dla (deltaA) encodes Delta-like protein A, one of four zebrafish Delta-class DSL ligands (with dlb, dlc and dld) and, with dld, a co-ortholog of mammalian DLL1. It is a single-pass type I membrane protein with an N-terminal MNNL domain, a DSL domain and eight EGF-like repeats that engage Notch receptors on adjacent cells. Dla protein localises in puncta at the cell membrane/cortex of neural precursors, and its signalling activity depends on ubiquitination and endocytosis driven by the E3 ligase Mind bomb (Mib1), which binds Dla. Dla-Notch signalling mediates lateral inhibition in primary neurogenesis (limiting Rohon-Beard neurons and promoting trunk neural crest), in inner ear hair-cell versus support-cell decisions, in dopaminergic and V2 interneuron neurogenesis, in hindbrain rhombomere boundary maintenance, and in the specification of midline floorplate, notochord and hypochord from common progenitors. The dx2 missense allele acts as a dominant-negative ligand.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005112 Notch binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER:PTN002371879 (Delta/DSL ligand node). Reason: Defining molecular function of Delta ligands; Dla genetically activates Notch1a, Notch1b and Notch3-dependent processes, and the dominant-negative dx2 allele interferes with receptor activation. Supporting Evidence: PMID:24768892 Two ligands, DeltaA and DeltaD, and three receptors, Notch1a, Notch1b, and Notch3 redundantly contribute to p2 progenitor maintenance. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro calcium-binding EGF repeats. Reason: Structural property of EGF repeats, not the signalling function. |
| GO:0005515 protein binding | IPI PMID:15013799 Three modules of zebrafish Mind bomb work cooperatively to p... | MODIFY | Summary: IPI with Mind bomb (Chen and Casey Corliss 2004). Reason: The interaction is the binding of Dla by the E3 ubiquitin ligase Mib, which ubiquitinates Dla and drives its endocytosis; ubiquitin protein ligase binding is the informative term. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:15013799 Mind bomb protein displays E3 ubiquitin ligase activity in vitro and that it is associated with Delta and enhances its ubiquitination and internalization in transfected cells file:DANRE/dla/dla-deep-research-falcon.md Mib1 is a RING-family E3 ubiquitin ligase that promotes DeltaA ubiquitination-dependent internalization; loss of Mib1 causes excessive DeltaA accumulation at the cell surface. |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | TOO GENERAL | Summary: True but broad: entailed by cell cortex, kept in this review. Reason: GO's cytoplasm covers everything inside the plasma membrane except the nucleus, organelles and secretory compartments included, so cell cortex, kept in this review, entails this term and the claim is true. TOO_GENERAL rather than REMOVE. The objection is a reason not to annotate a narrower term such as cytosol, not to remove this one. Objection recorded at removal: Dla immunolocalisation found punctate membrane/cortical staining and explicitly did not support broad cytoplasmic localisation; cytoplasm is not an appropriate location for this transmembrane ligand. Summary at removal: ARBA cytoplasm prediction. Supporting Evidence: PMID:19924821 widespread Dla localization in the cytoplasm is not supported by our data |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER:PTN001170801. Reason: Supported directly by Dla immunolocalisation (IDA, PMID:19924821). |
| GO:0005886 plasma membrane | IDA PMID:19924821 DeltaA mRNA and protein distribution in the zebrafish nervou... | ACCEPT | Summary: Dla antibody staining shows puncta at the membrane/cortex of neural precursors. Reason: Direct zebrafish evidence; consistent with juxtacrine signalling. Supporting Evidence: PMID:19924821 Both experiments suggest that in the embryonic spinal cord, Dla protein is localized to puncta at the cell membrane and/or cortex |
| GO:0005886 plasma membrane | IEA GO_REF:0000117 | ACCEPT | Summary: IEA plasma membrane (ARBA). Reason: Consistent with direct immunolocalisation. |
| GO:0005938 cell cortex | IDA PMID:19924821 DeltaA mRNA and protein distribution in the zebrafish nervou... | ACCEPT | Summary: Dla puncta at the cell cortex (Tallafuss et al. 2010). Reason: Direct observation; cortical puncta likely reflect membrane microdomains and endocytic intermediates of the ligand. Supporting Evidence: PMID:19924821 These Dla accumulations were typically localized to one region of the cell cortex and/or membrane |
| GO:0007154 cell communication | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro cell communication. Reason: Correct but general. |
| GO:0007219 Notch signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Notch signaling pathway (IBA PTN001170801 / InterPro). Reason: Dla is a Notch ligand; core process. |
| GO:0007219 Notch signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Notch signaling pathway (IBA PTN001170801 / InterPro). Reason: Dla is a Notch ligand; core process. |
| GO:0007389 pattern specification process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA pattern specification process. Reason: Dla contributes to midline and hindbrain patterning; general term. |
| GO:0008593 regulation of Notch signaling pathway | IGI PMID:24681783 Basal body proteins regulate Notch signaling through endosom... | KEEP AS NON CORE | Summary: Leitch et al. 2014 (BBS basal body proteins and Notch trafficking) used dla perturbation in zebrafish Notch reporter experiments. Reason: As a Notch ligand, Dla is a component of the pathway, not a modulator; the "regulation of" term is acceptable as a curator's reading of the reporter phenotype but the full text is not cached, so the curator's annotation is retained as non-core. |
| GO:0008593 regulation of Notch signaling pathway | IMP PMID:24681783 Basal body proteins regulate Notch signaling through endosom... | KEEP AS NON CORE | Summary: Leitch et al. 2014 (BBS basal body proteins and Notch trafficking) used dla perturbation in zebrafish Notch reporter experiments. Reason: As a Notch ligand, Dla is a component of the pathway, not a modulator; the "regulation of" term is acceptable as a curator's reading of the reporter phenotype but the full text is not cached, so the curator's annotation is retained as non-core. |
| GO:0009880 embryonic pattern specification | IMP PMID:15366005 Rhombomere boundaries are Wnt signaling centers that regulat... | KEEP AS NON CORE | Summary: dlA mutants disrupt hindbrain metameric patterning (Riley et al. 2004). Reason: Developmental context of Dla ligand function. Supporting Evidence: PMID:15366005 Mutations in dlA or mind bomb (mib) disrupt Delta-Notch signaling and cause a wide range of patterning defects in the hindbrain. |
| GO:0014032 neural crest cell development | IMP PMID:10851132 Delta signaling mediates segregation of neural crest and spi... | KEEP AS NON CORE | Summary: deltaA mutants lack trunk neural crest derivatives. Reason: Lateral inhibition between Rohon-Beard neurons and neural crest; developmental context. Supporting Evidence: PMID:10851132 have supernumerary Rohon-Beard neurons, reduced trunk-level expression of neural crest markers and lack trunk neural crest derivatives |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Membrane. Reason: Single-pass type I membrane protein. |
| GO:0021514 ventral spinal cord interneuron differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA ventral spinal cord interneuron differentiation. Reason: Supported by zebrafish V2 interneuron studies; developmental context. |
| GO:0021514 ventral spinal cord interneuron differentiation | IGI PMID:24768892 Different combinations of Notch ligands and receptors regula... | KEEP AS NON CORE | Summary: DeltaA contributes to p2 progenitor maintenance and V2a/V2b fate (Okigawa et al. 2014). Reason: Developmental context of Dla ligand activity. Supporting Evidence: PMID:24768892 On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the V2a/V2b cell fate determination. |
| GO:0021514 ventral spinal cord interneuron differentiation | IGI PMID:24768892 Different combinations of Notch ligands and receptors regula... | KEEP AS NON CORE | Summary: DeltaA contributes to p2 progenitor maintenance and V2a/V2b fate (Okigawa et al. 2014). Reason: Developmental context of Dla ligand activity. Supporting Evidence: PMID:24768892 On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the V2a/V2b cell fate determination. |
| GO:0021514 ventral spinal cord interneuron differentiation | IGI PMID:24768892 Different combinations of Notch ligands and receptors regula... | KEEP AS NON CORE | Summary: DeltaA contributes to p2 progenitor maintenance and V2a/V2b fate (Okigawa et al. 2014). Reason: Developmental context of Dla ligand activity. Supporting Evidence: PMID:24768892 On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the V2a/V2b cell fate determination. |
| GO:0021514 ventral spinal cord interneuron differentiation | IGI PMID:24768892 Different combinations of Notch ligands and receptors regula... | KEEP AS NON CORE | Summary: DeltaA contributes to p2 progenitor maintenance and V2a/V2b fate (Okigawa et al. 2014). Reason: Developmental context of Dla ligand activity. Supporting Evidence: PMID:24768892 On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the V2a/V2b cell fate determination. |
| GO:0021514 ventral spinal cord interneuron differentiation | IMP PMID:24768892 Different combinations of Notch ligands and receptors regula... | KEEP AS NON CORE | Summary: DeltaA contributes to p2 progenitor maintenance and V2a/V2b fate (Okigawa et al. 2014). Reason: Developmental context of Dla ligand activity. Supporting Evidence: PMID:24768892 On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the V2a/V2b cell fate determination. |
| GO:0021514 ventral spinal cord interneuron differentiation | IMP PMID:24768892 Different combinations of Notch ligands and receptors regula... | KEEP AS NON CORE | Summary: DeltaA contributes to p2 progenitor maintenance and V2a/V2b fate (Okigawa et al. 2014). Reason: Developmental context of Dla ligand activity. Supporting Evidence: PMID:24768892 On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the V2a/V2b cell fate determination. |
| GO:0021536 diencephalon development | IGI PMID:21148001 DeltaA/DeltaD regulate multiple and temporally distinct phas... | KEEP AS NON CORE | Summary: DeltaA/DeltaD control dopaminergic neurogenesis in the diencephalon. Reason: Developmental context of Dla ligand function. Supporting Evidence: PMID:21148001 In dla hi781 mutants, we detected a remarkable increase in the number of DC2 DA neurons already at early stages |
| GO:0021536 diencephalon development | IGI PMID:21148001 DeltaA/DeltaD regulate multiple and temporally distinct phas... | KEEP AS NON CORE | Summary: DeltaA/DeltaD control dopaminergic neurogenesis in the diencephalon. Reason: Developmental context of Dla ligand function. Supporting Evidence: PMID:21148001 In dla hi781 mutants, we detected a remarkable increase in the number of DC2 DA neurons already at early stages |
| GO:0021536 diencephalon development | IGI PMID:21148001 DeltaA/DeltaD regulate multiple and temporally distinct phas... | KEEP AS NON CORE | Summary: DeltaA/DeltaD control dopaminergic neurogenesis in the diencephalon. Reason: Developmental context of Dla ligand function. Supporting Evidence: PMID:21148001 In dla hi781 mutants, we detected a remarkable increase in the number of DC2 DA neurons already at early stages |
| GO:0021536 diencephalon development | IMP PMID:21148001 DeltaA/DeltaD regulate multiple and temporally distinct phas... | KEEP AS NON CORE | Summary: DeltaA/DeltaD control dopaminergic neurogenesis in the diencephalon. Reason: Developmental context of Dla ligand function. Supporting Evidence: PMID:21148001 In dla hi781 mutants, we detected a remarkable increase in the number of DC2 DA neurons already at early stages |
| GO:0022008 neurogenesis | IMP PMID:10074451 Delta-mediated specification of midline cell fates in zebraf... | KEEP AS NON CORE | Summary: dla mutants have neurogenic phenotypes (excess Rohon-Beard neurons, midline defects). Reason: Lateral inhibition during neurogenesis is a major biological role, but a consequence of ligand activity. |
| GO:0022008 neurogenesis | IMP PMID:10851132 Delta signaling mediates segregation of neural crest and spi... | KEEP AS NON CORE | Summary: dla mutants have neurogenic phenotypes (excess Rohon-Beard neurons, midline defects). Reason: Lateral inhibition during neurogenesis is a major biological role, but a consequence of ligand activity. |
| GO:0030901 midbrain development | IGI PMID:21148001 DeltaA/DeltaD regulate multiple and temporally distinct phas... | KEEP AS NON CORE | Summary: IGI midbrain development (Mahler et al. 2010). Reason: Developmental context of Dla ligand function. |
| GO:0033504 floor plate development | IMP PMID:10074451 Delta-mediated specification of midline cell fates in zebraf... | KEEP AS NON CORE | Summary: dlA dx2 mutants have reduced floorplate cells. Reason: Midline fate specification; developmental context. Supporting Evidence: PMID:10074451 The dlAdx2 mutant embryos had reduced numbers of floorplate and hypochord cells |
| GO:0043009 chordate embryonic development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA chordate embryonic development. Reason: Uninformative high-level term; specific developmental roles are annotated. |
| GO:0045746 negative regulation of Notch signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from PANTHER:PTN001170801, reflecting cis-inhibition by Delta-family ligands. Reason: Cis-inhibition is a well-established property of Delta ligands placed by PAINT at the ancestral node; no zebrafish Dla-specific evidence for or against it was found. Retained as non-core. |
| GO:0048863 stem cell differentiation | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA stem cell differentiation. Reason: Dla is expressed in adult proliferative zones, but there is no direct evidence that it regulates stem cell differentiation. |
| GO:0055016 hypochord development | IMP PMID:10074451 Delta-mediated specification of midline cell fates in zebraf... | KEEP AS NON CORE | Summary: dlA dx2 mutants have reduced hypochord cells. Reason: Midline fate specification; developmental context. Supporting Evidence: PMID:10074451 The dlAdx2 mutant embryos had reduced numbers of floorplate and hypochord cells |
| GO:0060034 notochord cell differentiation | IMP PMID:10074451 Delta-mediated specification of midline cell fates in zebraf... | KEEP AS NON CORE | Summary: dlA dx2 mutants have excess notochord cells. Reason: Midline fate specification; developmental context. Supporting Evidence: PMID:10074451 In addition, mutant embryos had excess notochord cells. |
| GO:0060113 inner ear receptor cell differentiation | IMP PMID:10572043 The deltaA gene of zebrafish mediates lateral inhibition of ... | KEEP AS NON CORE | Summary: deltaA dx2 mutants have excess hair cells in the inner ear. Reason: Lateral inhibition in the inner ear; developmental context. Supporting Evidence: PMID:10572043 homozygous mutants develop with a 5- to 6-fold excess of hair cells and a severe deficiency of support cells |
| GO:0060485 mesenchyme development | IEA GO_REF:0000117 | REMOVE | Summary: ARBA mesenchyme development. Reason: Transferred from mammalian Delta-like biology; in zebrafish, fin mesenchyme is present in deltaA mutants, and no evidence links Dla to mesenchyme development. Supporting Evidence: PMID:10851132 Fin mesenchyme, a putative trunk neural crest derivative, is present in deltaA mutants |
| GO:0048018 receptor ligand activity | IMP PMID:21148001 DeltaA/DeltaD regulate multiple and temporally distinct phas... | NEW | Summary: DeltaA activates Notch receptors on neighbouring cells; dla/dld loss reduces Notch activity in dopaminergic precursor specification. Reason: NEW, complementing Notch binding (GO:0005112): the ligand does the activating work, which is what receptor ligand activity asserts and what the perturbation evidence shows (DeltaA/DeltaD control Notch activity). Comparator check: Drosophila Dl, human DLL1 and mouse Dll1 carry GO:0048018 for the same role. Not applied to cis-inhibitory, non-activating Delta paralogs such as mammalian DLL3. Supporting Evidence: PMID:21148001 These data reveal that Notch signaling acts upstream of sim1 and otp in ventral diencephalic DA development, and that DeltaA and DeltaD appear to be the ligands controlling Notch activity in this process. |
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Download this section (compressed HTML)Q: Does Dla mediate cis-inhibition of Notch in zebrafish neural precursors, as inferred for the Delta family (IBA negative regulation of Notch signaling)?
Q: Which Notch paralog(s) does Dla preferentially activate in midline and inner-ear contexts, and is Fringe modification involved?
Experiment: Cell-aggregation or co-culture reporter assays with Dla and each zebrafish Notch paralog to measure trans-activation and cis-inhibition directly.
Experiment: Endogenous tagging of Dla to image Mib1-dependent endocytosis in vivo during lateral inhibition.
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