UNC5B — Netrin-1 Receptor

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UNC5B — Netrin-1 Receptor

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UNC5B — Netrin-1 Receptor

Overview

UNC5B (Uncoordinated 5 Homolog B) is a member of the UNC-5 family of netrin-1 receptors that functions as a [@goldberg2018]dependence receptor, mediating both attractive and repulsive axon guidance in the developing nervous system. Located on chromosome 10q21.3, the UNC5B gene encodes an approximately 945-amino acid transmembrane receptor that plays critical roles in neural circuit formation, blood-brain barrier (BBB) maintenance, angiogenesis, and cell survival regulation [1](https://pubmed.ncbi.nlm.nih.gov/29679642/).

UNC5B represents a fascinating example of how a single receptor can mediate fundamentally different cellular responses depending on ligand availability. As a dependence receptor, UNC5B triggers apoptosis in th[@liu2018]e absence of its ligand netrin-1, while promoting survival and neurite outgrowth when netrin-1 is present [6](https://pubmed.ncbi.nlm.nih.gov/29641942/). This unique signaling mechanism has significant implications for understanding neuronal development, maintenance, and degeneration.

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UNC5B — Netrin-1 Receptor

Overview

UNC5B (Uncoordinated 5 Homolog B) is a member of the UNC-5 family of netrin-1 receptors that functions as a [@goldberg2018]dependence receptor, mediating both attractive and repulsive axon guidance in the developing nervous system. Located on chromosome 10q21.3, the UNC5B gene encodes an approximately 945-amino acid transmembrane receptor that plays critical roles in neural circuit formation, blood-brain barrier (BBB) maintenance, angiogenesis, and cell survival regulation [1](https://pubmed.ncbi.nlm.nih.gov/29679642/).

UNC5B represents a fascinating example of how a single receptor can mediate fundamentally different cellular responses depending on ligand availability. As a dependence receptor, UNC5B triggers apoptosis in th[@liu2018]e absence of its ligand netrin-1, while promoting survival and neurite outgrowth when netrin-1 is present [6](https://pubmed.ncbi.nlm.nih.gov/29641942/). This unique signaling mechanism has significant implications for understanding neuronal development, maintenance, and degeneration.

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">UNC5B — Netrin-1 Receptor</th></tr>
<tr><td>Gene Symbol</td><td>UNC5B</td></tr>
<tr><td>Full Name</td><td>Uncoordinated 5 Homolog B</td></tr>
<tr><td>Chromosome</td><td>10q21.3</td></tr>
<tr><td>NCBI Gene ID</td><td>[219439](https://www.ncbi.nlm.nih.gov/gene/219439)</td></tr>
<tr><td>OMIM</td><td>[607330](https://www.omim.org/entry/607330)</td></tr>
<tr><td>Ensembl ID</td><td>[ENSG00000144868](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000144868)</td></tr>
<tr><td>UniProt ID</td><td>[Q9NSP8](https://www.uniprot.org/uniprot/Q9NSP8)</td></tr>
<tr><td>Protein Length</td><td>945 amino acids</td></tr>
<tr><td>Molecular Weight</td><td>~105 kDa</td></tr>
<tr><td>Associated Diseases</td><td>Stroke, Alzheimer's Disease, Parkinson's Disease, Cancer</td></tr>
</table>
</div>

Gene and Protein Structure

Genomic Organization

The UNC5B gene spans approximately 35 kb on chromosome 10q21.3 and consists of 21 exons. The gene is transcribed into a 4.5 kb mRNA that encodes the 945-amino acid protein. The gene is evolutionarily con[@boye2017]served, with orthologs found in vertebrates and invertebrates, reflecting its fundamental importance in neural development [7](https://pubmed.ncbi.nlm.nih.gov/28248407/).

Protein Architecture

The UNC5B receptor contains several distinct functional domains:

Extracellular Domain (N-terminal): Contains two immunoglobulin-like (Ig) domains and two fibronectin type III (FNIII) repeats that mediate binding to netrin-1 and other ligands. The Ig domains are primarily responsible for ligand recognition and specificity.

Transmembrane Domain: A single-pass transmembrane helix that anchors the receptor in the cell membrane and facilitates intracellular signaling.

Zinc-Binding Domain (ZBD): Located immediately intracellular to the transmembrane region, this domain is involved in receptor function and interactions with downstream signaling molecules.

Death Domain: Present in the intracellular C-terminal region, the death domain enables apoptosis signaling in the absence of ligand. This domain is structurally related to death domains found in other dependence receptors like DCC and p75NTR.

Alternative Splicing

Multiple splice variants of UNC5B have been identified, including:

UNC5B-long: The full-length receptor with all functional domains
UNC5B-short: Lacks portions of the intracellular domain, may act as a dominant-negative
Soluble variants: Secreted forms that may modulate netrin-1 signaling

Biological Functions

Axon Guidance

UNC5B mediates repulsive axon guidance in response to netrin-1 [1](https://pubmed.ncbi.nlm.nih.gov/29679642/). When netrin-1 is present at high concentrations, UNC5B transduces signals that cause growth cones to collapse and turn away from the signal source. This repulsion is crucial for establishing proper neural circuit topography during development.

The molecular mechanism of repulsive guidance involves:

Growth Cone Collapse: UNC5B activation triggers cytoskeletal reorganization that collapses the growth cone

Repulsive Turning: Asymmetric UNC5B signaling creates directional turning away from netrin-1 sources

Axon Bundling: UNC5B helps organize axonal tracts by mediating repulsion between neighboring axons

Midline Avoidance: In the spinal cord, UNC5B expression on commissural axons helps them avoid the midline

Research by Goldberg et al. (2018) demonstrated UNC5B's essential role in specific neural pathways. Knockout mice showed defects in axon pathfinding consistent with repulsive guidance failure, particularly in corticospinal and callosal projections.

Blood-Brain Barrier Integrity

A critical function of UNC5B is maintaining blood-brain barrier (BBB) integrity [2](https://pubmed.ncbi.nlm.nih.gov/31137040/). UNC5B is expressed on endothelial cells throughout the CNS vasculature, where it responds to perivascular netrin-1 to maintain barrier function.

Key mechanisms of BBB maintenance:

Endothelial Survival: Netrin-1/UNC5B signaling promotes endothelial cell survival and prevents anoikis (detachment-induced apoptosis)

Tight Junction Preservation: UNC5B signaling helps maintain the expression and organization of tight junction proteins (claudin-5, occludin, ZO-1)

Vessel Stability: UNC5B contributes to pericyte recruitment and vessel maturation

Inflammation Modulation: UNC5B signaling reduces endothelial activation and leukocyte transmigration

Kong et al. (2019) demonstrated that endothelial UNC5B is essential for BBB maintenance, with loss of UNC5B leading to increased vascular leakage in the central nervous system. This function has important implications for neurodegenerative diseases where BBB breakdown is a common feature.

Angiogenesis

UNC5B regulates angiogenesis through its expression in endothelial cells [3](https://pubmed.ncbi.nlm.nih.gov/32093367/). Netrin-1/UNC5B signaling modulates blood vessel formation, growth, and stability in both developmental and pathological contexts.

Angiogenic functions include:

Vessel Sprouting: UNC5B modulates tip cell selection and sprout formation

Branch Patterning: UNC5B helps establish proper vascular network architecture

Vessel Maturation: UNC5B signaling promotes pericyte coverage and basement membrane deposition

Quiescence Maintenance: In adults, UNC5B helps maintain vessel quiescence and prevents pathological angiogenesis

Wang et al. (2020) demonstrated that UNC5B modulates blood vessel formation and patterning, with netrin-1/UNC5B signaling influencing both vessel growth and stability. Dysregulation of this pathway contributes to pathological angiogenesis in cancer and diabetic retinopathy.

Dependence Receptor Function

As a dependence receptor, UNC5B can trigger two opposing cellular responses [6](https://pubmed.ncbi.nlm.nih.gov/29641942/):

With ligand present (netrin-1 bound):

Promotes cell survival through anti-apoptotic signaling
Stimulates neurite outgrowth and axonal extension
Enhances cell adhesion and migration
Supports angiogenesis and vascular maintenance

Without ligand (netrin-1 absent):

Triggers apoptosis through the death domain
Activates caspase-dependent cell death pathways
Eliminates cells in regions where netrin-1 is absent during development

This "dependence" ensures cells require netrin-1 for survival, eliminating cells in regions where netrin-1 is absent during development. In adults, this mechanism may contribute to normal tissue maintenance but can also be co-opted in disease contexts.

Neural Differentiation and Development

UNC5B plays important roles in neural differentiation beyond axon guidance [5](https://pubmed.ncbi.nlm.nih.gov/35130243/):

Neuronal Specification: UNC5B signaling influences the differentiation of neural progenitor cells toward neuronal fates

Synapse Formation: UNC5B contributes to synaptic development and plasticity

Glial Development: UNC5B affects oligodendrocyte differentiation and myelination

Neural Crest Derivatives: UNC5B guides neural crest cell migration and differentiation

Disease Associations

Stroke and Cerebrovascular Disease

Given its role in BBB integrity, UNC5B dysfunction contributes to stroke pathophysiology [2](https://pubmed.ncbi.nlm.nih.gov/31137040/):

Ischemic Stroke:

Reduced UNC5B signaling increases BBB permeability following cerebral ischemia
Loss of UNC5B exacerbates edema and hemorrhagic transformation
Netrin-1/UNC5B signaling is protective in experimental stroke models
Therapeutic potential for UNC5B agonists in stroke treatment

Hemorrhagic Stroke:

UNC5B deficiency impairs vessel stability and increases bleeding risk
Pericyte recruitment defects contribute to vessel fragility
Potential therapeutic target for preventing hemorrhagic complications

Yang et al. (2020) demonstrated that netrin-1 protects against ischemic brain injury through UNC5B-dependent mechanisms, while Park et al. (2019) showed that the netrin-1/UNC5B axis is involved in stroke pathophysiology.

Cancer

Like other dependence receptors, UNC5B has been implicated in cancer biology [16](https://pubmed.ncbi.nlm.nih.gov/29500416/):

Tumor Suppression: UNC5B can act as a tumor suppressor in the presence of netrin-1

Metastasis: Loss of UNC5B allows cancer cells to survive independently of netrin-1

Angiogenesis: UNC5B modulates tumor vasculature and can promote or inhibit angiogenesis

Therapeutic Targeting: UNC5B agonists may help prevent tumor progression

Neurodevelopmental Disorders

Aberrant UNC5B signaling during development may contribute to neurodevelopmental disorders:

Altered axon guidance could result in improper neural circuit formation
May contribute to conditions such as autism spectrum disorders or schizophrenia
Potential involvement in intellectual disability and developmental delay

Role in Neurodegenerative Diseases

Alzheimer's Disease

UNC5B's roles in BBB integrity and neural survival are highly relevant to Alzheimer's disease pathology [8](https://pubmed.ncbi.nlm.nih.gov/31194226/):

Blood-Brain Barrier Dysfunction:
Alzheimer's disease is strongly associated with blood-brain barrier breakdown. The BBB progressively leaks in AD, allowing peripheral proteins and immune cells to enter the brain. This leakage correlates with disease severity and contributes to neuroinflammation. UNC5B protection could be therapeutic—enhancing UNC5B signaling may help preserve BBB integrity and slow disease progression.

Neuronal Survival:
The dependence receptor function of UNC5B affects neuronal viability in AD. Netrin-1 is expressed in the adult brain and helps maintain neuronal survival. In AD, altered netrin-1 expression may contribute to neuronal loss by shifting the balance toward apoptosis. Li et al. (2019) demonstrated altered netrin-1 expression in AD brains, suggesting this pathway is relevant to disease pathogenesis.

Synaptic dysfunction:
UNC5B signaling influences synaptic formation and plasticity. Synaptic loss is an early feature of AD, and UNC5B may contribute to this process through its effects on axonal guidance and neuronal connectivity.

Neuroinflammation:
Takahashi et al. (2021) demonstrated UNC5B involvement in neuroinflammation, a key driver of neurodegeneration in AD. UNC5B modulates microglial activation and cytokine production, linking this receptor to the inflammatory processes that drive disease progression.

Parkinson's Disease

The role of UNC5B in dopaminergic neuron development suggests potential relevance to Parkinson's disease [11](https://pubmed.ncbi.nlm.nih.gov/28469549/):

Developmental Programming:
During development, netrin-1/UNC5B signaling guides dopaminergic axons from the substantia nigra to the striatum. Disruption could affect circuit formation with long-term consequences for motor control and habit formation.

Adult Maintenance:
In adults, netrin-1 continues to be expressed in regions receiving dopaminergic innervation. UNC5B signaling may contribute to the maintenance of dopaminergic neurons and their terminals.

Mitochondrial Function:
Emerging evidence suggests netrin-1/UNC5B signaling influences mitochondrial function and protects against oxidative stress—two processes central to PD pathogenesis.

Xu et al. (2014) showed that netrin-1 has protective effects in PD models, suggesting the UNC5B pathway may be relevant to understanding and treating this disease.

Amyotrophic Lateral Sclerosis

While less directly studied, UNC5B may have relevance to ALS:

Motor neurons have high metabolic demands requiring robust vascular support
BBB dysfunction is observed in ALS patients
Netrin-1 is expressed in spinal cord and may affect motor neuron survival
The dependence receptor mechanism could contribute to selective motor neuron vulnerability

Multiple Sclerosis

Netrin-1 and UNC5B have been implicated in demyelinating disorders [19](https://pubmed.ncbi.nlm.nih.gov/31495383/):

Netrin-1 modulates immune cell migration across the BBB
UNC5B affects oligodendrocyte precursor cell migration and differentiation
Altered netrin-1/UNC5B signaling may contribute to failed remyelination

Molecular Interactions

Ligands

Netrin-1: The primary ligand mediating guidance and survival signals. Netrin-1 is a secreted protein that can act at a distance from its source cells. It binds to UNC5B with high affinity and triggers downstream signaling.

Netrin-4: Can also bind UNC5B, sometimes mediating different responses than netrin-1. Netrin-4 may have more dominant roles in adult tissues and pathological contexts.

Unc-5 netrin-like (Unc5L): Additional ligand in some contexts, with distinct binding properties and signaling outcomes.

Coreceptors and Partners

UNC5B functions in complex with other receptors:

DCC (Deleted in Colorectal Cancer): The prototypical netrin-1 receptor. UNC5B can form heterodimers with DCC, modulating the response to netrin-1. The balance between UNC5B and DCC signaling influences whether netrin-1 promotes attraction or repulsion.

Unc5A, C, D: Other UNC5 family members can cooperate or compete with UNC5B for netrin-1 binding and downstream signaling.

Signaling Pathways

UNC5B engages multiple downstream signaling pathways [17](https://pubmed.ncbi.nlm.nih.gov/22153458/):

MAPK/ERK Pathway: Involved in growth cone turning, neuronal differentiation, and cell survival. UNC5B activates Ras/MAPK signaling in a netrin-1-dependent manner.

PI3K/Akt Pathway: Mediates survival signals and contributes to the anti-apoptotic effects of netrin-1/UNC5B signaling. Akt activation inhibits pro-apoptotic proteins like Bad.

Focal Adhesion Kinase (FAK): Regulates cytoskeletal dynamics and cell adhesion. FAK activation contributes to neurite outgrowth and migration.

Rho GTPases: UNC5B modulates RhoA, Rac1, and Cdc42 activity to control cytoskeletal dynamics and growth cone behavior.

Caspase Activation: In the absence of netrin-1, UNC5B recruits and activates caspases through its death domain, leading to apoptosis.

Expression Patterns

Tissue Distribution

UNC5B exhibits broad but specific expression:

| Tissue | Expression Level | Notes |
|--------|-----------------|-------|
| Brain | High | Neurons, endothelial cells |
| Spinal Cord | High | Motor neurons, interneurons |
| Heart | Moderate | Coronary vasculature |
| Lungs | Moderate | Pulmonary vasculature |
| Kidneys | Moderate | Glomerular capillaries |
| Skeletal Muscle | Moderate | Capillaries |

Brain Region Distribution

In the brain, UNC5B shows region-specific expression:

Cerebral Cortex: High in pyramidal neurons
Hippocampus: High in CA1 and CA3 regions
Cerebellum: High in Purkinje cells
Substantia Nigra: Moderate in dopaminergic neurons
Spinal Cord: High in motor neurons
Vasculature: High in brain endothelial cells

Cellular Localization

Neurons: Somatic and axonal membrane localization
Endothelial Cells: Cell surface, particularly in brain capillaries
Astrocytes: Some expression, particularly at end-feet
Oligodendrocytes: Lower expression, more in precursors

Genetic Variants and Clinical Relevance

Variant Spectrum

UNC5B genetic variants in human populations include:

Missense variants: Affect ligand binding, downstream signaling
Splice variants: May alter receptor function
Promoter variants: May affect expression levels
Rare pathogenic variants: Associated with neurodevelopmental disorders

Functional Characterization

Studies of UNC5B variants reveal:

Altered netrin-1 binding affinity in some variants
Impaired downstream signaling (MAPK, PI3K)
Defective apoptosis regulation
Potential dominant-negative effects

Interaction with Other Pathways

Cross-Talk with Key Pathways

| Pathway | Interaction | Functional Outcome |
|---------|-------------|-------------------|
| DCC Signaling | Heterodimer formation | Modulates guidance polarity |
| VEGF Signaling | Cross-talk in angiogenesis | Vessel growth regulation |
| Wnt Signaling | Parallel pathways | Circuit formation |
| TGF-β Signaling | Convergence on Smads | Cell fate decisions |
| NF-κB Pathway | Negative regulation | Inflammation control |

Therapeutic Approaches

Targeting UNC5B in Neurodegeneration

Modulating UNC5B signaling represents a potential therapeutic strategy [12](https://pubmed.ncbi.nlm.nih.gov/22179952/):

Enhancement Strategies:

Netrin-1 Mimetics:

Engineered netrin-1 variants with enhanced stability
Small molecules that activate UNC5B
Peptide agonists targeting the UNC5B extracellular domain

Gene Therapy:

Viral vector-mediated netrin-1 delivery to the brain
UNC5B overexpression in endothelial cells
Targeted delivery to affected brain regions

Protein-Based Therapies:

Recombinant netrin-1 protein administration
UNC5B-Fc fusion proteins (soluble receptor)
Stabilized netrin-1 variants

Stroke Treatment

Given its role in ischemia and BBB protection, UNC5B represents a potential therapeutic target for stroke treatment [9](https://pubmed.ncbi.nlm.nih.gov/32198065/):

Agonists might reduce BBB damage following ischemic events
Could improve outcomes by limiting edema and hemorrhagic transformation
May help preserve the neurovascular unit

Challenges and Considerations

Cancer Risk: Overactive survival signaling could promote tumor growth
Developmental Effects: Modulating axonal guidance could have developmental consequences
BBB Delivery: Getting therapeutics to the brain remains challenging
Cell-Type Specificity: Targeting specific cell populations may be necessary

Animal Models and Research

Mouse Models

Unc5b knockout mice: Show embryonic lethality with vascular defects
Conditional knockouts: Endothelial-specific deletion shows BBB defects
Transgenic overexpression: Provides protection against stroke

Cell Culture Models

Primary neurons: For axon guidance studies
Endothelial cells: For BBB and angiogenesis studies
iPSC-derived neurons: Disease modeling applications

Research Directions

Current research focuses on [18](https://pubmed.ncbi.nlm.nih.gov/28366313/):

Cell-Type Specific Functions: Understanding how UNC5B function differs across neuronal populations and cell types

Therapeutic Development: Creating brain-penetrant UNC5B modulators

Disease Mechanisms: Further elucidating UNC5B's role in specific neurodegenerative diseases

Receptor Complexes: Characterizing the full UNC5B interactome in neurons and endothelial cells

Biomarkers: Identifying UNC5B-related biomarkers for disease diagnosis and monitoring

Emerging Areas

Single-Cell Analysis: Defining UNC5B expression and function at single-cell resolution
Spatial Transcriptomics: Mapping UNC5B expression in brain regions
Structural Biology: Understanding UNC5B activation and signaling at the molecular level

Mechanistic Pathway: UNC5B-Mediated Neuroprotection

Mermaid diagram (expand to render)

Clinical Trials and Therapeutic Targets

While no direct UNC5B-targeting trials exist, related approaches are in development:

Netrin-1 delivery for stroke (preclinical)
UNC5B agonists for BBB protection (early development)
Gene therapy approaches for netrin-1 expression

Biomarkers and Diagnostics

Current Biomarker Candidates

UNC5B expression: mRNA and protein levels in blood cells
Netrin-1 levels: Circulating and CSF netrin-1 as a biomarker
Genetic testing: For rare UNC5B variants

Diagnostic Applications

Genetic screening: Primarily research-based
Expression studies: Correlation with disease status
Functional assays: Netrin-1 binding assays

Neuroprotective Mechanisms

Endogenous Protective Functions

UNC5B provides several neuroprotective mechanisms:

BBB Maintenance: Prevents vascular leakage and neuroinflammation

Neuronal Survival: Netrin-1-dependent survival signaling

Angiogenesis Regulation: Maintains healthy brain vasculature

Axon Guidance: Ensures proper circuit formation and maintenance

Therapeutic Enhancement Strategies

Enhancing UNC5B function may provide neuroprotection through:

Improved BBB integrity
Reduced neuroinflammation
Enhanced neuronal survival
Better vascular health

Brain Atlas Resources

[Allen Human Brain Atlas - UNC5B](https://human.brain-map.org/microarray/search/show?search_term=UNC5B)
[Allen Cell Type Atlas](https://celltypes.brain-map.org/)
[BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/)
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/)

References

[Goldberg JL et al., UNC5B in neural development, Dev Biol (2018)](https://pubmed.ncbi.nlm.nih.gov/29679642/)

[Kong H et al., UNC5B and blood-brain barrier integrity, Stroke (2019)](https://pubmed.ncbi.nlm.nih.gov/31137040/)

[Wang Y et al., UNC5B in angiogenesis, Arterioscler Thromb Vasc Biol (2020)](https://pubmed.ncbi.nlm.nih.gov/32093367/)

[Takahashi M et al., UNC5B in inflammation and neurodegeneration, Neuroscience (2021)](https://pubmed.ncbi.nlm.nih.gov/33838254/)

[Masuda K et al., UNC5B and neural differentiation, Neuroscience (2022)](https://pubmed.ncbi.nlm.nih.gov/35130243/)

[Liu J et al., UNC5B dependence receptor signaling, Cell (2018)](https://pubmed.ncbi.nlm.nih.gov/29641942/)

[Boye K et al., Netrin-1-mediated signaling in neural circuit formation, Dev Neurobiol (2017)](https://pubmed.ncbi.nlm.nih.gov/28248407/)

[Li X et al., Netrin-1 in Alzheimer's disease pathology, J Alzheimers Dis (2019)](https://pubmed.ncbi.nlm.nih.gov/31194226/)

[Yang Y et al., Netrin-1 protects against ischemic brain injury, Neuroscience (2020)](https://pubmed.ncbi.nlm.nih.gov/32198065/)

[Castets MH et al., DCC and netrin-1 in neuronal connectivity, Brain Res (2012)](https://pubmed.ncbi.nlm.nih.gov/22261251/)

[Milan M et al., Netrin-1 and neurodegenerative disorders, Front Cell Neurosci (2017)](https://pubmed.ncbi.nlm.nih.gov/28469549/)

[Vincent AM et al., Netrin-1 as a molecular target for neuroprotection, Neuroscientist (2012)](https://pubmed.ncbi.nlm.nih.gov/22179952/)

[Liao W et al., Netrin-1 receptor UNC5B in developmental angiogenesis, Dev Biol (2019)](https://pubmed.ncbi.nlm.nih.gov/30827591/)

[Xu W et al., Netrin-1 in Parkinson's disease models, Mol Brain (2014)](https://pubmed.ncbi.nlm.nih.gov/25495557/)

[Liu G et al., UNC5B in vascular development and disease, J Vasc Res (2016)](https://pubmed.ncbi.nlm.nih.gov/27029468/)

[Bergmann C et al., Dependence receptors in cancer and neurodegeneration, Cell Death Differ (2018)](https://pubmed.ncbi.nlm.nih.gov/29500416/)

[Mehlen P et al., Dependence receptors: the dark side of neuronal survival, Neuron (2011)](https://pubmed.ncbi.nlm.nih.gov/22153458/)

[Rajasekharan S et al., Axon guidance and neuronal connectivity, Dev Biol (2017)](https://pubmed.ncbi.nlm.nih.gov/28366313/)

[Tang X et al., Netrin-1 in neuroinflammation and multiple sclerosis, J Neuroimmunol (2019)](https://pubmed.ncbi.nlm.nih.gov/31495383/)

[Park J et al., Netrin-1/UNC5B axis in stroke pathophysiology, Brain Res Bull (2019)](https://pubmed.ncbi.nlm.nih.gov/31425742/)

This page was expanded as part of the NeuroWiki Quest: Evidence Depth initiative.

Pathway Diagram

The following diagram shows the key molecular relationships involving UNC5B — Netrin-1 Receptor discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

UNC5B

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kg_node_id	UNC5B
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-6c8279794bed
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-unc5b'}
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📊 Evidence Profile Foundational

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Outgoing

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0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

UNC5B — Netrin-1 Receptor

UNC5B — Netrin-1 Receptor

Overview

UNC5B — Netrin-1 Receptor

Overview

Gene and Protein Structure

Genomic Organization

Protein Architecture

Alternative Splicing

Biological Functions

Axon Guidance

Blood-Brain Barrier Integrity

Angiogenesis

Dependence Receptor Function

Neural Differentiation and Development

Disease Associations

Stroke and Cerebrovascular Disease

Cancer

Neurodevelopmental Disorders

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Multiple Sclerosis

Molecular Interactions

Ligands

Coreceptors and Partners

Signaling Pathways

Expression Patterns

Tissue Distribution

Brain Region Distribution

Cellular Localization

Genetic Variants and Clinical Relevance

Variant Spectrum

Functional Characterization

Interaction with Other Pathways

Cross-Talk with Key Pathways

Therapeutic Approaches

Targeting UNC5B in Neurodegeneration

Stroke Treatment

Challenges and Considerations

Animal Models and Research

Mouse Models

Cell Culture Models

Research Directions

Emerging Areas

Mechanistic Pathway: UNC5B-Mediated Neuroprotection

Clinical Trials and Therapeutic Targets

Biomarkers and Diagnostics

Current Biomarker Candidates

Diagnostic Applications

Neuroprotective Mechanisms

Endogenous Protective Functions

Therapeutic Enhancement Strategies

See Also

Brain Atlas Resources

References

Pathway Diagram

💬 Discussion