment swapping Nature High 17721508
2007 Dscam mediates dendrite self-avoidance in all four classes of Drosophila da sensory neurons; identical isoforms on sister dendrites drive homophilic repulsion, while Dscam diversity between neighboring neurons prevents inappropriate inter-neuronal repulsion. The cytoplasmic tail converts homophilic recognition into repulsion. Loss-of-function genetics, single isoform rescue, live imaging of dendrite behavior Cell High 17481394 17481395 17482551
2007 Dscam diversity is essential for neural circuit assembly; reduction of the entire ectodomain repertoire to a single isoform by homologous recombination severely disorganizes neural circuits. Neighboring neurons must express distinct isoforms, but the specific identity of isoforms in any individual neuron is unimportant. Homologous recombination to generate single-isoform knock-in, genetic mosaic analysis Nature High 17851526
2007 Specific Drosophila Dscam juxtamembrane variants differentially control dendritic elaboration (exon 17.1-containing) versus axonal arborization (exon 17.2-containing); differential targeting of Dscam isoforms to dendrites versus axons underlies these distinct functions. microRNA-based RNAi knockdown of specific isoform subsets, transgenic rescue, subcellular localization The Journal of neuroscience Medium 17581959
2008 DSCAM is a netrin-1 receptor expressed on spinal commissural axons; it binds netrin-1, and is necessary for commissural axon growth toward and across the midline. DSCAM can mediate turning responses to netrin-1 independently of DCC in Xenopus spinal neurons. Binding assay (DSCAM–netrin-1 interaction), siRNA knockdown, in vitro turning assay, Xenopus overexpression Cell High 18585357
2008 Vertebrate Dscam and DscamL mediate homophilic adhesion and are expressed in non-overlapping subsets of chick retinal neurons that form synapses in distinct IPL sublaminae; loss- and gain-of-function show these molecules direct lamina-specific synaptic partner arborization. In vivo loss- and gain-of-function, homophilic adhesion assay, anatomical lamination analysis Nature High 18216854
2008 Mouse DSCAM mediates isoneuronal self-avoidance for process arborization and heteroneuronal self-avoidance within specific amacrine cell types, preventing fasciculation and preserving mosaic spacing; loss of DSCAM causes hyperfasciculated processes and clumped cell bodies. Spontaneous mouse mutation analysis, anatomical phenotyping, loss-of-function Nature High 18216855
2008 Drosophila Dscam binds Netrin with the same affinity as DCC in cell overlay assays; Dscam and its paralog Dscam3 act redundantly to promote midline crossing. Overexpression of Dscam induces ectopic midline crossing, consistent with an attractive receptor function. Dose-sensitive genetic interactions between Dscam and Netrin mutants confirm pathway membership. Cell overlay binding assay, genetic dose-sensitive interaction analysis, overexpression-induced ectopic crossing Development (Cambridge, England) Medium 18948420
2009 Vertebrate DSCAM interacts with Netrin-1 and activates phosphorylation of Fyn and Pak1 in transfected cells independently of DCC; siRNA knockdown of DSCAM inhibits netrin-induced axon outgrowth and commissural axon turning in vitro and causes commissural axon pathfinding defects in ovo. Co-immunoprecipitation (DSCAM–Netrin-1), siRNA knockdown, in vitro turning assay, in ovo knockdown Proceedings of the National Academy of Sciences of the United States of America High 19196994
2009 DSCAM endodomain diversity governs stage-specific neuronal morphogenesis: exon 19-containing Dscam controls embryonic neuron wiring, while Dscam lacking exon 19 is more efficiently targeted to neurites and more potently suppresses axon bifurcation at postembryonic stages. Stage-specific RNAi silencing, transgenic rescue, subcellular localization of tagged isoforms The Journal of neuroscience Medium 19211897
2009 DSCAM-deficient mice lose synchrony of pre-inspiratory neurons in the rostral ventrolateral medulla (rhythm generator for respiration), resulting in irregular respiratory rhythm and perinatal death in null mutants. Gene knockout, whole-body plethysmography, medulla-spinal cord preparation, voltage-sensitive dye optical imaging The Journal of neuroscience High 19261893
2009 Mouse DSCAM and DSCAML1 function in self-avoidance in multiple retinal cell types including retinal ganglion cells and rod circuit neurons; Dscam-/- RGCs have fasciculated dendrites and clumped cell bodies. Neurons in Dscam or Dscaml1 mutant retinas still stratify appropriately and form functional synapses, indicating self-avoidance and synaptic specificity are separable functions. Knockout mouse analysis, anatomical phenotyping, electrophysiology Neuron High 19945391
2010 DSCAM mRNA localizes to dendrites in adult mouse hippocampal neurons and associates with CPEB1, a regulator of mRNA transport and local translation. NMDA stimulation induces DSCAM dendritic translation in wild-type neurons but not in Ts1Cje (Down syndrome model) neurons. Overexpression of DSCAM in hippocampal neurons inhibits dendritic branching. In situ hybridization, co-immunoprecipitation of mRNP (DSCAM mRNA–CPEB1), metabolic labeling, neuronal overexpression The Journal of neuroscience Medium 20926679
2010 Drosophila Dscam1 and Dscam2 act redundantly to ensure the invariable combination of L1 and L2 postsynaptic elements at photoreceptor tetrad synapses; Dscam1;Dscam2 double mutants lose this strict pairing, showing that homophilic repulsion by Dscams excludes inappropriate postsynaptic partners. Double mutant analysis, electron microscopy of synaptic ultrastructure Neuron High 20826308
2012 DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1; DSCAM partially co-localizes with UNC5C in neurons. Knockdown of DSCAM or UNC5C suppresses netrin-1-induced growth cone collapse of cerebellar granule cells. Netrin-1 increases tyrosine phosphorylation of DSCAM, UNC5C, FAK, Fyn, and PAK1 via Src family kinases, and promotes complex formation of these signaling molecules. Co-immunoprecipitation, shRNA knockdown, growth cone collapse assay, phosphorylation analysis, Src kinase inhibition The Journal of biological chemistry High 22685302
2012 DSCAM localizes to synaptic plasma membranes during cortical dendrite arborization and spine formation. DSCAM loss-of-function (del17 mutation) causes transient reductions in pyramidal neuron dendritic branching and lasting changes in dendritic spine morphology, with a decrease in large stable spines and increase in small immature spines. Subcellular fractionation, Golgi staining, in vivo mutant analysis, spine morphology quantification The Journal of neuroscience Medium 23175819
2012 Genetic ablation of DSCAM in mice does not impair Netrin-1-induced commissural axon outgrowth or guidance to the floor plate; DSCAM-null commissural neurons show normal DCC and Neogenin levels and normal in vitro response to Netrin-1. DSCAM-null mouse genetics, in vitro axon outgrowth assay, receptor expression analysis The Journal of neuroscience Medium 22238077
2012 DSCAM cell autonomy in the mouse retina: conditional deletion of Dscam reproduces spacing and arborization defects; in chimeric retinas, Dscam-mutant cells entangle adjacent wild-type cells of the same type, consistent with DSCAM-dependent spacing mediated through homophilic binding between cells of the same type. Conditional knockout, chimeric retina analysis, inducible deletion Developmental biology High 22063212
2015 Dysregulated (elevated) Dscam levels in Drosophila enlarge presynaptic arbors, and this phenotype can be suppressed by genetic or pharmacological inhibition of Abelson kinase (Abl), placing Abl downstream of Dscam in the pathway controlling presynaptic arbor size. Genetic epistasis, pharmacological Abl inhibition, loss-of-function/gain-of-function eLife Medium 25988807
2015 Tubulin folding cofactor D (TBCD) physically interacts with the intracellular domain of Drosophila Dscam; genetic analyses show TBCD cooperates with Dscam in vivo for dendritic targeting in projection neurons. Loss of TBCD disrupts microtubules and causes ectopic dendrite arborization similar to Dscam phenotypes. Co-immunoprecipitation (Dscam ICD–TBCD), genetic epistasis, single-cell clone analysis The Journal of neuroscience Medium 25653356
2016 Dscam2 directs dendritic targeting of lamina neuron L4 through homophilic adhesion (not repulsion); Dscam4 acts in the same pathway as Dscam2 to regulate L4 targeting through heterotypic interactions, demonstrating that different Dscam proteins can act through distinct (adhesive vs. repulsive) mechanisms in closely related neurons. Live imaging, genetic mosaic analysis, genetic screen, double mutant analysis Neuron High 26844831
2018 Mouse DSCAM promotes self-avoidance by masking the adhesive functions of cadherin superfamily members; in vivo and in vitro evidence shows that DSCAM opposes cadherin-mediated adhesion, acting as a generalized modulator of cell adhesion rather than through isoform diversity. In vivo genetic analysis, in vitro adhesion assay, double mutant analysis with cadherins Proceedings of the National Academy of Sciences of the United States of America Medium 30297418
2019 The DSCAM intracellular domain (ICD) is released by γ-secretase-dependent cleavage and translocates to the nucleus via direct interaction with IPO5 (importin beta family) through a conserved nuclear localization signal. Nuclear DSCAM ICD alters expression of genes associated with neuronal differentiation, apoptosis, and synapse formation, and increased DSCAM ICD levels decrease synapse numbers in hippocampal neurons. High-throughput ORFeome screen, co-immunoprecipitation (ICD–IPO5), gamma-secretase inhibition, RNA sequencing, gain-of-function in primary neurons The EMBO journal High 30745319
2019 Neuronal sphingolipids (produced by SPT enzyme) are required for correct axonal sorting of Drosophila Dscam; reduced sphingolipids cause aggregation of axonal and dendritic Dscam isoforms, impairing precise Dscam localization and axon branch segregation. Forward genetic screen, loss- and gain-of-function analysis of SPT, Dscam localization imaging Nature communications Medium 30778062
2020 DSCAM controls neuronal delamination in the developing mouse midbrain by locally suppressing the RapGEF2–Rap1–N-cadherin cascade at apical endfeet; DSCAM associates with RapGEF2 to inactivate Rap1, reducing N-cadherin membrane localization and allowing endfeet detachment from the ventricular surface. Cre-loxP neuronal labeling, shRNA knockdown, co-immunoprecipitation (DSCAM–RapGEF2), epistasis with RapGEF2 and N-cadherin co-knockdown, N-cadherin localization imaging Science advances High 32917586
2021 The DSCAM extracellular domain interacts with neuroligin-1 (NLGN1) and blocks the NLGN1–neurexin1β interaction; DSCAM deficiency causes premature dendritic spine maturation, increased glutamatergic transmission, and autism-like behaviors. Expression of the DSCAM extracellular domain rescues spine overmaturation in DSCAM knockdown neurons. Co-immunoprecipitation (DSCAM–NLGN1), rescue with extracellular domain, spine morphology analysis, electrophysiology, behavioral assays The Journal of neuroscience High 34848499
2021 Suppression of the DSCAM/PAK1 pathway (which is hyperactivated in trisomy 21) by CRISPR/Cas9, CRISPRi, or small-molecule inhibitors reverses deficient neurogenesis in Down syndrome iPSC-derived cerebral organoids, directly linking DSCAM overexpression to PAK1-dependent neurogenesis defects. iPSC-derived cerebral organoids, scRNA-Seq, CRISPR/Cas9 and CRISPRi pathway suppression, small-molecule PAK1 inhibition The Journal of clinical investigation High 33945512
2021 DSCAM co-localizes with NMDA receptor components in dendritic spines; DSCAM mutation in an ASD patient reduces NMDA receptor-mediated currents, and restoring wild-type DSCAM rescues normal NMDA-R currents while truncated DSCAM expression reduces them. DSCAM knockdown downregulates NMDA-R subunit expression via reduced phospho-ERK1/2. iPSC-derived neurons from ASD patient, rescue with WT DSCAM, electrophysiology, RNA-Seq, co-localization imaging, shRNA knockdown Molecular psychiatry High 34253863

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 808 10892653
2008 Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina. Nature 309 18216854
2007 Dendrite self-avoidance is controlled by Dscam. Cell 289 17482551
2008 Neurite arborization and mosaic spacing in the mouse retina require DSCAM. Nature 224 18216855
1998 DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system. Human molecular genetics 223 9426258
2007 Drosophila sensory neurons require Dscam for dendritic self-avoidance and proper dendritic field organization. Neuron 219 17481394
2007 Homophilic Dscam interactions control complex dendrite morphogenesis. Neuron 215 17481395
2008 DSCAM is a netrin receptor that collaborates with DCC in mediating turning responses to netrin-1. Cell 212 18585357
2004 Stochastic yet biased expression of multiple Dscam splice variants by individual cells. Nature genetics 201 14758360
2009 DSCAM and DSCAML1 function in self-avoidance in multiple cell types in the developing mouse retina. Neuron 196 19945391
2016 The lncRNA landscape of breast cancer reveals a role for DSCAM-AS1 in breast cancer progression. Nature communications 192 27666543
2004 Analysis of Dscam diversity in regulating axon guidance in Drosophila mushroom bodies. Neuron 181 15339649
2007 Dscam diversity is essential for neuronal wiring and self-recognition. Nature 174 17851526
2003 Axonal targeting of olfactory receptor neurons in Drosophila is controlled by Dscam. Neuron 173 12546818
2002 Drosophila Dscam is required for divergent segregation of sister branches and suppresses ectopic bifurcation of axons. Neuron 172 11856530
2008 Dscam-mediated cell recognition regulates neural circuit formation. Annual review of cell and developmental biology 160 18837673
2006 The molecular diversity of Dscam is functionally required for neuronal wiring specificity in Drosophila. Cell 153 16678102
2004 Transmembrane/juxtamembrane domain-dependent Dscam distribution and function during mushroom body neuronal morphogenesis. Neuron 143 15339648
2009 DSCAM functions as a netrin receptor in commissural axon pathfinding. Proceedings of the National Academy of Sciences of the United States of America 137 19196994
2009 Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes. Genes & development 136 19171779
2006 Dendritic patterning by Dscam and synaptic partner matching in the Drosophila antennal lobe. Nature neuroscience 133 16474389
2020 LncRNA DSCAM-AS1 interacts with YBX1 to promote cancer progression by forming a positive feedback loop that activates FOXA1 transcription network. Theranostics 128 32929382
2007 Structural basis of Dscam isoform specificity. Nature 128 17721508
2008 The Dscam homologue of the crustacean Daphnia is diversified by alternative splicing like in insects. Molecular biology and evolution 110 18403399
2021 DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome. The Journal of clinical investigation 106 33945512
2008 Dscam guides embryonic axons by Netrin-dependent and -independent functions. Development (Cambridge, England) 104 18948420
2011 Bacteria-Induced Dscam Isoforms of the Crustacean, Pacifastacus leniusculus. PLoS pathogens 85 21695245
2007 A regulator of Dscam mutually exclusive splicing fidelity. Nature structural & molecular biology 85 21188797
2011 Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects. PLoS genetics 76 22072978
2001 Alternative splicing of the Drosophila Dscam pre-mRNA is both temporally and spatially regulated. Genetics 74 11606537
2010 NMDA-mediated regulation of DSCAM dendritic local translation is lost in a mouse model of Down's syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 20926679
2004 The organization and evolution of the dipteran and hymenopteran Down syndrome cell adhesion molecule (Dscam) genes. RNA (New York, N.Y.) 72 15383675
2009 The putative invertebrate adaptive immune protein Litopenaeus vannamei Dscam (LvDscam) is the first reported Dscam to lack a transmembrane domain and cytoplasmic tail. Developmental and comparative immunology 68 19635499
2018 DSCAM-AS1 promotes tumor growth of breast cancer by reducing miR-204-5p and up-regulating RRM2. Molecular carcinogenesis 67 30457164
2012 Down syndrome cell adhesion molecule (DSCAM) associates with uncoordinated-5C (UNC5C) in netrin-1-mediated growth cone collapse. The Journal of biological chemistry 65 22685302
2010 Drosophila dscam proteins regulate postsynaptic specificity at multiple-contact synapses. Neuron 65 20826308
2014 Dscam and pancrustacean immune memory - a review of the evidence. Developmental and comparative immunology 64 24657209
2000 Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion. Brain research. Molecular brain research 64 10925149
2018 Pathogen-Specific Binding Soluble Down Syndrome Cell Adhesion Molecule (Dscam) Regulates Phagocytosis via Membrane-Bound Dscam in Crab. Frontiers in immunology 61 29720978
2018 LncRNA DSCAM-AS1 acts as a sponge of miR-137 to enhance Tamoxifen resistance in breast cancer. Journal of cellular physiology 61 30203615
2001 Cloning and functional characterization of DSCAML1, a novel DSCAM-like cell adhesion molecule that mediates homophilic intercellular adhesion. Biochemical and biophysical research communications 61 11453658
2001 The sorting nexin, DSH3PX1, connects the axonal guidance receptor, Dscam, to the actin cytoskeleton. The Journal of biological chemistry 60 11546816
2012 DSCAM contributes to dendrite arborization and spine formation in the developing cerebral cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 23175819
2013 Ultra-deep profiling of alternatively spliced Drosophila Dscam isoforms by circularization-assisted multi-segment sequencing. The EMBO journal 56 23792425
2006 Got diversity? Wiring the fly brain with Dscam. Trends in biochemical sciences 56 16919957
2014 Review of Dscam-mediated immunity in shrimp and other arthropods. Developmental and comparative immunology 55 24727482
2009 Endodomain diversity in the Drosophila Dscam and its roles in neuronal morphogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 19211897
2010 Competing RNA secondary structures are required for mutually exclusive splicing of the Dscam exon 6 cluster. RNA (New York, N.Y.) 51 21159795
2008 Dscam-mediated repulsion controls tiling and self-avoidance. Current opinion in neurobiology 50 18538559
2011 Penaeus monodon Dscam (PmDscam) has a highly diverse cytoplasmic tail and is the first membrane-bound shrimp Dscam to be reported. Fish & shellfish immunology 49 21338689
2019 Nuclear import of the DSCAM-cytoplasmic domain drives signaling capable of inhibiting synapse formation. The EMBO journal 48 30745319
2017 DSCAM promotes axon fasciculation and growth in the developing optic pathway. Proceedings of the National Academy of Sciences of the United States of America 48 28137836
2013 Immunoglobulin superfamily protein Dscam exhibited molecular diversity by alternative splicing in hemocytes of crustacean, Eriocheir sinensis. Fish & shellfish immunology 46 23856639
2011 Alternative splicing of the Anopheles gambiae Dscam gene in diverse Plasmodium falciparum infections. Malaria journal 46 21651790
2012 The evolution of Dscam genes across the arthropods. BMC evolutionary biology 44 22500922
2001 DSCAM, a highly conserved gene in mammals, expressed in differentiating mouse brain. Biochemical and biophysical research communications 44 11237714
2020 Long non-coding RNA DSCAM-AS1 contributes to the tumorigenesis of cervical cancer by targeting miR-877-5p/ATXN7L3 axis. Bioscience reports 43 31737900
2016 Dscam Proteins Direct Dendritic Targeting through Adhesion. Neuron 43 26844831
2015 DSCAM promotes refinement in the mouse retina through cell death and restriction of exploring dendrites. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 25855178
2004 The Down syndrome cell adhesion molecule (DSCAM) interacts with and activates Pak. The Journal of biological chemistry 42 15169762
2013 Properties of Litopenaeus vannamei Dscam (LvDscam) isoforms related to specific pathogen recognition. Fish & shellfish immunology 41 23932986
2011 Cell autonomy of DSCAM function in retinal development. Developmental biology 41 22063212
2006 Tracking the evolution of alternatively spliced exons within the Dscam family. BMC evolutionary biology 41 16483367
2019 Dscam in immunity: A question of diversity in insects and crustaceans. Developmental and comparative immunology 40 31734281
2018 DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members. Proceedings of the National Academy of Sciences of the United States of America 40 30297418
2012 Genetic analysis of DSCAM's role as a Netrin-1 receptor in vertebrates. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 22238077
2019 Alternatively spliced down syndrome cell adhesion molecule (Dscam) controls innate immunity in crab. The Journal of biological chemistry 39 31537644
2012 Shrimp Dscam and its cytoplasmic tail splicing activator serine/arginine (SR)-rich protein B52 were both induced after white spot syndrome virus challenge. Fish & shellfish immunology 39 23123640
2007 Specific Drosophila Dscam juxtamembrane variants control dendritic elaboration and axonal arborization. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 17581959
2009 DSCAM deficiency causes loss of pre-inspiratory neuron synchroneity and perinatal death. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 19261893
2007 Molecular diversity of Dscam: recognition of molecular identity in neuronal wiring. Nature reviews. Neuroscience 36 18026165
2020 Up-Regulation of FSTL3, Regulated by lncRNA DSCAM-AS1/miR-122-5p Axis, Promotes Proliferation and Migration of Non-Small Cell Lung Cancer Cells. OncoTargets and therapy 35 32280246
2012 Neuronal clustering and fasciculation phenotype in Dscam- and Bax-deficient mouse retinas. The Journal of comparative neurology 35 22396220
2009 Massive expansions of Dscam splicing diversity via staggered homologous recombination during arthropod evolution. RNA (New York, N.Y.) 35 19934230
2012 An RNA architectural locus control region involved in Dscam mutually exclusive splicing. Nature communications 34 23212384
2015 Linking cell surface receptors to microtubules: tubulin folding cofactor D mediates Dscam functions during neuronal morphogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 25653356
2021 DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 34848499
2016 A large family of Dscam genes with tandemly arrayed 5' cassettes in Chelicerata. Nature communications 28 27080167
2015 Dysregulated Dscam levels act through Abelson tyrosine kinase to enlarge presynaptic arbors. eLife 28 25988807
2014 DSCAM and DSCAML1 regulate the radial migration and callosal projection in developing cerebral cortex. Brain research 28 25451118
2020 DSCAM-AS1-Driven Proliferation of Breast Cancer Cells Involves Regulation of Alternative Exon Splicing and 3'-End Usage. Cancers 27 32503257
2019 Long noncoding RNA DSCAM-AS1 functions as an oncogene in non-small cell lung cancer by targeting BCL11A. European review for medical and pharmacological sciences 27 30779076
2019 Long non-coding RNA DSCAM-AS1 accelerates the progression of hepatocellular carcinoma via sponging miR-338-3p. American journal of translational research 27 31396335
2012 A novel mouse Dscam mutation inhibits localization and shedding of DSCAM. PloS one 27 23300735
2020 DSCAM regulates delamination of neurons in the developing midbrain. Science advances 26 32917586
2014 WSSV-induced crayfish Dscam shows durable immune behavior. Fish & shellfish immunology 26 24973514
2011 Dscam mutation leads to hydrocephalus and decreased motor function. Protein & cell 25 21904980
2017 DSCAM-mediated control of dendritic and axonal arbor outgrowth enforces tiling and inhibits synaptic plasticity. Proceedings of the National Academy of Sciences of the United States of America 24 29114051
2014 DSCAM localization and function at the mouse cone synapse. The Journal of comparative neurology 24 24477985
2001 Dscam is associated with axonal and dendritic features of neuronal cells. Journal of neuroscience research 24 11746351
2020 LncRNA DSCAM-AS1 promotes colorectal cancer progression by acting as a molecular sponge of miR-384 to modulate AKT3 expression. Aging 23 32453706
2018 DSCAM differentially modulates pre- and postsynaptic structural and functional central connectivity during visual system wiring. Neural development 23 30219101
2016 Overexpressed Down Syndrome Cell Adhesion Molecule (DSCAM) Deregulates P21-Activated Kinase (PAK) Activity in an In Vitro Neuronal Model of Down Syndrome: Consequences on Cell Process Formation and Extension. Neurotoxicity research 23 26966010
2021 Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice. Molecular psychiatry 22 34253863
2020 Long non-coding RNA DSCAM-AS1 upregulates USP47 expression through sponging miR-101-3p to accelerate osteosarcoma progression. Biochemistry and cell biology = Biochimie et biologie cellulaire 22 32379981
2020 Long Noncoding RNA DSCAM-AS1 Facilitates Colorectal Cancer Cell Proliferation and Migration via miR-137/Notch1 Axis. Journal of Cancer 21 33046983
2014 Roles for DSCAM and DSCAML1 in central nervous system development and disease. Advances in neurobiology 21 25300140
2021 A Review on the Carcinogenic Roles of DSCAM-AS1. Frontiers in cell and developmental biology 20 34708048
2019 Sphingolipid-dependent Dscam sorting regulates axon segregation. Nature communications 20 30778062
2013 Chromosome 21 scan in Down syndrome reveals DSCAM as a predisposing locus in Hirschsprung disease. PloS one 20 23671607

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