GO:0038026 reelin-mediated signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0038026 (reelin-mediated signaling pathway) describes the molecular cascade triggered when secreted reelin binds to cell-surface receptors, leading to regulation of downstream cellular processes such as transcription.
• The pathway is best known for its role in neuronal migration, dendritic development, and synaptic plasticity, and it is implicated in neuropsychiatric and neurodegenerative diseases.
• Core signaling involves reelin binding to ApoER2/VLDLR, phosphorylation of Dab1 by Src-family kinases, and activation of downstream effectors including Akt and GSK3beta.
• Reelin signaling also intersects with metabolic enzymes; Aldolase A has been identified as a novel effector in reelin-mediated dendritic development.
• Dysregulation of reelin signaling is linked to Alzheimer's disease, schizophrenia, and other brain disorders, making it a target for therapeutic research.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of reelin pathway components in vitro and in vivo.
Description
The reelin-mediated signaling pathway (GO:0038026) is a fundamental biological process that orchestrates a series of molecular events initiated by the binding of reelin, a large secreted glycoprotein, to receptors on the surface of target cells. This pathway is highly conserved and plays critical roles in brain development, including neuronal positioning, dendritic arborization, and synaptic function. Beyond development, reelin signaling contributes to synaptic plasticity and cognitive processes in the adult brain, and its dysfunction has been linked to a range of neurological and psychiatric conditions. Researchers study this pathway to understand how extracellular cues are translated into intracellular responses that regulate transcription and other cellular outcomes. The pathway's complexity, involving multiple receptors, adaptor proteins, kinases, and downstream effectors, makes it a rich subject for genetic and biochemical investigation. Advances in CRISPR gene editing and high-throughput screening now allow precise manipulation of pathway components, accelerating discoveries in neurobiology and disease modeling.
reelin-mediated signaling pathway At A Glance
| GO ID | GO:0038026 |
|---|---|
| GO term | reelin-mediated signaling pathway |
| Ontology | biological_process |
| Synonym | reeler-mediated signaling pathway; reelin-mediated signalling pathway; reelin-mediated signal transduction pathway |
| Major function | Transduces extracellular reelin signals to regulate neuronal migration, dendritic development, synaptic plasticity, and transcription |
| Key receptors | ApoER2 (LRP8), VLDLR |
| Key adaptor | Dab1 (phosphorylated by Src-family kinases) |
| Downstream effectors | Akt, GSK3beta, Aldolase A |
| Associated diseases | Alzheimer's disease, schizophrenia, other neuropsychiatric disorders |
What Is GO:0038026?
According to the Gene Ontology, GO:0038026 (reelin-mediated signaling pathway) is defined as the series of molecular signals initiated by the binding of reelin (a secreted glycoprotein) to a receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. In simpler terms, it is the entire communication chain that starts when reelin docks onto a cell and finishes with changes in how the cell behaves, such as turning genes on or off.
Why Is reelin-mediated signaling pathway Important in Cell Biology?
The reelin-mediated signaling pathway is essential for proper brain development and function, and its dysregulation is a hallmark of several devastating neurological and psychiatric disorders. Understanding this pathway provides insights into fundamental mechanisms of cell signaling, neuronal positioning, and synaptic plasticity, and it offers potential therapeutic targets for conditions such as Alzheimer's disease and schizophrenia. Moreover, the pathway serves as a model for studying how secreted factors control gene expression and cell behavior, with implications for regenerative medicine and neurodevelopmental research.
• Critical for neuronal migration and cortical layering during development.
• Regulates dendritic spine morphology and synaptic plasticity in the adult brain.
• Implicated in the pathophysiology of Alzheimer's disease and other dementias.
• Associated with schizophrenia and bipolar disorder through genetic and expression studies.
• Modulates key signaling nodes such as Akt and GSK3beta, linking to metabolism and cell survival.
• Involves metabolic enzymes like Aldolase A, expanding its functional repertoire beyond classical signaling.
• Serves as a paradigm for understanding extracellular matrix-cell communication.
• Provides targets for pharmacological intervention, including ketamine-mediated behavioral effects.
• Enables mechanistic studies using mathematical modeling and quantitative biochemistry.
• Offers opportunities for CRISPR-based disease modeling and drug discovery.
What Happens During reelin-mediated signaling pathway?
Reelin Binding to Receptors
In simple terms: Reelin, a large secreted protein, attaches to specific receptors on the cell surface, like a key fitting into a lock.
The pathway begins when reelin binds to its receptors, primarily Apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR). This binding triggers receptor clustering and activation of intracellular signaling cascades. The interaction is highly specific and is the first step in transducing the reelin signal across the plasma membrane.
Dab1 Phosphorylation by Src-Family Kinases
In simple terms: Once reelin binds, an adaptor protein called Dab1 gets tagged with phosphate groups by enzymes, which acts as a switch to turn on the pathway.
Reelin binding induces phosphorylation of the intracellular adaptor protein Dab1 by Src-family kinases (SFKs) such as Fyn and Src. This phosphorylation is a key event that creates docking sites for downstream signaling molecules. Mathematical models have been developed to describe the kinetics of early reelin-induced SFK-mediated signaling.
Activation of Downstream Effectors: Akt and GSK3beta
In simple terms: The signal then travels to other proteins that control cell survival and metabolism, including Akt and GSK3beta.
Phosphorylated Dab1 recruits and activates phosphatidylinositol 3-kinase (PI3K), leading to activation of Akt and inhibition of glycogen synthase kinase 3beta (GSK3beta). This regulation is critical for neuronal development and has been shown to occur locally at the sites of reelin signaling.
Regulation of Transcription and Cellular Responses
In simple terms: Ultimately, the signal reaches the cell nucleus and changes which genes are turned on or off, altering cell behavior.
The reelin pathway culminates in the regulation of downstream cellular processes, including transcription. This can involve modulation of transcription factors and chromatin remodeling, although the exact mechanisms are context-dependent. The pathway also influences cytoskeletal dynamics and membrane trafficking, contributing to neuronal migration and dendritic development.
Emerging Role of Metabolic Enzymes: Aldolase A
In simple terms: Recent research shows that a metabolic enzyme called Aldolase A also participates in reelin signaling, linking energy metabolism to brain development.
Beyond classical signaling components, Aldolase A has been identified as a novel effector in reelin-mediated dendritic development. This finding expands the pathway's scope, suggesting that metabolic enzymes can directly influence neuronal morphogenesis downstream of reelin.
Key Genes Involved in GO:0038026 reelin-mediated signaling pathway
The following genes and proteins are core components or effectors of the reelin-mediated signaling pathway, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| RELN | Encodes reelin, the secreted ligand that initiates the pathway | Mutations cause lissencephaly and are linked to psychiatric disorders |
| LRP8 (ApoER2) | Reelin receptor; mediates signal transduction | Knockout models show defective neuronal migration |
| VLDLR | Reelin receptor; redundant with ApoER2 | Double knockout with LRP8 mimics reeler phenotype |
| DAB1 | Adaptor protein phosphorylated by SFKs; essential for downstream signaling | Dab1 mutants exhibit reeler-like phenotype |
| FYN | Src-family kinase that phosphorylates Dab1 | Fyn knockout mice show impaired reelin signaling |
| SRC | Src-family kinase that phosphorylates Dab1 | Involved in early signaling events |
| PIK3CA | PI3K catalytic subunit; activates Akt | Links reelin to cell survival pathways |
| AKT1 | Serine/threonine kinase; regulates metabolism and survival | Phosphorylated upon reelin stimulation |
| GSK3B | Kinase inhibited by reelin signaling; regulates cytoskeleton | Dysregulation linked to neurodegeneration |
| ALDOA | Glycolytic enzyme; novel effector in dendritic development | Identified as downstream of reelin in neurons |
| MAPK1 (ERK2) | Kinase in MAPK cascade; may modulate reelin signaling | Potential crosstalk with reelin pathway |
| CREB1 | Transcription factor; may mediate reelin-induced transcription | Implicated in synaptic plasticity |
| GRIN2B (NR2B) | NMDA receptor subunit; interacts with reelin signaling | Modulates synaptic plasticity |
| BDNF | Neurotrophin; interacts with reelin pathway in plasticity | Linked to ketamine effects |
| APOE | Lipoprotein; modulates reelin signaling via receptor competition | Risk factor for Alzheimer's disease |
| BCHE | Butyrylcholinesterase; emerging target in Alzheimer's disease | Inhibitors under investigation |
How Is reelin-mediated signaling pathway Regulated?
The reelin-mediated signaling pathway is tightly regulated at multiple levels. Receptor availability and clustering are controlled by expression levels and post-translational modifications. Dab1 phosphorylation is balanced by phosphatases and degradation pathways. Downstream, Akt and GSK3beta activities are modulated by feedback loops and crosstalk with other signaling cascades. Additionally, the pathway can be influenced by metabolic status, as seen with Aldolase A. External factors such as ketamine have been shown to require synaptic reelin signaling for their behavioral and synaptic effects, indicating activity-dependent regulation.
reelin-mediated signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| RELN | Lissencephaly, schizophrenia, Alzheimer's disease | Reln knockout mouse; patient-derived iPSCs |
| DAB1 | Epilepsy, neurodevelopmental disorders | Dab1 conditional knockout; CRISPR point mutations |
| LRP8 | Alzheimer's disease risk | ApoER2 knockout and knock-in mice |
| GSK3B | Alzheimer's disease, mood disorders | GSK3B knock-in for phospho-mimetic mutations |
| ALDOA | Dendritic development, potential neurodevelopmental roles | AldoA knockout and overexpression in neurons |
Reelin Signaling in Neuropsychiatric Disorders
Alterations in reelin expression and signaling have been observed in schizophrenia, bipolar disorder, and major depression. Post-mortem studies show reduced reelin levels in specific brain regions, and genetic variants in RELN are associated with increased risk. The pathway's role in synaptic plasticity suggests that its dysfunction contributes to cognitive deficits.
Reelin Signaling in Neurodegenerative Diseases
In Alzheimer's disease, reelin signaling is implicated in amyloid-beta metabolism and tau phosphorylation through GSK3beta regulation. Reduced reelin levels correlate with cognitive decline, and therapeutic strategies targeting the pathway are being explored. Butyrylcholinesterase inhibitors, for example, may modulate cholinergic and reelin-related pathways.
Reelin Signaling in Developmental Brain Disorders
Mutations in RELN cause lissencephaly with cerebellar hypoplasia, a severe developmental disorder characterized by abnormal neuronal migration. Animal models with disrupted reelin signaling exhibit inverted cortical layers and ataxia, underscoring the pathway's essential role in brain architecture.
From reelin-mediated signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of Reln impair neuronal migration? | RELN knockout mouse or human iPSC-derived neurons |
| How does a specific Dab1 phosphorylation site affect signaling? | Dab1 point-mutation knock-in mice (e.g., Y-to-F) |
| Can reelin signaling be monitored in live cells? | Tagged knock-in of ApoER2 or Dab1 with fluorescent proteins |
| What are the transcriptional targets of reelin signaling? | Overexpression of constitutively active Akt or GSK3beta mutants |
| Does Aldolase A mediate reelin-dependent dendritic growth? | ALDOA knockout and rescue in cultured neurons |
| How does ketamine require reelin signaling? | Conditional knockout of reelin in adult mice combined with behavioral tests |
How to Study the reelin-mediated signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Western blot | Protein phosphorylation and expression levels | Assessing Dab1, Akt, GSK3beta activation |
| Co-immunoprecipitation | Protein-protein interactions | Reelin receptor-Dab1 binding |
| RNA-seq | Transcriptional changes | Identifying reelin target genes |
| Proteomics | Global protein expression and modifications | Discovering novel effectors like Aldolase A |
| Confocal microscopy | Dendritic morphology and spine density | Evaluating reelin effects on neuronal development |
| Electrophysiology | Synaptic plasticity (LTP/LTD) | Linking reelin signaling to circuit function |
| Behavioral tests | Learning, memory, and sensorimotor gating | Assessing cognitive phenotypes in models |
| Mathematical modeling | Signaling kinetics and network behavior | Simulating early reelin-induced SFK signaling |
Genetic and Biochemical Approaches
Standard methods include Western blotting for phosphorylated Dab1, Akt, and GSK3beta after reelin stimulation. Co-immunoprecipitation can reveal receptor-adaptor interactions. Mathematical modeling complements these experiments by simulating signaling kinetics.
Imaging and Morphological Analysis
Confocal microscopy of cultured neurons allows visualization of dendritic arborization and spine density following reelin treatment. Live-cell imaging with fluorescently tagged proteins can track receptor trafficking and signaling dynamics.
Transcriptomics and Proteomics
RNA sequencing (RNA-seq) identifies transcriptional changes downstream of reelin signaling. Proteomics can uncover novel effectors like Aldolase A and post-translational modifications.
Behavioral and Electrophysiological Assays
Animal models with disrupted reelin signaling undergo behavioral tests for learning and memory, and electrophysiology measures synaptic plasticity. These approaches link molecular events to circuit function.
How CRISPR Can Be Used to Study GO:0038026 reelin-mediated signaling pathway
Knockout
CRISPR knockout of RELN, DAB1, or receptors (LRP8, VLDLR) in cell lines or primary neurons can abolish reelin signaling, providing a clean background to study pathway necessity. Knockout models also help validate drug targets and identify compensatory mechanisms.
Point Mutation
Introducing precise point mutations (e.g., in DAB1 phosphorylation sites or RELN receptor-binding domains) via CRISPR base editing or HDR allows dissection of specific signaling events without confounding effects of complete protein loss. Such models are valuable for understanding structure-function relationships.
Knock-in
Knock-in of fluorescent tags (e.g., GFP) or epitope tags into endogenous loci (e.g., DAB1, LRP8) enables real-time tracking of protein localization and interactions. Knock-in of disease-associated variants (e.g., RELN mutations) creates isogenic models for mechanistic studies.
Overexpression
CRISPR activation (CRISPRa) or transgenic overexpression of pathway components (e.g., constitutively active AKT1, GSK3B mutants) can amplify signaling and reveal downstream effects. Overexpression of ALDOA may rescue or enhance dendritic phenotypes.
How EDITGENE Supports reelin-mediated signaling pathway Research
Researchers studying reelin-mediated signaling pathway-related genes often need to determine whether a candidate gene is causally involved in neuronal development, synaptic function, or disease. EDITGENE provides comprehensive CRISPR-based services to create precisely engineered cell and animal models, enabling rigorous functional validation of genes in this pathway.
Contact EDITGENE today to design your custom CRISPR model for reelin-mediated signaling pathway research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| STAT5A Knockout HEK293 Cell Line | EDJ-KQ538 | Human | 6776 | Details Get a Quote |
| RELN Knockout HEK293 Cell Line | EDJ-KQ863 | Human | 5649 | Details Get a Quote |
| DAB1 Knockout HEK293 Cell Line | EDJ-KQ4414 | Human | 1600 | Details Get a Quote |
| RNF7 Knockout HEK293 Cell Line | EDJ-KQ6006 | Human | 9616 | Details Get a Quote |
| CUL5 Knockout HEK293 Cell Line | EDJ-KQ6164 | Human | 8065 | Details Get a Quote |
| LRP8 Knockout HEK293 Cell Line | EDJ-KQ11993 | Human | 7804 | Details Get a Quote |
| VLDLR Knockout HEK293 Cell Line | EDJ-KQ12141 | Human | 7436 | Details Get a Quote |
| FYN Knockout HEK293 Cell Line | EDJ-KQ17821 | Human | 2534 | Details Get a Quote |
| DAB1 Knockout HeLa Cell Line | EDJ-KQ26940 | Human | 1600 | Details Get a Quote |
| CUL5 Knockout A-549 Cell Line | EDJ-KQ29979 | Human | 8065 | Details Get a Quote |
| CUL5 Knockout HCT 116 Cell Line | EDJ-KQ29980 | Human | 8065 | Details Get a Quote |
| CUL5 Knockout HeLa Cell Line | EDJ-KQ29981 | Human | 8065 | Details Get a Quote |
| RNF7 Knockout A-549 Cell Line | EDJ-KQ30964 | Human | 9616 | Details Get a Quote |
| RNF7 Knockout HCT 116 Cell Line | EDJ-KQ30966 | Human | 9616 | Details Get a Quote |
| RNF7 Knockout HeLa Cell Line | EDJ-KQ30967 | Human | 9616 | Details Get a Quote |
- 1
- 2
- Next Page »
Frequently Asked Questions About reelin-mediated signaling pathway
What is the reelin-mediated signaling pathway?
It is the series of molecular signals initiated by reelin binding to cell-surface receptors, leading to regulation of downstream cellular processes such as transcription (GO:0038026).
What genes are involved in reelin-mediated signaling pathway?
Key genes include RELN, LRP8 (ApoER2), VLDLR, DAB1, FYN, SRC, AKT1, GSK3B, and ALDOA.
What is the function of reelin-mediated signaling pathway?
It regulates neuronal migration, dendritic development, synaptic plasticity, and transcription, and is critical for brain development and function.
Which diseases are associated with reelin-mediated signaling pathway?
Alzheimer's disease, schizophrenia, lissencephaly, and other neuropsychiatric and neurodegenerative disorders.
How is reelin-mediated signaling pathway regulated?
It is regulated by receptor availability, Dab1 phosphorylation/dephosphorylation, feedback loops involving Akt and GSK3beta, and activity-dependent mechanisms.
What are the key receptors for reelin?
ApoER2 (LRP8) and VLDLR are the primary receptors that bind reelin and initiate signaling.
What is the role of Dab1 in reelin signaling?
Dab1 is an adaptor protein that becomes phosphorylated by Src-family kinases upon reelin binding, serving as a critical hub for downstream signaling.
How does reelin signaling affect synaptic plasticity?
It modulates NMDA receptor function and dendritic spine morphology, influencing learning and memory processes.
Can CRISPR be used to study reelin-mediated signaling pathway?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable precise dissection of pathway components and their roles in disease.
What research methods are used to study reelin signaling?
Common methods include Western blot, co-immunoprecipitation, RNA-seq, proteomics, confocal microscopy, electrophysiology, and mathematical modeling.
Conclusion
The reelin-mediated signaling pathway (GO:0038026) is a cornerstone of neurodevelopment and synaptic function, with far-reaching implications for understanding brain disorders. Its intricate molecular machinery, from receptor binding to transcriptional regulation, offers numerous targets for therapeutic intervention. Continued research using advanced CRISPR models and multi-omics approaches will further illuminate its roles in health and disease.
References
- 1. Lee GH et al.. 2016. New Insights into Reelin-Mediated Signaling Pathways.. Front Cell Neurosci 10:122 PMID: 27242434
- 2. Knuesel I. 2010. Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases.. Prog Neurobiol 91(4):257-74 PMID: 20417248
- 3. Kim JW et al.. 2021. A key requirement for synaptic Reelin signaling in ketamine-mediated behavioral and synaptic action.. Proc Natl Acad Sci U S A 118(20) PMID: 33975959
- 4. Hass H et al.. 2017. Mathematical model of early Reelin-induced Src family kinase-mediated signaling.. PLoS One 12(10):e0186927 PMID: 29049379
- 5. Beffert U et al.. 2002. Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3beta.. J Biol Chem 277(51):49958-64 PMID: 12376533
- 6. Lagani GD et al.. 2024. Beyond Glycolysis: Aldolase A Is a Novel Effector in Reelin-Mediated Dendritic Development.. J Neurosci 44(42) PMID: 39227156
- 7. Sang Z et al.. 2025. Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease.. Acta Pharm Sin B 15(4):2134-2155 PMID: 40486835
- 8. Lagani GD et al.. 2024. Beyond Glycolysis: Aldolase A is a Novel Effector in Reelin Mediated Dendritic Development.. bioRxiv PMID: 38260505
