RELN encodes reelin, a large secreted extracellular-matrix glycoprotein that assembles into signaling-competent multimers. Reelin binds the lipoprotein-family receptors VLDLR and LRP8/ApoER2, inducing receptor-associated DAB1 phosphorylation and downstream signaling that coordinates neuronal polarization, positioning, and layer formation during brain development and modulates synaptic maturation and plasticity later in life. Biallelic loss-of-function variants cause lissencephaly with cerebellar hypoplasia in humans. An intrinsic serine peptidase activity has been reported but remains disputed and is not considered an established core activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007417 central nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome central nervous system development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0001764 neuron migration | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome neuron migration. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Reelin is a secreted glycoprotein that functions in the extracellular matrix; the extracellular matrix localization is biologically appropriate. Reason: Human genetics and biochemical studies describe RELN as a large secreted extracellular protein, consistent with this extracellular localization. |
| GO:0043005 neuron projection | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Reelin signaling affects neuronal projections, but neuron projection does not specify the extracellular compartment in which reelin acts. Reason: The transferred localization may reflect secretion near or receptor binding on neuronal processes; it does not establish the projection interior as a primary active site. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: MGI:MGI:103022 · mouse Reln UNRESOLVED Listed as an IBA source in GOA; the local evidence does not establish whether neuron projection denotes extracellular activity adjacent to a projection or localization inside it. PANTHER:PTN002625842 · RELN family phylogenetic node UNRESOLVED Listed as an IBA source; the issue is the cellular-component scope for a secreted ligand, not RELN family identity. RGD:3553 · rat Reln UNRESOLVED Listed as an IBA source in GOA; source-side projection localization was not independently resolved. |
| GO:0070325 lipoprotein particle receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Reelin directly binds ApoER2/LRP8 and VLDLR; this lipoprotein particle receptor binding annotation captures its defining extracellular receptor-binding activity. Reason: Direct binding and receptor-dependent DAB1 phosphorylation are supported by PMID:10571240 and PMID:12670700. |
| GO:0001764 neuron migration | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome neuron migration. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0005886 plasma membrane | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Reelin can contact the cell surface through its receptors but is a soluble secreted ligand rather than a membrane-resident protein. Reason: This IEA localization is logically inferred from a receptor-clustering process and conflates transient receptor association with residence in the plasma membrane. |
| GO:0007417 central nervous system development | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome central nervous system development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0070325 lipoprotein particle receptor binding | IEA GO_REF:0000120 | ACCEPT | Summary: Reelin directly binds ApoER2/LRP8 and VLDLR; this lipoprotein particle receptor binding annotation captures its defining extracellular receptor-binding activity. Reason: Direct binding and receptor-dependent DAB1 phosphorylation are supported by PMID:10571240 and PMID:12670700. |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | ACCEPT | Summary: Reelin is a secreted glycoprotein that functions in the extracellular matrix; the extracellular region localization is biologically appropriate. Reason: Human genetics and biochemical studies describe RELN as a large secreted extracellular protein, consistent with this extracellular localization. |
| GO:0007612 learning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog evidence supports a role for reelin signaling in the organism-level outcome learning. Reason: This behavioral phenotype is a downstream, context-specific consequence of reelin signaling and not a molecular activity of the gene product. |
| GO:0007616 long-term memory | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog evidence supports a role for reelin signaling in the organism-level outcome long-term memory. Reason: This behavioral phenotype is a downstream, context-specific consequence of reelin signaling and not a molecular activity of the gene product. |
| GO:0008236 serine-type peptidase activity | IEA GO_REF:0000107 | UNDECIDED | Summary: Intrinsic serine-type peptidase activity of reelin is unresolved because direct studies reached opposing conclusions. Reason: PMID:11689558 reported serine-protease activity and extracellular-matrix substrate cleavage, whereas PMID:20522975 found that wild-type and catalytic-site-mutant reelin behaved identically and neither degraded laminin. The transferred annotation should not be treated as established until this conflict is resolved. |
| GO:0008306 associative learning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog evidence supports a role for reelin signaling in the organism-level outcome associative learning. Reason: This behavioral phenotype is a downstream, context-specific consequence of reelin signaling and not a molecular activity of the gene product. |
| GO:0010976 positive regulation of neuron projection development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome positive regulation of neuron projection development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0021517 ventral spinal cord development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome ventral spinal cord development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0021766 hippocampus development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome hippocampus development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0021819 layer formation in cerebral cortex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome layer formation in cerebral cortex. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0032008 positive regulation of TOR signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin-receptor signaling can feed into positive regulation of TOR signaling through DAB1-dependent downstream branches. Reason: This is a context-dependent downstream signaling consequence rather than the defining extracellular receptor-binding activity of reelin. |
| GO:0035418 protein localization to synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process protein localization to synapse. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0038026 reelin-mediated signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Reelin binding to ApoER2/LRP8 and VLDLR initiates the canonical reelin pathway and DAB1 phosphorylation. Reason: This is the core signaling process enabled by the secreted ligand activity of reelin. |
| GO:0048018 receptor ligand activity | IEA GO_REF:0000107 | ACCEPT | Summary: Reelin is an extracellular ligand for ApoER2/LRP8 and VLDLR. Reason: This broad receptor-ligand term is correct and is complemented by the more specific lipoprotein particle receptor-binding annotations. |
| GO:0050795 regulation of behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog evidence supports a role for reelin signaling in the organism-level outcome regulation of behavior. Reason: This behavioral phenotype is a downstream, context-specific consequence of reelin signaling and not a molecular activity of the gene product. |
| GO:0050804 modulation of chemical synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process modulation of chemical synaptic transmission. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin-receptor signaling can feed into positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction through DAB1-dependent downstream branches. Reason: This is a context-dependent downstream signaling consequence rather than the defining extracellular receptor-binding activity of reelin. |
| GO:0051968 positive regulation of synaptic transmission, glutamatergic | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of synaptic transmission, glutamatergic. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0060291 long-term synaptic potentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process long-term synaptic potentiation. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0061003 positive regulation of dendritic spine morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of dendritic spine morphogenesis. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0070326 very-low-density lipoprotein particle receptor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Reelin directly binds ApoER2/LRP8 and VLDLR; this very-low-density lipoprotein particle receptor binding annotation captures its defining extracellular receptor-binding activity. Reason: Direct binding and receptor-dependent DAB1 phosphorylation are supported by PMID:10571240 and PMID:12670700. |
| GO:0090129 positive regulation of synapse maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of synapse maturation. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097107 postsynaptic density assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process postsynaptic density assembly. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097114 NMDA glutamate receptor clustering | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process NMDA glutamate receptor clustering. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097119 postsynaptic density protein 95 clustering | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process postsynaptic density protein 95 clustering. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097120 receptor localization to synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process receptor localization to synapse. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097477 lateral motor column neuron migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome lateral motor column neuron migration. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:1900273 positive regulation of long-term synaptic potentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of long-term synaptic potentiation. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:1902078 positive regulation of lateral motor column neuron migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome positive regulation of lateral motor column neuron migration. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:2000463 positive regulation of excitatory postsynaptic potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of excitatory postsynaptic potential. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0140149 non-collagenous component of interstitial matrix | TAS PMID:36399478 MatrisomeDB 2.0: 2023 updates to the ECM-protein knowledge d... | ACCEPT | Summary: Reelin is a secreted glycoprotein that functions in the extracellular matrix; the non-collagenous component of interstitial matrix localization is biologically appropriate. Reason: Human genetics and biochemical studies describe RELN as a large secreted extracellular protein, consistent with this extracellular localization. |
| GO:0038026 reelin-mediated signaling pathway | NAS PMID:21844191 Functional importance of covalent homodimer of reelin protei... | ACCEPT | Summary: Reelin binding to ApoER2/LRP8 and VLDLR initiates the canonical reelin pathway and DAB1 phosphorylation. Reason: This is the core signaling process enabled by the secreted ligand activity of reelin. |
| GO:0045664 regulation of neuron differentiation | NAS PMID:28887403 The functions of Reelin in membrane trafficking and cytoskel... | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome regulation of neuron differentiation. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0060025 regulation of synaptic activity | NAS PMID:28887403 The functions of Reelin in membrane trafficking and cytoskel... | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process regulation of synaptic activity. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0110157 reelin complex | IDA PMID:21844191 Functional importance of covalent homodimer of reelin protei... | ACCEPT | Summary: Reelin forms a covalent homodimer and higher-order multimer required for full signaling activity. Reason: PMID:21844191 identifies Cys2101-linked homodimerization and shows that a non-covalent but non-disulfide-linked mutant retains receptor binding yet loses signaling activity. |
| GO:2001222 regulation of neuron migration | NAS PMID:28887403 The functions of Reelin in membrane trafficking and cytoskel... | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome regulation of neuron migration. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0008236 serine-type peptidase activity | ISS GO_REF:0000024 | UNDECIDED | Summary: Intrinsic serine-type peptidase activity of reelin is unresolved because direct studies reached opposing conclusions. Reason: PMID:11689558 reported serine-protease activity and extracellular-matrix substrate cleavage, whereas PMID:20522975 found that wild-type and catalytic-site-mutant reelin behaved identically and neither degraded laminin. The transferred annotation should not be treated as established until this conflict is resolved. |
| GO:0021819 layer formation in cerebral cortex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome layer formation in cerebral cortex. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0038026 reelin-mediated signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Reelin binding to ApoER2/LRP8 and VLDLR initiates the canonical reelin pathway and DAB1 phosphorylation. Reason: This is the core signaling process enabled by the secreted ligand activity of reelin. |
| GO:0007616 long-term memory | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog evidence supports a role for reelin signaling in the organism-level outcome long-term memory. Reason: This behavioral phenotype is a downstream, context-specific consequence of reelin signaling and not a molecular activity of the gene product. |
| GO:0008306 associative learning | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog evidence supports a role for reelin signaling in the organism-level outcome associative learning. Reason: This behavioral phenotype is a downstream, context-specific consequence of reelin signaling and not a molecular activity of the gene product. |
| GO:0010976 positive regulation of neuron projection development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome positive regulation of neuron projection development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0032008 positive regulation of TOR signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin-receptor signaling can feed into positive regulation of TOR signaling through DAB1-dependent downstream branches. Reason: This is a context-dependent downstream signaling consequence rather than the defining extracellular receptor-binding activity of reelin. |
| GO:0035418 protein localization to synapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process protein localization to synapse. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0048018 receptor ligand activity | ISS GO_REF:0000024 | ACCEPT | Summary: Reelin is an extracellular ligand for ApoER2/LRP8 and VLDLR. Reason: This broad receptor-ligand term is correct and is complemented by the more specific lipoprotein particle receptor-binding annotations. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin-receptor signaling can feed into positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction through DAB1-dependent downstream branches. Reason: This is a context-dependent downstream signaling consequence rather than the defining extracellular receptor-binding activity of reelin. |
| GO:0051968 positive regulation of synaptic transmission, glutamatergic | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of synaptic transmission, glutamatergic. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0061003 positive regulation of dendritic spine morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of dendritic spine morphogenesis. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0090129 positive regulation of synapse maturation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of synapse maturation. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097107 postsynaptic density assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process postsynaptic density assembly. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097114 NMDA glutamate receptor clustering | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process NMDA glutamate receptor clustering. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097119 postsynaptic density protein 95 clustering | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process postsynaptic density protein 95 clustering. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0097120 receptor localization to synapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process receptor localization to synapse. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:1900273 positive regulation of long-term synaptic potentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of long-term synaptic potentiation. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:2000463 positive regulation of excitatory postsynaptic potential | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process positive regulation of excitatory postsynaptic potential. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8854466 | ACCEPT | Summary: Reelin is a secreted glycoprotein that functions in the extracellular matrix; the extracellular region localization is biologically appropriate. Reason: Human genetics and biochemical studies describe RELN as a large secreted extracellular protein, consistent with this extracellular localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8855232 | ACCEPT | Summary: Reelin is a secreted glycoprotein that functions in the extracellular matrix; the extracellular region localization is biologically appropriate. Reason: Human genetics and biochemical studies describe RELN as a large secreted extracellular protein, consistent with this extracellular localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8855237 | ACCEPT | Summary: Reelin is a secreted glycoprotein that functions in the extracellular matrix; the extracellular region localization is biologically appropriate. Reason: Human genetics and biochemical studies describe RELN as a large secreted extracellular protein, consistent with this extracellular localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8855259 | ACCEPT | Summary: Reelin is a secreted glycoprotein that functions in the extracellular matrix; the extracellular region localization is biologically appropriate. Reason: Human genetics and biochemical studies describe RELN as a large secreted extracellular protein, consistent with this extracellular localization. |
| GO:0050795 regulation of behavior | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog evidence supports a role for reelin signaling in the organism-level outcome regulation of behavior. Reason: This behavioral phenotype is a downstream, context-specific consequence of reelin signaling and not a molecular activity of the gene product. |
| GO:0050804 modulation of chemical synaptic transmission | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling modulates the postnatal neuronal or synaptic process modulation of chemical synaptic transmission. Reason: The annotation is compatible with ortholog and review evidence, but it represents a downstream synaptic outcome rather than the core ligand-receptor activity. |
| GO:0021766 hippocampus development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome hippocampus development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0038026 reelin-mediated signaling pathway | ISS PMID:10571240 Reelin is a ligand for lipoprotein receptors. | ACCEPT | Summary: Reelin binding to ApoER2/LRP8 and VLDLR initiates the canonical reelin pathway and DAB1 phosphorylation. Reason: This is the core signaling process enabled by the secreted ligand activity of reelin. |
| GO:0070325 lipoprotein particle receptor binding | ISS PMID:10571240 Reelin is a ligand for lipoprotein receptors. | ACCEPT | Summary: Reelin directly binds ApoER2/LRP8 and VLDLR; this lipoprotein particle receptor binding annotation captures its defining extracellular receptor-binding activity. Reason: Direct binding and receptor-dependent DAB1 phosphorylation are supported by PMID:10571240 and PMID:12670700. |
| GO:0070326 very-low-density lipoprotein particle receptor binding | ISS PMID:10571240 Reelin is a ligand for lipoprotein receptors. | ACCEPT | Summary: Reelin directly binds ApoER2/LRP8 and VLDLR; this very-low-density lipoprotein particle receptor binding annotation captures its defining extracellular receptor-binding activity. Reason: Direct binding and receptor-dependent DAB1 phosphorylation are supported by PMID:10571240 and PMID:12670700. |
| GO:0000902 cell morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome cell morphogenesis. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0001764 neuron migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome neuron migration. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: Reelin is a secreted glycoprotein that functions in the extracellular matrix; the extracellular region localization is biologically appropriate. Reason: Human genetics and biochemical studies describe RELN as a large secreted extracellular protein, consistent with this extracellular localization. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Cytoplasmic localization is not an established site of reelin signaling activity. Reason: Intracellular biosynthetic transit does not establish the cytoplasm as the functional location of this secreted extracellular ligand. |
| GO:0007411 axon guidance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome axon guidance. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0007417 central nervous system development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome central nervous system development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0007420 brain development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome brain development. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0010001 glial cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome glial cell differentiation. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0021511 spinal cord patterning | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome spinal cord patterning. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0021800 cerebral cortex tangential migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin signaling contributes to the developmental or cellular outcome cerebral cortex tangential migration. Reason: This annotation is biologically concordant with reelin-dependent neuronal positioning, polarization, or differentiation, but it is an organismal or cellular outcome downstream of the core extracellular ligand-receptor signaling activity. |
| GO:0030425 dendrite | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Reelin signaling affects neuronal projections, but dendrite does not specify the extracellular compartment in which reelin acts. Reason: The transferred localization may reflect secretion near or receptor binding on neuronal processes; it does not establish the projection interior as a primary active site. |
| GO:0048265 response to pain | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog evidence supports a role for reelin signaling in the organism-level outcome response to pain. Reason: This behavioral phenotype is a downstream, context-specific consequence of reelin signaling and not a molecular activity of the gene product. |
| GO:0051057 positive regulation of small GTPase mediated signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reelin-receptor signaling can feed into positive regulation of small GTPase mediated signal transduction through DAB1-dependent downstream branches. Reason: This is a context-dependent downstream signaling consequence rather than the defining extracellular receptor-binding activity of reelin. |
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Download this section (compressed HTML)Q: Does rigorously purified human reelin possess any intrinsic protease activity under physiological conditions, or were reported cleavage activities caused by associated proteases or preparation-specific artifacts?
Q: How broadly does the Reelin-dependent posture-change mechanism observed in early/posterior-born mouse lateral-cerebellar Purkinje cells apply to other Purkinje-cell cohorts and to human cerebellar development?
Experiment: Compare independently purified wild-type and candidate catalytic-serine-mutant human reelin preparations using receptor-binding, DAB1-phosphorylation, and orthogonal protease assays with protease-free controls and quantitative substrate mass spectrometry.
Hypothesis: Canonical receptor-ligand signaling, but not intrinsic proteolysis, accounts for the core activity of human reelin.
Type: recombinant-protein biochemistry and neuronal signaling assay
Experiment: Use lineage-resolved human cerebellar organoids or fetal-tissue models with RELN perturbation and rescue to measure Purkinje-cell polarity, somal orientation, axon position, and layer assembly while tracking VLDLR/LRP8-DAB1 pathway activation.
Hypothesis: Human RELN signaling contributes to Purkinje-cell reorientation and nascent layer formation in a cohort- and stage-restricted manner.
Type: spatiotemporal perturbation in human cerebellar developmental models
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether human reelin has an intrinsic serine peptidase activity remains unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Reelin receptor binding, multimerization, and DAB1-dependent signaling are established, but direct protease studies reached opposite conclusions.
Significance: Resolving this determines whether GO:0008236 represents a genuine second molecular activity or a propagated experimental artifact.
What would resolve it: Independent biochemical replication with protease-free human reelin and catalytic-site controls.
Provenance (the field's own admissions):
Gap: The cellular mechanics and cohort scope of RELN-dependent Purkinje-layer formation in humans are not established.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: A full-text mouse study demonstrates Reelin-dependent reorientation initiating plate formation specifically in early/posterior-born lateral-cerebellar Purkinje cells.
Significance: This limits direct translation of the mouse cerebellar mechanism into a human developmental decomposition.
What would resolve it: Lineage- and stage-resolved RELN perturbation in human cerebellar developmental tissue or organoid models.
Provenance (the field's own admissions):
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