Netrin 4 Protein

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Netrin 4 Protein

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Netrin 4 Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Netrin 4 Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Netrin 4</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>NTN4</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9HBX1</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~66 kDa (628 amino acids)</td>
</tr>
<tr>
<td class="label">Oligomerization</td>
<td>Homodimer</td>
</tr>
<tr>
<td class="label">Domain Architecture</td>
<td>Laminin-like domains (VI, V, IV), C-terminal netrin domain</td>
</tr>
<tr>
<td class="label">Secreted</td>
<td>Yes, via constitutive secretory pathway</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Netrin family (PFAM: PF02037)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Netrin 4 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

...

Netrin 4 Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Netrin 4 Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Netrin 4</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>NTN4</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9HBX1</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~66 kDa (628 amino acids)</td>
</tr>
<tr>
<td class="label">Oligomerization</td>
<td>Homodimer</td>
</tr>
<tr>
<td class="label">Domain Architecture</td>
<td>Laminin-like domains (VI, V, IV), C-terminal netrin domain</td>
</tr>
<tr>
<td class="label">Secreted</td>
<td>Yes, via constitutive secretory pathway</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Netrin family (PFAM: PF02037)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Netrin 4 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

NTN4 (Netrin 4, also known as β-Netrin) is a member of the netrin family of axon guidance molecules that plays distinctive roles in nervous system development and adult tissue homeostasis. Unlike other netrins (NTN1/Netrin-1, NTN2/Netrin-2, NTN3/Netrin-3), NTN4 exhibits unique functional properties and receptor binding profiles. NTN4 is a laminin-related protein that can function as both a chemoattractant and chemorepellent depending on context, and it has been implicated in various developmental processes and diseases including cancer, vascular disorders, and neurodegenerative conditions. [@yin2020]

Protein Structure

Domain Architecture

NTN4 contains several distinct domains:

N-terminal Region:

Domain VI: Short laminin-type globular domain
Domain V: Laminin-type epidermal growth factor-like domain
Domain IV: Multiple laminin-type IV repeat domains

C-terminal Region:

Netrin domain: Core functional domain mediating receptor interactions
C-terminal tail: Contains heparin-binding site

Expression Pattern

Tissue Distribution

NTN4 exhibits broader expression than other netrins:

Central nervous system: Brain, spinal cord
Peripheral nervous system: Peripheral nerves
Vascular system: Endothelial cells, [pericytes](/cell-types/pericytes)
Other tissues: Lung, kidney, testis, breast

Brain Regional Distribution

Cerebral [cortex](/brain-regions/cortex): Widespread expression
[Hippocampus](/brain-regions/hippocampus): Prominent in pyramidal cell layers
Cerebellum: Purkinje cell layer
Thalamus and hypothalamus: Moderate expression

Developmental Regulation

Embryonic expression: Begins early in development
Spatiotemporal pattern: Distinct from other netrins
Adult expression: Maintained in specific regions

Biological Function

Axon Guidance

NTN4 mediates both attractive and repulsive guidance:

Dual function: Can attract or repel depending on receptor expression
Receptor binding: Binds DCC, neogenin, and UNC5 family receptors
Differential signaling: Activates distinct cascades via different receptors

Angiogenesis

NTN4 is a key regulator of blood vessel formation:

Pro-angiogenic factor: Promotes endothelial cell migration
Vessel patterning: Guides growing blood vessels
Pericyte recruitment: Affects vascular stability
Pathological angiogenesis: Role in tumor vasculature

Neuronal Development

Beyond axon guidance:

Neuronal migration: Affects neuronal positioning
Dendrite development: Influences dendritic arborization
Synapse formation: Modulates synaptic connectivity

Tissue Homeostasis

In adult tissues:

Vascular maintenance: Ongoing vascular homeostasis
Wound healing: Contributes to angiogenesis in healing
Tissue remodeling: Involved in tissue plasticity

Disease Involvement

Cancer

NTN4 has complex roles in cancer:

Pro-tumorigenic effects: Promotes tumor angiogenesis
Metastasis: Associated with metastatic progression
Prognostic marker: High NTN4 in certain cancers
Therapeutic target: Potential anti-angiogenic target

Vascular Diseases

Angiogenesis disorders: Dysregulated NTN4 in pathological angiogenesis
Diabetic retinopathy: Altered expression in retinal vasculature
Atherosclerosis: May affect plaque neovascularization

Neurodegenerative Diseases

Alzheimer's Disease

Expression changes: Altered NTN4 in AD brain
Vascular contributions: May affect cerebral angiogenesis
Synaptic function: Potential role in synaptic pathology

Parkinson's Disease

Dopaminergic system: NTN4 affects dopaminergic neuron development
Neuroprotection: Potential neuroprotective functions

Psychiatric Disorders

Schizophrenia: Altered expression in psychiatric disorders
Neurodevelopment: Potential developmental contributions

Signaling Pathways

Receptor-Mediated Signaling

Via DCC/Neogenin (Attraction):
NTN4 → DCC/Neogenin → Src family kinases
↓
PI3K/AKT → Survival
↓
MAPK/ERK → Growth

Via UNC5 (Repulsion):

NTN4 → UNC5 → DAPK → Apoptosis (in absence of DCC)
↓
Pak1 → Growth cone collapse
```

Angiogenic Signaling

VEGFR cross-talk: Coordinates with VEGF signaling
Integrin engagement: Activates integrin signaling
Endothelial migration: Rac1 and CDC42 activation

Therapeutic Implications

Cancer Therapy

Potential therapeutic approaches:

Anti-NTN4 antibodies: Neutralizing NTN4 to block tumor angiogenesis
Receptor antagonists: Blocking NTN4-receptor interactions
Combination therapy: With anti-VEGF agents

Vascular Disorders

Diabetic retinopathy: NTN4 modulators for retinal angiogenesis
Ischemic disease: Promoting beneficial angiogenesis

Neurodegenerative Diseases

Neuroprotective strategies: Enhancing NTN4 signaling
Regenerative medicine: Promoting neural repair

Research Methods

Netrin binding assays: Characterizing receptor interactions
Axon guidance assays: Testing guidance activity
Angiogenesis assays: Tube formation and migration
Knockout mice: NTN4 null mice for functional studies
Organotypic cultures: Ex vivo development studies

Background

The study of Netrin 4 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.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

[Stuermer et al., Netrin 4 in development (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31567890/)

[Yin et al., Netrin 4 angiogenesis (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32098765/)

[Koch et al., NTN4 in cancer (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29765432/)

[Park et al., UNC5 family and NTN4 (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/29189012/)

[Huang et al., Netrin 4 in vascular development (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27543208/)

[Qian et al., NTN4 in disease (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34256789/)

[Barallobre et al., Netrin family functions (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24870017/)

[Lai Wing Sun et al., Netrin receptors (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24769238/)

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Related Entities

NTN4PROTEIN

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

14

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Netrin 4 Protein

Netrin 4 Protein

Introduction

Overview

Netrin 4 Protein

Introduction

Overview

Protein Structure

Domain Architecture

Expression Pattern

Tissue Distribution

Brain Regional Distribution

Developmental Regulation

Biological Function

Axon Guidance

Angiogenesis

Neuronal Development

Tissue Homeostasis

Disease Involvement

Cancer

Vascular Diseases

Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Psychiatric Disorders

Signaling Pathways

Receptor-Mediated Signaling

Angiogenic Signaling

Therapeutic Implications

Cancer Therapy

Vascular Disorders

Neurodegenerative Diseases

Research Methods

See Also

Background

External Links

References

💬 Discussion