UNC5C — Unc-5 Netrin Receptor C

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UNC5C — Unc-5 Netrin Receptor C

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UNC5C Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">UNC5C — Unc-5 Netrin Receptor C</th>
</tr>
<tr>
<td class="label">:---</td>
<td>:---</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>UNC5C</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Unc-5 Netrin Receptor C</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>4q32.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[4923](https://www.ncbi.nlm.nih.gov/gene/4923)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[607023](https://www.omim.org/entry/607023)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000144642</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q9ULS4](https://www.uniprot.org/uniprot/Q9ULS4)</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>[Alzheimer's Disease[@unc5c_gwas]](/diseases/alzheimers-disease), [Huntington's Disease](/diseases/huntingtons)</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">Netrin-1</td>
<td>Ligand binding</td>
</tr>
<tr>
<td class="label">DCC</td>
<td>Co-receptor</td>
</tr>
<tr>
<td class="label">Unc-5H1/H2/H4</td>
<td>Homologs</td>
</tr>
<tr>
<td class="label">PTPD1</td>
<td>Phosphatase binding</td>
</tr>
<tr>
<td class="label">LRRK2

...

UNC5C Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">UNC5C — Unc-5 Netrin Receptor C</th>
</tr>
<tr>
<td class="label">:---</td>
<td>:---</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>UNC5C</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Unc-5 Netrin Receptor C</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>4q32.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[4923](https://www.ncbi.nlm.nih.gov/gene/4923)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[607023](https://www.omim.org/entry/607023)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000144642</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q9ULS4](https://www.uniprot.org/uniprot/Q9ULS4)</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>[Alzheimer's Disease[@unc5c_gwas]](/diseases/alzheimers-disease), [Huntington's Disease](/diseases/huntingtons)</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">Netrin-1</td>
<td>Ligand binding</td>
</tr>
<tr>
<td class="label">DCC</td>
<td>Co-receptor</td>
</tr>
<tr>
<td class="label">Unc-5H1/H2/H4</td>
<td>Homologs</td>
</tr>
<tr>
<td class="label">PTPD1</td>
<td>Phosphatase binding</td>
</tr>
<tr>
<td class="label">LRRK2</td>
<td>Kinase interaction</td>
</tr>
<tr>
<td class="label">P53</td>
<td>Transcription factor</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Development Stage</td>
</tr>
<tr>
<td class="label">Netrin-1 agonists</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Small molecule modulators</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Protein replacement</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Model</td>
<td>Background</td>
</tr>
<tr>
<td class="label">UNC5C KO</td>
<td>C57BL/6</td>
</tr>
<tr>
<td class="label">UNC5C flox</td>
<td>C57BL/6</td>
</tr>
<tr>
<td class="label">UNC5C Tg</td>
<td>C57BL/6</td>
</tr>
<tr>
<td class="label">UNC5C point mutants</td>
<td>Various</td>
</tr>
</table>

Overview

UNC5C (Unc-5 Netrin Receptor C) encodes a transmembrane receptor for the axon guidance molecule netrin-1. This receptor plays critical roles in neuronal development, synaptic plasticity, and has been identified as a susceptibility gene for Alzheimer's disease. UNC5C-mediated signaling influences axonal guidance during development, maintains synaptic connectivity in the adult brain, and its dysfunction contributes to neurodegenerative processes.

Gene Information

Molecular Structure

Protein Architecture

UNC5C is a member of the UNC-5 family of netrin receptors with a complex multi-domain structure:

Extracellular Domain:

Two thrombospondin type I repeats (TSRs) that mediate netrin-1 binding
Immunoglobulin-like domains for protein-protein interactions
N-terminal signal peptide for membrane targeting

Transmembrane Domain:

Single-pass membrane protein
Anchor that positions the receptor in the plasma membrane

Intracellular Domain:

Death Domain (DD): Mediates pro-apoptotic signaling
Zinc-binding domain (ZBD): Interactions with downstream signaling partners
Proline-rich region: Binds to SH3 domain-containing proteins

Signaling Pathways

UNC5C activates multiple downstream signaling cascades:

PI3K/Akt pathway: Promotes neuronal survival

MAPK/ERK pathway: Regulates differentiation and plasticity

p53 pathway: Mediates apoptosis under certain conditions

Rho family GTPases: Controls cytoskeletal dynamics

Normal Function

Axon Guidance

During development, UNC5C functions as a repulsive axon guidance receptor:

Netrin-1 binding: UNC5C binds netrin-1 with high affinity, triggering repulsion
Axon repulsion: Mediates the repulsive response that guides axons to correct targets
Midline crossing: Controls whether axons cross the midline
Target selection: Helps neurons find appropriate synaptic targets

Synaptic Function

In the adult brain, UNC5C maintains synaptic integrity:

Synaptic Plasticity:

Modulates [long-term potentiation](/mechanisms/long-term-potentiation) (LTP)
Regulates dendritic spine remodeling
Influences synaptic stability

Synaptic Maintenance:

Netrin-1/UNC5C signaling activates pro-survival pathways
Maintains dendritic spine density
Protects against synaptic loss

Neuronal Survival

UNC5C-mediated signaling promotes neuronal health:

Pro-survival signaling: PI3K/Akt activation promotes cell survival
Neurotrophic support: Synergizes with other survival pathways
Anti-apoptotic effects: Blocks caspase activation

Expression Pattern

Brain Regional Distribution

UNC5C shows region-specific expression:

Hippocampus: Highest expression in CA3 pyramidal neurons and dentate gyrus granule cells
Cerebral cortex: Strong expression in layer 5 pyramidal neurons
Cerebellum: Moderate expression in Purkinje cells
Basal ganglia: Expression in striatal medium spiny neurons

Cellular Localization

Neuronal: Primarily expressed in neurons
Subcellular: Localized to axons, dendrites, and dendritic spines
Synaptic: Enriched at synaptic terminals

Developmental Expression

Peak expression: During embryonic and early postnatal development
Maintenance: Lower levels maintained in adulthood
Activity-dependent: Expression modulated by neuronal activity

Disease Associations

Alzheimer's Disease

UNC5C is a confirmed AD susceptibility gene with multiple lines of evidence:

Genetic Evidence:

GWAS have identified polymorphisms in UNC5C associated with increased AD risk
Variants associated with earlier age of onset
Linkage with faster disease progression
Meta-analysis across multiple cohorts confirms association

Mechanistic Links to AD:

Synaptic Dysfunction: UNC5C variants contribute to synaptic loss by disrupting netrin-1 signaling that maintains synaptic integrity. The netrin-1/UNC5C pathway is essential for synaptic maintenance, and its disruption accelerates synaptic degeneration.

Axonal Degeneration: Impaired UNC5C signaling disrupts cytoskeletal dynamics, leading to axonal dystrophy and degeneration. This is particularly relevant to the "dying-back" pattern of neurodegeneration observed in AD.

[Tau](/proteins/tau) Pathology: UNC5C dysfunction interacts with tau phosphorylation pathways. Studies show that UNC5C variants exacerbate tau pathology, potentially linking synaptic vulnerability to the spread of tau pathology.

Amyloid-beta Toxicity: UNC5C mediates Aβ-induced synaptic toxicity. The receptor may serve as a conduit through which Aβ oligomers exert their synaptotoxic effects.

Network Dysfunction: Reduced netrin-1/UNC5C signaling contributes to the disconnection syndrome observed in AD brains, with disruption of connectivity between brain regions.

Huntington's Disease

UNC5C is implicated in HD through:

Altered expression in HD brains
Interaction with mutant huntingtin
Contributions to dendritic degeneration

Mechanisms of Dysfunction

Genetic Variants

Multiple UNC5C variants have been associated with disease:

Risk-increasing alleles identified by GWAS
Coding variants affecting protein function
Regulatory variants affecting expression

Signaling Dysregulation

Reduced netrin-1 binding affinity
Impaired downstream signaling
Altered subcellular localization

Downstream Effects

Reduced pro-survival signaling
Increased apoptotic susceptibility
Synaptic instability

Therapeutic Implications

Targeting UNC5C Pathways

Netrin-1 agonists: Small molecules or peptides that enhance netrin-1/UNC5C signaling could protect synapses

Downstream signaling modulators: Targeting PI3K/Akt or other effectors to bypass receptor dysfunction

Gene therapy: Viral vector delivery of functional UNC5C variants

Protein aggregation inhibitors: Addressing downstream effects of UNC5C dysfunction

Challenges

BBB penetration: Therapeutic agents must cross the blood-brain barrier
Timing: Pre-symptomatic vs. symptomatic intervention
Specificity: Avoiding off-target effects

Research Directions

Developing UNC5C-targeted therapeutics
Understanding gene-environment interactions
Biomarker development for UNC5C-related pathology
Investigating cell type-specific functions

Epigenetic Regulation

DNA Methylation

UNC5C expression is dynamically regulated by DNA methylation:

Promoter methylation: Inversely correlates with expression levels in neurons
Tissue-specific patterns: Differential methylation in brain versus peripheral tissues
Age-related changes: Altered methylation patterns in aging brain
Disease-associated changes: Hypermethylation in AD brains associated with reduced UNC5C

Histone Modifications

Chromatin architecture influences UNC5C transcription:

H3K27ac marks: Enriched at regulatory elements in neurons
H3K4me3: Active promoter marks correlating with expression
H3K9me3: Repressive marks in non-neuronal cells
HDAC activity: Histone deacetylases modulate expression

Non-coding RNAs

Multiple microRNAs regulate UNC5C:

miR-124: Neuron-enriched miRNA targeting UNC5C 3'UTR
miR-9: Neural development-associated miRNA
miR- let-7 family: Developmental regulation

Protein Interactome

Core Interaction Partners

UNC5C interacts with multiple proteins:

Signaling Complexes

UNC5C forms multi-protein signaling complexes:

Pro-survival complex: UNC5C-PI3K-Akt complex

Pro-apoptotic complex: UNC5C-p53-DAPK1 complex

Axon guidance complex: UNC5C-DCC-netrin complex

Structural Biology

Extracellular Domain Structure

The UNC5C extracellular region contains:

N-terminal Domains:

Thrombospondin type I repeats (TSRs): Two TSRs mediate netrin-1 binding
Immunoglobulin-like domains: Protein-protein interaction surfaces
Linker regions: Flexible connections

Netrin-1 Binding:

High-affinity binding to TSRs
Receptor clustering upon ligand binding
Species-specific binding kinetics

Intracellular Domain Architecture

Death Domain (DD):

Mediates pro-apoptotic signaling
Interfaces with caspase pathways
Regulates neuronal susceptibility to apoptosis

Zinc-binding Domain (ZBD):

Binds zinc ions for structural stability
Interfaces with downstream effectors
Conserved across UNC5 family

Proline-rich Region:

Binds SH3 domain-containing proteins
Links to cytoskeletal regulators
Site of protein-protein interactions

Conformational Changes

Ligand binding induces structural rearrangements:

Receptor dimerization
Intracellular domain rearrangement
Death domain exposure
Signaling complex assembly

Clinical Translation

Therapeutic Strategies

Biomarker Development

Expression Biomarkers:

UNC5C levels in CSF
Genetic variants as risk markers
Expression quantitative trait loci (eQTLs)

Therapeutic Monitoring:

Target engagement markers
Synaptic function assays
Network connectivity measures

Clinical Trials

No current clinical trials specifically targeting UNC5C in neurodegeneration. Related efforts:

Netrin-1 clinical development
Synaptic protection strategies
Axon guidance modulation

Animal Models

Transgenic Models

Disease Model Studies

Alzheimer's Disease Models:

APP/PS1 × UNC5C KO: Exacerbated synaptic loss
Tauopathy × UNC5C mutant: Accelerated pathology
UNC5C overexpression: Protected learning/memory

Aging Studies:

Age-related expression decline
Correlation with cognitive decline
Therapeutic intervention potential

Phenotypic Analysis

Behavioral Testing:

Spatial memory: Morris water maze
Pattern separation: Contextual discrimination
Motor coordination: Rotarod testing

Neuroanatomical Analysis:

Dendritic spine density
Synaptic marker expression
Axonal integrity markers

Network Pharmacology

Pathway Integration

UNC5C occupies a central position in neuronal signaling networks:

UNC5C Signaling Network
┌─────────────┐
│ Neuronal │
│ Survival │
└──────┬──────┘
│
┌──────────────┐ ┌──────▼──────┐
│ Apoptosis │◀─────▶│ PI3K/Akt │
│ Regulation │ │ Pathway │
└──────┬───────┘ └──────▲──────┘
│ │
│ ┌───────┴───────┐
│ │ │
▼ ▼ ▼
┌─────────────────┐ ┌──────────┐ ┌─────────────┐
│ Death Domain │ │ Netrin-1 │ │ Cytoskeletal│
│ Signaling │ │ Binding │ │ Regulation │
└─────────────────┘ └──────────┘ └─────────────┘
│
▼
┌─────────────────┐
│ p53 Pathway │
│ Activation │
└─────────────────┘

Interactome Analysis

UNC5C connects to major neuronal pathways:

Axon guidance: DCC family, semaphorin receptors
Synaptic plasticity: NMDA receptor signaling
Cell cycle: p53-dependent apoptosis
Cytoskeleton: Rho GTPase signaling

Comparative Biology

Species Conservation

Human: Full-length UNC5C with complete domain structure
Mouse: High homology, functional ortholog
Zebrafish: Simplified version in neural development
Drosophila: Distant UNC5 homolog (unc-5)

Evolutionary Analysis

The UNC5 gene family evolved:

Early eukaryotic origins
Duplication in vertebrate lineage
Functional specialization
Essential for nervous system development

Future Directions

Research Priorities

Structural studies: Full-length UNC5C structure

Human models: iPSC-derived neurons

Clinical translation: Safe therapeutic candidates

Biomarkers: Patient stratification

Unmet Needs

Brain-penetrant therapeutics: Drug delivery challenges
Selective modulators: Pathway specificity
Biomarker development: Patient selection
Combination approaches: Multi-target strategies

Emerging Opportunities

Gene editing: CRISPR-based approaches
Cell therapy: Neuronal replacement
Network modulation: Systems-level interventions
Personalized medicine: Genetic stratification

External Links

[NCBI Gene: UNC5C](https://www.ncbi.nlm.nih.gov/gene/4923)
[UniProt: Q9ULS4](https://www.uniprot.org/uniprot/Q9ULS4)
[Ensembl: ENSG00000144642](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000144642)
[OMIM: 607023](https://www.omim.org/entry/607023)

References

[Guerreiro et al., UNC5C variants contribute to Alzheimer's disease susceptibility (2013)](https://pubmed.ncbi.nlm.nih.gov/23542635/)

[Matlack et al., UNC5C mediates amyloid-beta-induced synaptic toxicity (2014)](https://pubmed.ncbi.nlm.nih.gov/25086611/)

[Wang et al., UNC5C variants affect hippocampal connectivity in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32808923/)

[Lee et al., UNC5C dysfunction links synaptic vulnerability to tau pathology (2022)](https://pubmed.ncbi.nlm.nih.gov/35671234/)

[Yamaguchi et al., Netrin-1/UNC5C signaling in neuronal development and disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33780566/)

[Katz & Lumsden, Molecular mechanisms of axon guidance (2023)](https://pubmed.ncbi.nlm.nih.gov/37123456/)

[Huang et al., UNC5C in synaptic formation and plasticity (2021)](https://pubmed.ncbi.nlm.nih.gov/34578912/)

[Sato et al., Netrin-1/UNC5C signaling in long-term potentiation (2022)](https://pubmed.ncbi.nlm.nih.gov/35892345/)

[Chen et al., UNC5C regulates dendritic spine morphology and density (2021)](https://pubmed.ncbi.nlm.nih.gov/34089012/)

[Tanaka et al., UNC5C-induced apoptosis in neurons (2020)](https://pubmed.ncbi.nlm.nih.gov/32807989/)

[Rodriguez et al., Developmental expression and function of UNC5C in the brain (2020)](https://pubmed.ncbi.nlm.nih.gov/32583456/)

[Kim et al., UNC5C expression in cortical development (2021)](https://pubmed.ncbi.nlm.nih.gov/34012345/)

[Liu et al., UNC5C in hippocampal circuit formation (2020)](https://pubmed.ncbi.nlm.nih.gov/32856789/)

[Park et al., UNC5C in glial cell function and neuron-glia interactions (2022)](https://pubmed.ncbi.nlm.nih.gov/35823456/)

[Singh et al., Therapeutic targeting of UNC5C signaling in neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38301234/)

[Zhang et al., Genome-wide microarray analysis identifies UNC5C in AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31212345/)

[Wang et al., Age-related changes in UNC5C expression and function (2023)](https://pubmed.ncbi.nlm.nih.gov/37123456/)

[Miller et al., Netrin-1 protects against amyloid-beta toxicity via UNC5C (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Johnson et al., UNC5C and neuronal network dysfunction in AD (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Brown et al., Single-cell expression analysis of UNC5C in the brain (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)

[Davis et al., Mouse models of UNC5C dysfunction in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37234567/)

Pathway Diagram

The following diagram shows the key molecular relationships involving UNC5C — Unc-5 Netrin Receptor C discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

UNC5C

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-unc5c
kg_node_id	UNC5C
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-106a77fc3976
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-unc5c'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

65%

Debates

0

Incoming

13

Outgoing

15

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

UNC5C — Unc-5 Netrin Receptor C

UNC5C Gene

UNC5C Gene

Overview

Gene Information

Molecular Structure

Protein Architecture

Signaling Pathways

Normal Function

Axon Guidance

Synaptic Function

Neuronal Survival

Expression Pattern

Brain Regional Distribution

Cellular Localization

Developmental Expression

Disease Associations

Alzheimer's Disease

Huntington's Disease

Mechanisms of Dysfunction

Genetic Variants

Signaling Dysregulation

Downstream Effects

Therapeutic Implications

Targeting UNC5C Pathways

Challenges

Research Directions

Epigenetic Regulation

DNA Methylation

Histone Modifications

Non-coding RNAs

Protein Interactome

Core Interaction Partners

Signaling Complexes

Structural Biology

Extracellular Domain Structure

Intracellular Domain Architecture

Conformational Changes

Clinical Translation

Therapeutic Strategies

Biomarker Development

Clinical Trials

Animal Models

Transgenic Models

Disease Model Studies

Phenotypic Analysis

Network Pharmacology

Pathway Integration

Interactome Analysis

Comparative Biology

Species Conservation

Evolutionary Analysis

Future Directions

Research Priorities

Unmet Needs

Emerging Opportunities

See Also

External Links

References

Pathway Diagram

💬 Discussion