Reelin Protein

Pathway Diagram

flowchart TD
    REELIN["REELIN"]
    NEURONAL_MIGRATION["NEURONAL MIGRATION"]
    REELIN -->|"regulates"| NEURONAL_MIGRATION
    dendritic_growth_and_branching["dendritic growth and branching"]
    REELIN -->|"regulates"| dendritic_growth_and_branching
    dendritic_spine_formation["dendritic spine formation"]
    REELIN -->|"regulates"| dendritic_spine_formation
    synaptogenesis["synaptogenesis"]
    REELIN -->|"regulates"| synaptogenesis
    synaptic_plasticity["synaptic plasticity"]
    REELIN -->|"regulates"| synaptic_plasticity
    lissencephaly["lissencephaly"]
    REELIN -->|"implicated in"| lissencephaly
    AUTISM["AUTISM"]
    REELIN -->|"implicated in"| AUTISM
    schizophrenia["schizophrenia"]
    REELIN -->|"implicated in"| schizophrenia
    DAB1["DAB1"]
    DAB1 -->|"interacts with"| REELIN
    style REELIN fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
    style NEURONAL_MIGRATION fill:#263238,stroke:#90a4ae,color:#90a4ae
    style dendritic_growth_and_branching fill:#e65100,stroke:#ff8a65,color:#ff8a65
    style dendritic_spine_formation fill:#e65100,stroke:#ff8a65,color:#ff8a65
    style synaptogenesis fill:#e65100,stroke:#ff8a65,color:#ff8a65
    style synaptic_plasticity fill:#e65100,stroke:#ff8a65,color:#ff8a65
    style lissencephaly fill:#4a0000,stroke:#ef5350,color:#ef5350
    style AUTISM fill:#4a0000,stroke:#ef5350,color:#ef5350
    style schizophrenia fill:#4a0000,stroke:#ef5350,color:#ef5350
    style DAB1 fill:#263238,stroke:#90a4ae,color:#90a4ae

Knowledge graph relationships for REELIN (316 total edges in KG)

Introduction

Reelin Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Reelin is a large extracellular matrix protein that plays critical roles in neuronal migration, cortical layer formation, and synaptic plasticity during brain development and in the adult brain. Reelin signaling through ApoE receptors modulates dendritic spine morphology and synaptic function. Reelin dysfunction is implicated in Alzheimer’s disease and neuropsychiatric disorders. ^{1(2002)2002 · J Biol Chem · PMID 11741897Open reference}

This protein is involved in: ^{2(2006)2006 · J Neurochem · PMID 16478526Open reference}

• Neuronal migration: Essential for cortical layer formation

• Synaptic plasticity: Regulates spine density and function

• Dendritic development: Controls dendritic arborization

• Disease associations: Alzheimer’s disease, autism, schizophrenia, lissencephaly

Reelin is a large extracellular glycoprotein that plays essential roles in neuronal migration, synaptic plasticity, and cognitive function. It is a key regulator of brain development and is critically involved in the pathogenesis of Alzheimer’s Disease and neuropsychiatric disorders. ^{3(2005)2005 · Proc Natl Acad Sci USA · PMID 15677321Open reference}

Structure

Gene and Protein Overview

• Gene Symbol: RELN

• Gene ID: 5649

• Chromosome: 7q22.1

• Protein Length: 3,460 amino acids

• Molecular Weight: ~388 kDa (one of the largest secreted proteins)

• UniProt ID: P78536

• PDB Structures: 7JX6, 7JX7 (reelin domains)

Reelin is a member of the reelin family of extracellular matrix proteins. It contains an N-terminal signal peptide, followed by a Reelin domain, 8 EGF-like repeats, and 3 Reelin repeat domains (R1-R3), each containing 300 amino acids.

Domain Organization

• Signal peptide (aa 1-27): Secretory pathway targeting

• Reelin N-terminal domain (aa 28-189): Receptor binding

• EGF-like domains (aa 190-327): Protein-protein interactions

• Reelin repeat domains R1-R3 (aa 328-3460): Core functional domains

  • R1: aa 328-711

  • R2: aa 712-1095

  • R3: aa 1096-1480

• C-terminal region (aa 1481-3460): Full-length reelin contains 8 repeats

Normal Function

Neuronal Migration

Reelin is best known for its role in cortical lamination:^{4(1995)1995 · Nature · PMID 7643043Open reference}

• Secreted by Cajal-Retzius cells in the marginal zone

• Guides radial migration of neurons during development

• Controls proper positioning of pyramidal neurons in cortex

• Essential for layer formation in hippocampus and cerebellum

Synaptic Plasticity

In the adult brain, Reelin modulates:^{1(2002)2002 · J Biol Chem · PMID 11741897Open reference}

• Long-term potentiation (LTP) and depression (LTD)

• Dendritic spine morphology and density

• Synaptic vesicle release probability

• NMDA receptor trafficking and function

Cognitive Function

Reelin is essential for:

• Spatial learning and memory

• Contextual fear conditioning

• Social behavior

• Mood regulation

Role in Disease

Alzheimer’s Disease

Reelin is significantly implicated in AD pathogenesis:^{2(2006)2006 · J Neurochem · PMID 16478526Open reference}

• Reelin expression is reduced in AD brains, particularly in the entorhinal cortex and hippocampus

• Amyloid-beta (Aβ) oligomers suppress Reelin expression

• Reduced Reelin contributes to synaptic dysfunction and memory impairment

• Reelin interacts with APP and affects amyloid precursor protein processing

• Reelin-containing neurons are vulnerable in AD

Reelin-Aβ Interaction:

• Aβ oligomers bind to Reelin receptors, disrupting downstream signaling

• This leads to impaired synaptic plasticity

• Contributes to early memory deficits before significant amyloid deposition

Schizophrenia and Bipolar Disorder

Reelin is a major susceptibility factor:^{3(2005)2005 · Proc Natl Acad Sci USA · PMID 15677321Open reference}

• RELN promoter hypermethylation reduces expression

• Reduced Reelin protein in prefrontal cortex

• Genetic variants associated with disease risk

• Developmental disruption of cortical layering

Autism Spectrum Disorder

• Reduced Reelin levels in some ASD patients

• Mouse models show Reelin haploinsufficiency leads to ASD-like behaviors

• Interaction with autism-linked genes (CNTNAP2, FLNB)

Epilepsy

• Reelin mutations cause lissencephaly in humans

• Altered Reelin signaling contributes to epileptogenesis

• Reelin supplementation reduces seizure frequency in models

Therapeutic Targeting

Reelin-Based Therapies

Clinical Trials

• No active clinical trials for Reelin-targeted therapy as of 2026

• Biomarker development ongoing (Reelin in CSF)

Mechanism-Based Strategies

• Aβ-Reelin interaction blockers: Prevent Aβ-mediated Reelin dysfunction

• Dab1 activators: Downstream signaling molecule enhancement

• LRP8/ApoER2 agonists: Reelin receptor stimulation

Background

The study of Reelin Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

See Also

• Amyloid Precursor Protein (APP)

• ApoE Protein

• Amyloid-Beta

• Tau Protein

• Neuroinflammation

• Alzheimer’s Disease

Brain Atlas Resources

The following resources from the Allen Brain Atlas provide expression and connectivity data for this protein/gene:

• Allen Human Brain Atlas - Gene Expression: Searchable gene expression database from adult human brain

• Allen Brain Atlas - RNA Sequencing: RNA sequencing data across brain regions

• Allen Cell Type Atlas: Single-cell transcriptomic data for cell type classification

• Allen Mouse Brain Atlas: Comprehensive mouse brain gene expression database

• BrainSpan Atlas of the Developing Human Brain: Developmental expression data across brain regions and ages

External Links

• UniProt P78536

• GeneCards RELN

• PubMed Reelin