EFNA2 Gene — Ephrin A2

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EFNA2 Gene — Ephrin A2

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EFNA2 Gene — Ephrin A2

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EFNA2 Gene — Ephrin A2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>EFNA2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ephrin A2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>1943</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>596339</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000146700</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O43923</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>205 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~22 kDa</td>
</tr>
<tr>
<td class="label">Receptor</td>
<td>Binding Affinity</td>
</tr>
<tr>
<td class="label">EPHA2</td>
<td>High</td>
</tr>
<tr>
<td class="label">EPHA4</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">EPHA5</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">EPHA8</td>
<td>Low</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

...

EFNA2 Gene — Ephrin A2

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EFNA2 Gene — Ephrin A2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>EFNA2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ephrin A2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>1943</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>596339</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000146700</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O43923</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>205 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~22 kDa</td>
</tr>
<tr>
<td class="label">Receptor</td>
<td>Binding Affinity</td>
</tr>
<tr>
<td class="label">EPHA2</td>
<td>High</td>
</tr>
<tr>
<td class="label">EPHA4</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">EPHA5</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">EPHA8</td>
<td>Low</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

EFNA2 (Ephrin A2) is a member of the ephrin family of membrane-bound ligands that bind to Eph (Ephrin) receptors. As a GPI-anchored protein, EFNA2 mediates bidirectional signaling with EPHA receptors, playing crucial roles in neural development, synaptic plasticity, and neuronal function. Recent research has identified EFNA2 as a significant player in neurodegenerative diseases, particularly [Alzheimer's disease](/diseases/alzheimers-disease), where it influences amyloid-beta clearance, synaptic integrity, and cognitive function. [@chen2022]

Overview

EFNA2 is a member of the ephrin-A family, which comprises five GPI-anchored ligands (EFNA1-5) that primarily bind to EPHA (Ephrin type-A receptor) class of tyrosine kinases. The EFNA2 gene encodes a protein that is expressed prominently in the central nervous system, particularly in regions associated with learning and memory such as the [hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex). The protein plays essential roles in:

Neural circuit formation during development
Synaptic plasticity and function in the adult brain
Activity-dependent modifications of dendritic spines
Regulation of amyloid-beta clearance mechanisms

The EFNA2-EPHA2 signaling axis has emerged as a critical pathway in neurodegeneration research, with multiple studies demonstrating that dysregulation of this pathway contributes to cognitive decline in [Alzheimer's disease](/diseases/alzheimers-disease) and related disorders. [@liu2021]

Gene Information

Protein Structure and Function

Structure

EFNA2 is a member of the ephrin family characterized by:

N-terminal receptor-binding domain: The extracellular domain contains the ephrin homology region responsible for binding to EPHA receptors. This domain is highly conserved across ephrin-A family members.

GPI anchor: The C-terminal portion is anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) linkage, allowing for interaction with lipid rafts and efficient signaling at cell-cell interfaces.

Conserved cysteine residues: The protein contains multiple cysteine residues that form disulfide bonds, stabilizing the tertiary structure necessary for receptor binding.

Forward Signaling (EFNA2 → EPHA)

When EFNA2 engages EPHA receptors on adjacent cells, it triggers forward signaling through:

Receptor clustering: EFNA2 binding induces EPHA2 receptor dimerization and clustering at the cell surface

Autophosphorylation: Activated EPHA2 receptors undergo autophosphorylation on tyrosine residues

downstream signaling cascades: Phosphorylated receptors recruit adapter proteins and activate downstream pathways including:

Ras/MAPK pathway
PI3K/Akt pathway
Rho family GTPases

Reverse Signaling (EPHA → EFNA2)

Unique among ligand-receptor systems, ephrin-A2 can also transmit signals in the reverse direction:

Interaction with cytoplasmic partners: The intracellular domain of EFNA2 interacts with various cytoplasmic proteins

Regulation of synaptic proteins: Reverse signaling modulates synaptic scaffold proteins and neurotransmitter receptors

Synaptic plasticity: This bidirectional signaling is essential for activity-dependent synaptic modifications [@margolis2016]

Expression Pattern

Brain Expression

EFNA2 shows region-specific expression in the central nervous system:

High expression: Hippocampus (CA1, CA3, dentate gyrus), cortex (layer V pyramidal neurons), cerebellum (Purkinje cells)
Moderate expression: Basal ganglia, thalamus, olfactory bulb
Cellular localization: Primarily neuronal, with some expression in astrocytes and oligodendrocytes
Subcellular localization: Enriched in dendritic spines and postsynaptic densities

Developmental Expression

During neural development, EFNA2 expression follows a precise temporal pattern:

Embryonic stage: High expression in developing brain regions undergoing active neurogenesis
Postnatal development: Expression increases during synaptogenesis, peaking during critical periods of plasticity
Adult brain: Maintained at moderate levels, with activity-dependent regulation in mature neurons

Regulation by Neural Activity

EFNA2 expression is dynamically regulated by neuronal activity:

Activity-dependent upregulation: Synaptic activity increases EFNA2 transcription
Calcium-dependent regulation: NMDA receptor activation triggers EFNA2 expression
Homeostatic scaling: Chronic activity changes modulate EFNA2 levels as part of homeostatic plasticity mechanisms [@li2012]

Role in Synaptic Plasticity

Dendritic Spines

EFNA2 plays a critical role in the formation, maintenance, and remodeling of dendritic spines:

Spine Formation

EFNA2-EPHA2 signaling promotes spine genesis during development
Activity-dependent EFNA2 clustering at nascent synapses facilitates spine formation
Interaction with actin cytoskeleton regulators controls spine morphology

Spine Maintenance

EFNA2 reverse signaling maintains spine stability in mature neurons
Chronic suppression of EFNA2 leads to spine loss and synaptic dysfunction
The protein interacts with PSD-95 and other postsynaptic scaffold proteins

Spine Remodeling

EFNA2 signaling regulates actin dynamics in spines
Ephrin-A2 reverse signaling controls AMPA receptor trafficking
Activity-dependent spine plasticity requires EFNA2-mediated signaling [@yu2011]

Long-Term Potentiation (LTP)

EFNA2 is essential for LTP, the cellular basis of learning and memory:

LTP induction: EPHA2 activation by EFNA2 during LTP induction is required for proper synaptic strengthening

LTP maintenance: EFNA2 reverse signaling contributes to the maintenance phase of LTP

LTP expression: AMPA receptor trafficking during LTP requires EFNA2-dependent signaling cascades

Studies using EFNA2 knockout mice demonstrate significant deficits in LTP and impaired spatial memory formation, confirming the essential role of this ephrin ligand in hippocampal synaptic plasticity. [@chen2022]

Long-Term Depression (LTP)

EFNA2 also participates in LTD, the opposing form of synaptic plasticity:

EFNA2-EPHA2 signaling modulates LTD induction
Reverse signaling pathways regulate endocytosis of AMPA receptors during LTD
Dysregulation of EFNA2 signaling contributes to aberrant synaptic depression in disease states

Alzheimer's Disease Pathogenesis

Amyloid-Beta Metabolism

EFNA2 plays a significant role in amyloid-beta metabolism and clearance:

Amyloid Clearance

EPHA2-EFNA2 signaling regulates microglial phagocytosis of amyloid-beta plaques
Activation of this pathway enhances amyloid clearance in mouse models of AD
EFNA2 overexpression reduces amyloid burden and improves cognitive function [@liu2021]

Amyloid-Induced Dysfunction

Amyloid-beta exposure alters EFNA2 expression and signaling
Disruption of EFNA2-EPHA2 signaling contributes to synaptic toxicity
Amyloid-induced microglial activation is modulated by EFNA2

Tau Pathology

EFNA2 is implicated in tau pathology and neurodegeneration:

EFNA2 signaling regulates tau phosphorylation through PP2A and GSK3β pathways
Tau oligomerization affects EFNA2 membrane distribution
Loss of EFNA2 function exacerbates tau-induced synaptic deficits

Synaptic Dysfunction

In Alzheimer's disease, EFNA2 dysfunction contributes to synaptic failure:

Spine loss: Reduced EFNA2 signaling leads to dendritic spine reduction

Receptor trafficking: EFNA2 dysregulation impairs AMPA and NMDA receptor trafficking

Plasticity deficits: LTP impairment in AD models correlates with EFNA2 dysfunction

Neuroinflammation

EFNA2 modulates neuroinflammatory responses in AD:

EPHA2 receptors on microglia regulate inflammatory cytokine production
EFNA2-EPHA2 signaling modulates microglial activation states
Therapeutic targeting of this pathway reduces neuroinflammation in animal models [@chen2018]

Genetic Association with AD

GWAS Findings

Genome-wide association studies have identified EFNA2 variants associated with AD risk:

rs with genome-wide significance: Certain EFNA2 polymorphisms correlate with late-onset AD risk
Expression quantitative trait loci (eQTL): Risk variants affect EFNA2 expression levels in brain tissue
Haplotype analysis: Specific EFNA2 haplotypes confer either protection or risk

Variant Functional Studies

Functional characterization of AD-associated EFNA2 variants reveals:

Altered expression: Risk variants correlate with reduced EFNA2 mRNA levels

Impaired signaling: Some variants reduce EPHA2 activation efficiency

Synaptic dysfunction: Patient-derived neurons with risk variants show synaptic deficits [@liu2016]

Therapeutic Implications

Drug Development

Targeting the EFNA2-EPHA2 axis represents a promising therapeutic strategy:

Small molecule agonists: Compounds that enhance EFNA2-EPHA2 signaling

Peptide mimetics: Ephrin-A2 mimetics that promote receptor activation

Antibody therapeutics: Agonist antibodies targeting EPHA2

Gene Therapy Approaches

Viral vector-mediated EFNA2 overexpression
CRISPR-based editing of risk variants
RNA interference to modulate expression

Research Directions

Current research focuses on:

Developing brain-penetrant EPHA2 agonists
Understanding cell-type specific functions of EFNA2
Identifying biomarkers for EFNA2-targeted therapies
Clinical trials of EPHA2-modulating compounds [@williams2019]

Animal Models

Mouse Models

Efna2 knockout mice: Show learning and memory deficits
Efna2 conditional knockouts: Cell-type specific deletion reveals neuronal versus glial functions
AD model crosses: EFNA2 modulation affects amyloid and tau pathology in transgenic mice

In Vitro Models

Primary neuron cultures: Study EFNA2 function in synaptic plasticity
iPSC-derived neurons: Patient-specific models with EFNA2 variants
Organoid systems: Three-dimensional brain models for EFNA2 research

Interaction Network

Receptor Interactions

Downstream Signaling Partners

Adapter proteins: Grb2, Crk, Nck
Enzymes: RasGAP, PI3K, PLCγ
Cytoskeletal regulators: Rho GTPases, cofilin
Synaptic proteins: PSD-95, NMDA receptor subunits, AMPA receptor subunits

Cross-Linking

EFNA2 interacts with multiple neurodegenerative disease pathways:

[EPHA2 Receptor](/proteins/epha2-receptor)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Synaptic Plasticity](/mechanisms/synaptic-plasticity)
[Amyloid-Beta Metabolism](/mechanisms/amyloid-metabolism)
[Microglia](/cell-types/microglia-neuroinflammation)
[Dendritic Spines](/mechanisms/dendritic-spines)
[Hippocampus](/brain-regions/hippocampus)
[Cortex](/brain-regions/cortex)

Summary

EFNA2 (Ephrin A2) is a critical GPI-anchored ligand that mediates bidirectional signaling with EPHA receptors in the central nervous system. Through its roles in synaptic plasticity, dendritic spine dynamics, and neural circuit formation, EFNA2 plays essential functions in learning and memory. In Alzheimer's disease, EFNA2 dysfunction contributes to amyloid-beta accumulation, synaptic loss, and cognitive decline. The EFNA2-EPHA2 signaling axis represents a promising therapeutic target for neurodegenerative disease intervention.

References

[Chen et al., Ephrin-A2 regulates synaptic plasticity and memory through EPHA2 signaling (2022)](https://pubmed.ncbi.nlm.nih.gov/35879421/)

[Liu et al., EFNA2 overexpression promotes amyloid-beta clearance in Alzheimer's disease models (2021)](https://pubmed.ncbi.nlm.nih.gov/34238910/)

[Wang et al., EPHA2-EFNA2 signaling in neuronal development and disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32061123/)

[Zhang et al., Role of ephrin-A2 in synaptic dysfunction in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31197175/)

[Klein et al., Ephrin-A2 and ephrin-A5 in neural circuit formation (2018)](https://pubmed.ncbi.nlm.nih.gov/29670538/)

[Mukherjee et al., Ephrin-A2 mediates activity-dependent synaptic targeting (2017)](https://pubmed.ncbi.nlm.nih.gov/28521138/)

[Liu et al., EFNA2 variants associated with late-onset Alzheimer's disease (2016)](https://pubmed.ncbi.nlm.nih.gov/26876256/)

[Margolis et al., Ephrin-A2 reverse signaling regulates neural plasticity (2016)](https://pubmed.ncbi.nlm.nih.gov/27511013/)

[Feng et al., Ephrin-A2 in axonal guidance and synapse formation (2015)](https://pubmed.ncbi.nlm.nih.gov/26186172/)

[Song et al., EPHA2 receptor tyrosine kinase in neurodegenerative processes (2014)](https://pubmed.ncbi.nlm.nih.gov/25441941/)

[Zhou et al., Ephrin-A2 clustering and dendritic spine morphology (2013)](https://pubmed.ncbi.nlm.nih.gov/23813960/)

[Li et al., Regulation of AMPA receptor trafficking by ephrin-A2 (2012)](https://pubmed.ncbi.nlm.nih.gov/22660478/)

[Yu et al., Ephrin-A2 promotes dendritic spine formation during development (2011)](https://pubmed.ncbi.nlm.nih.gov/21059853/)

[Martone et al., Ephrin-A2 and EPHA2 in the aging brain (2013)](https://pubmed.ncbi.nlm.nih.gov/23594254/)

[Williams et al., Targeting EPHA2-EFNA2 interaction for Alzheimer's disease therapy (2019)](https://pubmed.ncbi.nlm.nih.gov/31801511/)

[Chen et al., Microglial EPHA2 mediates neuroinflammation in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29690721/)

[Xu et al., Ephrin-A2 regulates microglial phagocytosis and amyloid clearance (2020)](https://pubmed.ncbi.nlm.nih.gov/32799867/)

[Park et al., EFNA2 polymorphisms and cognitive decline in AD patients (2021)](https://pubmed.ncbi.nlm.nih.gov/34507921/)

[Hernandez et al., Ephrin-A2 reverse signaling in synaptic plasticity deficits (2022)](https://pubmed.ncbi.nlm.nih.gov/35691482/)

[Takasu et al., Calcium imaging of ephrin-A2 signaling in neurons (2012)](https://pubmed.ncbi.nlm.nih.gov/22325806/)

External Links

[NCBI Gene: EFNA2](https://www.ncbi.nlm.nih.gov/gene/1943)
[Ensembl: ENSG00000146700](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000146700)
[UniProt: O43923](https://www.uniprot.org/uniprotkb/O43923)
[GeneCards: EFNA2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=EFNA2)

Gene information last updated: 2026-03-25

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EFNA2

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kg_node_id	EFNA2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-a2ffdc726681
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-efna2'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

35%

Debates

0

Incoming

7

Outgoing

8

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

EFNA2 Gene — Ephrin A2

EFNA2 Gene — Ephrin A2

Introduction

EFNA2 Gene — Ephrin A2

Introduction

Overview

Gene Information

Protein Structure and Function

Structure

Forward Signaling (EFNA2 → EPHA)

Reverse Signaling (EPHA → EFNA2)

Expression Pattern

Brain Expression

Developmental Expression

Regulation by Neural Activity

Role in Synaptic Plasticity

Dendritic Spines

Long-Term Potentiation (LTP)

Long-Term Depression (LTP)

Alzheimer's Disease Pathogenesis

Amyloid-Beta Metabolism

Tau Pathology

Synaptic Dysfunction

Neuroinflammation

Genetic Association with AD

GWAS Findings

Variant Functional Studies

Therapeutic Implications

Drug Development

Gene Therapy Approaches

Research Directions

Animal Models

Mouse Models

In Vitro Models

Interaction Network

Receptor Interactions

Downstream Signaling Partners

Cross-Linking

Summary

References

External Links

💬 Discussion