DNER (delta and Notch-like epidermal growth factor-related receptor) is a neuron-enriched type-I single-pass transmembrane glycoprotein with ten extracellular EGF-like repeats and cytoplasmic sorting motifs. It is concentrated in the somatodendritic plasma membrane and endosomal system, where AP-1/AP-2-linked and clathrin-independent endocytic pathways regulate its polarized surface distribution. DNER phosphorylation and surface residence are modulated by pleiotrophin-PTPRZ signaling and can influence neurite morphogenesis. Mouse loss-of-function studies establish roles in Bergmann-glial radial-fiber differentiation, cerebellar morphogenesis, synaptic refinement, and motor coordination. DNER was originally reported to bind NOTCH1 and activate a gamma-secretase- and Deltex-dependent, RBP-J-independent response at Purkinje-cell/Bergmann-glia contacts, but a later direct replication study found that DNER neither bound nor activated NOTCH1. Consequently, the developmental phenotype is well supported whereas direct Notch ligand activity remains unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005112 Notch binding | IBA GO_REF:0000033 | UNDECIDED | Summary: Phylogenetic inference assigns Notch binding, and the original mouse cerebellar study reported DNER binding to Notch1. However, a later full-text replication study found that DNER did not bind Notch1-Fc and did not activate NOTCH1 in either cis or trans assays. Reason: Direct primary studies conflict. PMID:15965470 supports binding and noncanonical signaling, whereas PMID:27622512 failed to reproduce binding or activation with DLL1 as a positive control. The IBA should not be treated as a settled core molecular function until the discrepancy is resolved. Propagation Review Root cause: UNRESOLVED Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002371879 · PANTHER Notch-binding inference node UNRESOLVED The target-level primary evidence conflicts, so the phylogenetic Notch-binding inference cannot be classified as a safe transfer without resolving the donor activities and the DNER-specific experimental discrepancy. Supporting Evidence: PMID:15965470 DNER binds to Notch1 at cell-cell contacts and activates Notch signaling in vitro. PMID:27622512 The established Notch ligand Delta-like 1 (DLL1), but not DNER, activated Notch1 in a luciferase assay, prevented the differentiation of myoblasts through Notch signaling, and bound Notch-fc in a cell-based assay. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro mapping derives from calcium-binding EGF-like domains (IPR001881 and IPR018097), which are present repeatedly in DNER's extracellular region. Reason: Calcium coordination is a plausible structural property of the EGF-like repeats, but it does not define DNER's unresolved intercellular activity. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping places this type-I membrane protein at the plasma membrane, concordant with direct dendritic localization and surface-expression experiments. Reason: Plasma-membrane localization is directly supported by the discovery study and is central to DNER's somatodendritic distribution. Supporting Evidence: PMID:11950833 DNER protein is localized to the dendritic plasma membrane and endosomes and is excluded from the axons, even when overexpressed. |
| GO:0007399 nervous system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The ARBA inference is broad, but mouse Dner loss-of-function causes delayed cerebellar morphogenesis, abnormal fissure organization, and defects in Bergmann-glial maturation and cerebellar physiology. Reason: Retain as a broad developmental umbrella supported by ortholog phenotypes, while preferring the more precise Bergmann-glial and cerebellar processes in synthesis. Supporting Evidence: PMID:16298139 The cerebellum from the knockout mice showed significant retardation in morphogenesis and persistent abnormality in fissure organization. |
| GO:0030425 dendrite | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA-predicted dendritic location is independently supported by direct localization of DNER to dendritic plasma membrane and endosomes. Reason: Dendritic localization is a reproducible defining feature of neuronal DNER and is independently represented by an IDA annotation. Supporting Evidence: PMID:11950833 DNER protein is localized to the dendritic plasma membrane and endosomes and is excluded from the axons, even when overexpressed. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The human binary-interactome screen reports an interaction with PDLIM7 (Q9NR12), also recorded by IntAct/UniProt, but does not establish a specific molecular activity or biological consequence for DNER. Reason: Generic protein binding is uninformative, and no more specific interaction class or functional consequence can be assigned from this high-throughput pair alone. |
| GO:0005509 calcium ion binding | NAS PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | KEEP AS NON CORE | Summary: The sequence contains ten extracellular EGF-like repeats, including predicted calcium-binding EGF-like domains, but the abstract does not report a biochemical calcium-binding assay. Reason: Plausible domain-level structural activity, retained as non-core rather than a defining signaling function. Supporting Evidence: PMID:11950833 Sequence analysis revealed that the 10 EGF-like repeats in the extracellular domain are closely related to those of the developmentally important receptor Notch and its ligand Delta. |
| GO:0006897 endocytosis | NAS PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | MARK AS OVER ANNOTATED | Summary: DNER undergoes endocytic trafficking, and later work shows its own polarized targeting and surface abundance depend on clathrin-dependent and -independent endocytosis. Reason: The experiments establish DNER as endocytic cargo, not as a general causal regulator or machinery component of the endocytosis process. Supporting Evidence: PMID:20367751 Our data suggest that clathrin-independent endocytosis is critical for the polarized targeting of somatodendritic proteins. |
| GO:0001764 neuron migration | NAS PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | MARK AS OVER ANNOTATED | Summary: The cited discovery study establishes neuronal expression and somatodendritic targeting but does not demonstrate a causal role in neuron migration. Mouse cerebellar phenotypes could indirectly affect migration through the Bergmann-glial scaffold, but this broad claim has not been isolated experimentally. Reason: A possible indirect developmental consequence should not be represented as a direct DNER role in neuron migration without cell-type-specific evidence. |
| GO:0004888 transmembrane signaling receptor activity | TAS PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | REMOVE | Summary: DNER was named a receptor based on its topology and EGF-repeat similarity, but the discovery study does not identify an extracellular ligand or demonstrate ligand-triggered receptor signal transduction. Subsequent studies mainly treat DNER as trafficking cargo or a proposed ligand. Reason: No direct receptor activity has been established. Membrane topology and a regulated cytoplasmic tail are insufficient to assign transmembrane signaling receptor activity. |
| GO:0005515 protein binding | IPI PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | MODIFY | Summary: The annotation's with/from protein is AP1G1 (P22892), and the paper reports direct in-vivo binding of DNER to the AP-1 coat-adaptor complex. Reason: Replace uninformative protein binding with the experimentally appropriate and more specific AP-1 adaptor complex binding term. Proposed replacements: AP-1 adaptor complex binding Supporting Evidence: PMID:11950833 Direct in vivo binding of DNER to the coat-associated protein complex AP-1 strongly suggests that DNER undergoes AP-1-dependent sorting to the somatodendritic compartments from the trans-Golgi network and subsequent passage through the endosomal system. |
| GO:0005769 early endosome | IDA PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | UNDECIDED | Summary: The accessible abstract directly reports DNER in dendritic endosomes but does not identify those compartments as early endosomes. Reason: The cited paper is abstract-only in the local cache, so the specificity of the experimental early-endosome assignment cannot be verified. General endosomal localization is supported. Supporting Evidence: PMID:11950833 DNER protein is localized to the dendritic plasma membrane and endosomes and is excluded from the axons, even when overexpressed. |
| GO:0005886 plasma membrane | IDA PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | ACCEPT | Summary: Direct localization placed DNER at the dendritic plasma membrane, with later studies showing that phosphorylation and endocytosis regulate its surface abundance. Reason: The experimental location is explicit in the accessible source and biologically central to DNER trafficking. Supporting Evidence: PMID:11950833 DNER protein is localized to the dendritic plasma membrane and endosomes and is excluded from the axons, even when overexpressed. |
| GO:0007416 synapse assembly | NAS PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | MARK AS OVER ANNOTATED | Summary: The cited discovery study reports expression and dendritic trafficking rather than synapse-assembly experiments. Dner-null mice show persistent multiple climbing-fiber innervation and impaired Bergmann-glial physiology, which concern synaptic refinement and support rather than direct synapse assembly. Reason: Available evidence is compatible with indirect effects on synaptic maturation but does not demonstrate that DNER directly executes synapse assembly. Supporting Evidence: PMID:16298139 Histochemical and electrophysiological analyses detected that PCs retained multiple innervations from climbing fibers (CFs) in the mutant cerebellum. |
| GO:0007417 central nervous system development | IEP PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | KEEP AS NON CORE | Summary: The original evidence is expression in developing and mature CNS neurons. Later mouse knockout experiments establish a cerebellar developmental phenotype. Reason: Retain the broad developmental context, but the IEP evidence alone is not causal and more precise cerebellar/Bergmann-glial processes are preferred. Supporting Evidence: PMID:16298139 Our results indicate that DNER takes part in stimulation of BG maturation via intercellular communication and is essential for precise cerebellar development. |
| GO:0030276 clathrin binding | TAS PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | MODIFY | Summary: The paper reports binding to the coat-associated AP-1 adaptor complex, not direct clathrin binding. Later work similarly reports AP-2 adaptor-complex binding. Reason: Replace clathrin binding with AP-1 adaptor complex binding to represent the demonstrated physical target precisely. Proposed replacements: AP-1 adaptor complex binding Supporting Evidence: PMID:11950833 Direct in vivo binding of DNER to the coat-associated protein complex AP-1 strongly suggests that DNER undergoes AP-1-dependent sorting to the somatodendritic compartments from the trans-Golgi network and subsequent passage through the endosomal system. |
| GO:0030425 dendrite | IDA PMID:11950833 Delta/notch-like epidermal growth factor (EGF)-related recep... | ACCEPT | Summary: DNER was directly localized to dendritic plasma membrane and endosomes and excluded from axons; its cytoplasmic sorting motifs are required for this polarized targeting. Reason: Direct and mechanistically supported localization that defines neuronal DNER. Supporting Evidence: PMID:11950833 The tyrosine-based sorting motif in the cytoplasmic domain is required for dendritic targeting of DNER. |
| GO:0035612 AP-2 adaptor complex binding | ISO PMID:20367751 Polarized targeting of DNER into dendritic plasma membrane i... | NEW | Summary: A rat hippocampal-neuron study showed that the DNER cytoplasmic domain binds AP-2 through a proximal tyrosine motif and an additional mid-domain segment. Reason: Proposed for human DNER by orthology because the primary study identifies a precise, motif-dependent adaptor-complex interaction relevant to DNER surface trafficking. Supporting Evidence: PMID:20367751 The DNER cytoplasmic domain binds to a clathrin adaptor protein complex-2 via a proximal tyrosine motif and a 40 amino acid stretch in the mid-domain, but not by the C-terminal tail. |
| GO:0060020 Bergmann glial cell differentiation | ISO PMID:15965470 DNER acts as a neuron-specific Notch ligand during Bergmann ... | NEW | Summary: Mouse Dner deficiency retards Bergmann radial-fiber formation and disrupts Bergmann-glial arrangement; an independent knockout study also finds reduced Bergmann-glial GLAST and impaired cerebellar maturation. Reason: Proposed for human DNER by orthology from direct mouse loss-of-function evidence. The developmental phenotype is retained without asserting a canonical Notch-ligand mechanism, which is disputed by PMID:27622512. Supporting Evidence: PMID:15965470 Additionally, deficiency of DNER retards the formation of radial fibers and results in abnormal arrangement of Bergmann glia. PMID:16298139 Our results indicate that DNER takes part in stimulation of BG maturation via intercellular communication and is essential for precise cerebellar development. |
| GO:0061938 protein localization to somatodendritic compartment | ISO PMID:20367751 Polarized targeting of DNER into dendritic plasma membrane i... | NEW | Summary: DNER cytoplasmic motifs and endocytosis are required for its polarized targeting to the somatodendritic membrane in cultured rat hippocampal neurons. Reason: Proposed for human DNER by orthology because motif mutation and endocytosis perturbation directly alter DNER somatodendritic localization. Supporting Evidence: PMID:20367751 Furthermore, inhibition of endocytosis resulted in disruption of the somatodendritic localization of DNER, indicating that the somatodendritic targeting of DNER is dependent on endocytosis. |
| GO:0010975 regulation of neuron projection development | ISO PMID:18474614 Receptor type protein tyrosine phosphatase zeta-pleiotrophin... | NEW | Summary: DNER surface accumulation and endocytosis alter neurite extension in mouse Purkinje cells and Neuro-2A cells downstream of pleiotrophin-PTPRZ signaling. Reason: Proposed for human DNER by orthology using the conservative regulation term because DNER trafficking can either inhibit or permit neurite outgrowth depending on its phosphorylation and surface residence. Supporting Evidence: PMID:18474614 These observations suggest that pleiotrophin-PTPzeta signaling controls subcellular localization of DNER and thereby regulates neuritogenesis. |
| GO:0021590 cerebellum maturation | ISO PMID:16298139 Impaired cerebellar functions in mutant mice lacking DNER. | NEW | Summary: Dner-null mice exhibit delayed cerebellar morphogenesis, abnormal fissure organization, impaired Bergmann-glial physiology, persistent multiple climbing-fiber innervation, and motor discoordination. Reason: Proposed for human DNER by orthology from direct knockout evidence. This captures the established organ-level phenotype without encoding the disputed NOTCH1 mechanism. Supporting Evidence: PMID:16298139 By producing and analyzing knockout mice lacking DNER, we demonstrate its essential roles in functional and morphological maturation of the cerebellum. |
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Download this section (compressed HTML)Q: Does endogenous DNER directly bind and activate NOTCH1 at Purkinje-cell/Bergmann-glia contacts, and what experimental conditions explain the conflicting 2005 and 2016 results?
Suggested experts: Eiraku M, Kengaku M, Lancaster E
Q: Which extracellular counter-receptor or ligand mediates the Dner-dependent Bergmann-glial phenotype if NOTCH1 is not the direct binding partner?
Suggested experts: Kengaku M, Takeshima H
Q: Is AP-1/AP-2-dependent DNER trafficking itself required for Bergmann-glial differentiation, or does it primarily regulate an independent neuronal morphogenesis function?
Suggested experts: Kengaku M, Maeda N
Experiment: Use extracellular proximity labeling and crosslinking proteomics at human iPSC-derived Purkinje-cell/Bergmann-glia contacts, followed by CRISPR knockout and rescue of candidate receptors; assay radial-process morphogenesis and compare NOTCH1/DTX/RBPJ reporters.
Hypothesis: Endogenous DNER has a cell-contact-dependent counter-receptor distinct from canonical Notch ligands.
Type: proximity labeling, receptor identification, and functional rescue
Experiment: Rescue DNER-null Purkinje cells with wild-type DNER, AP-1/AP-2-binding-motif mutants, and phosphosite mutants; quantify surface residence, endocytosis, Bergmann-glial radial fibers, and synaptic refinement in cerebellar organoids or organotypic slices.
Hypothesis: DNER's cytoplasmic sorting motifs couple its surface residence to the cerebellar developmental phenotype.
Type: structure-function rescue and live-cell trafficking assay
Experiment: Compare endogenous DNER loss and rescue using orthogonal NOTCH1 cleavage, CSL/RBP-J, Deltex-dependent, and gamma-secretase-sensitive reporters in matched Purkinje/Bergmann co-cultures, with DLL1 and receptor-null controls.
Hypothesis: DNER does not activate canonical RBP-J-dependent Notch signaling but may regulate a Deltex-dependent response.
Type: pathway-dissection reporter assay
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