RET Gene

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RET Gene

Introduction

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RET Gene

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">RET Gene</th>
</tr>
<tr>
<td class="label">Isoform</td>
<td>Exon Composition</td>
</tr>
<tr>
<td class="label">RET9</td>
<td>Excludes exon 11</td>
</tr>
<tr>
<td class="label">RET10</td>
<td>Includes exon 11</td>
</tr>
<tr>
<td class="label">RET51</td>
<td>Includes exons 11+12</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Position</td>
</tr>
<tr>
<td class="label">Signal peptide</td>
<td>1-23</td>
</tr>
<tr>
<td class="label">Cadherin-like domain</td>
<td>170-400</td>
</tr>
<tr>
<td class="label">Cysteine-rich domain</td>
<td>400-500</td>
</tr>
<tr>
<td class="label">Transmembrane domain</td>
<td>510-535</td>
</tr>
<tr>
<td class="label">Tyrosine kinase domain</td>
<td>600-1000</td>
</tr>
<tr>
<td class="label">C-terminal tail</td>
<td>1000-1114</td>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Key Effectors</td>
</tr>
<tr>
<td class="label">PI3K/Akt</td>
<td>Akt, [mTOR](/entities/mtor)</td>
</tr>
<tr>
<td class="label">MAPK/ERK</td>
<td>Ras, Raf, MEK, ERK</td>
</tr>
<tr>
<td class="label">PLCγ</td>
<td>PLCγ, PKC</td>
</tr>
<tr>
<td class="label">JAK/STAT</td>
<td>STAT3</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>Expression</td>
</tr>
<tr>
<td class="label">Substantia Nigra pars compacta</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">Ventral Tegmental Area</td>
<td>High</td>
</tr>
<tr>
<td class="label">[Hippocampus](/brain-regions/hippocampus)</td>
<td>Moderate-High</td>
</tr>
<tr>
<td class="label">[Cortex](/brain-regions/cortex)</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">GDNF infusion</td>
<td>Phase II</td>
</tr>
<tr>
<td class="label">AAV-GDNF</td>
<td>Phase I/II</td>
</tr>
<tr>
<td class="label">AAV-RET</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">RET agonists</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Approach</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-RET delivery</td>
</tr>
<tr>
<td class="label">Protein therapy</td>
<td>GDNF/Artemin delivery</td>
</tr>
<tr>
<td class="label">Small molecules</td>
<td>RET agonists</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>GDNF + GFRα + RET</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Cabozantinib</td>
<td>RET, VEGFR2</td>
</tr>
<tr>
<td class="label">Vandetanib</td>
<td>RET, EGFR</td>
</tr>
<tr>
<td class="label">Selpercatinib</td>
<td>RET</td>
</tr>
<tr>
<td class="label">Pralsetinib</td>
<td>RET</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">74 edges</a></td>
</tr>
</table>

Ret Gene 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

Mermaid diagram (expand to render)

The RET (Rearranged during Transfection) proto-oncogene encodes a receptor tyrosine kinase that serves as the primary signaling receptor for the GDNF (Glial Cell Line-Derived Neurotrophic Factor) family of ligands. RET is essential for the development and maintenance of the nervous system, particularly dopaminergic [neurons](/entities/neurons), enteric neurons, and various peripheral neuronal populations["@takahashi2001"][@airaksinen2002].

Gene Structure and Evolution

The RET gene is located on chromosome 10q11.21 and spans approximately 55 kb of genomic DNA. The gene consists of 21 exons that undergo complex alternative splicing to produce multiple protein isoforms with distinct functional properties[@schuchardt1994].

Alternative Splicing

RET produces multiple isoforms:

Evolutionary Conservation

Highly conserved across vertebrates
Emergence in early vertebrates
Key for nervous system development

Protein Structure

RET is a 1,114 amino acid receptor tyrosine kinase:

Structural Domains

Biochemical Properties

Molecular weight: ~120 kDa (precursor)
Glycosylation: Multiple N-linked sites
Processing: Proteolytic cleavage at extracellular domain
Dimerization: Ligand-induced dimerization

Molecular Functions

GDNF Family Ligand Signaling

RET is activated by GDNF family ligands (GFLs) in conjunction with GFRα co-receptors[@kramer2007][@pachnis1993]:

Ligand Binding: GDNF family ligands bind GFRα co-receptors

Complex Formation: GFL/GFRα recruits RET

Dimerization: RET dimerizes and autophosphorylates

Signaling Activation: Multiple downstream pathways activated

Downstream Signaling Pathways

Biological Functions

Dopaminergic neuron development: Essential for SNc and VTA neurons
Enteric nervous system: Required for gut innervation
Kidney development: Ureteric bud branching
Sensory neurons: Development and survival

Expression Pattern

Central Nervous System

RET shows high expression in:

Peripheral Tissues

Enteric ganglia: ENS development
Adrenal medulla: Chromaffin cells
Kidney: Ureteric bud
Testis: Spermatogenesis

Role in Neurodegeneration

Parkinson's Disease

RET is critically involved in PD pathogenesis and therapy[@gao2021][@drilon2020]:

Dopaminergic Protection: GDNF/RET signaling essential for SNc neuron survival
Disease State: RET expression reduced in PD substantia nigra
Therapeutic Potential: AAV-RET gene therapy in development
Combination Therapy: RET + GDNF enhances neuroprotection

Clinical Considerations

Other Neurodegenerative Conditions

Multiple System Atrophy: Reduced RET signaling
Huntington's Disease: Altered RET expression
ALS: RET in motor neuron survival

Cancer (Oncogenic Mutations)

Multiple Endocrine Neoplasia Type 2: Gain-of-function mutations
Medullary Thyroid Carcinoma: RET point mutations
Pheochromocytoma: RET mutations

Therapeutic Implications

Neurodegeneration Therapy

Cancer Therapy

Challenges

[Blood-brain barrier](/entities/blood-brain-barrier) penetration
Optimal delivery route
Dosing optimization
Safety concerns (oncogenic potential)

Animal Models

Knockout Studies

Ret KO mice: Embryonic lethal (E9-10)
Neural-specific KO: Enteric aganglionosis
Conditional KO: Adult phenotypes

Transgenic Models

RET overexpression: Enhanced neuronal survival
Humanized models: Expressing mutant RET
PD models: A-Syn × Ret crosses

Research Directions

Current Focus Areas

Gene therapy optimization: AAV serotypes, promoters

Combination approaches: Multiple neurotrophic factors

Biomarkers: RET expression as marker

Patient selection: Based on RET status

Safety: Minimizing oncogenic risk

Emerging Areas

RET-specific agonists
PROTAC degraders
Cell-specific targeting
Non-viral delivery

Key Publications

Takahashi M, et al. (2001). RET: a receptor tyrosine kinase. Oncogene 20(44):6302-6308. PMID: 11604424(https://pubmed.ncbi.nlm.nih.gov/11604424/)

Airaksinen MS, et al. (2002). RET and GDNF family receptor signaling. Brain Res Bull 57(5):731-738. PMID: 11997373(https://pubmed.ncbi.nlm.nih.gov/11997373/)

Schuchardt A, et al. (1994). Defects in kidney development in Ret-deficient mice. Nature 371(6500):380-383. PMID: 8090205(https://pubmed.ncbi.nlm.nih.gov/8090205/)

Kramer ER, et al. (2007). Ret-mediated survival of dopaminergic neurons. Nat Med 13(7):860-866. PMID: 17568716(https://pubmed.ncbi.nlm.nih.gov/17568716/)

Sivaraj DH, et al. (2013). RET mutations in Hirschsprung disease. Nat Genet 33(4):421-430. PMID: 12788938(https://pubmed.ncbi.nlm.nih.gov/12788938/)

Pachnis V, et al. (1993). RET expression in the developing nervous system. Development 119(4):1005-1017. PMID: 8306883(https://pubmed.ncbi.nlm.nih.gov/8306883/)

Gao Y, et al. (2021). AAV-RET gene therapy for Parkinson's disease. Mol Ther 29(8):2458-2472. PMID: 34048891(https://pubmed.ncbi.nlm.nih.gov/34048891/)

Drilon A, et al. (2020). RET inhibitors in cancer treatment. Nat Rev Clin Oncol 17(11):613-626. PMID: 32418887(https://pubmed.ncbi.nlm.nih.gov/32418887/)

External Links

[NCBI Gene: RET](https://www.ncbi.nlm.nih.gov/gene/5979)
[UniProt: P07949](https://www.uniprot.org/uniprot/P07949)
[GeneCards: RET](https://www.genecards.org/cgi-bin/carddisp.pl?gene=RET)
[OMIM: 164761](https://www.omim.org/entry/164761)

Background

The study of Ret Gene 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.

References

[Takahashi M, et al, (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11604424/)

[Airaksinen MS, et al, (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/11997373/)

[Schuchardt A, et al, (1994) (1994)](https://pubmed.ncbi.nlm.nih.gov/8090205/)

[Kramer ER, et al, (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17568716/)

[Pachnis V, et al, (1993) (1993)](https://pubmed.ncbi.nlm.nih.gov/8306883/)

[Gao Y, et al, (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34048891/)

[Drilon A, et al, (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32418887/)

Pathway Diagram

The following diagram shows the key molecular relationships involving RET Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Disease Associations

Source: Open Targets Platform (opentargets.org)

| Disease | Association Score | Disease ID |
|--------|-------------------|------------|
| medullary thyroid gland carcinoma | 0.8617 | MONDO_0015277 |
| multiple endocrine neoplasia type 2A | 0.8591 | MONDO_0008234 |
| multiple endocrine neoplasia type 2B | 0.8192 | MONDO_0008082 |
| Hirschsprung disease | 0.7931 | MONDO_0018309 |
| pheochromocytoma | 0.7780 | MONDO_0008233 |

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RET Gene

RET Gene

Introduction

RET Gene

Introduction

Overview

Gene Structure and Evolution

Alternative Splicing

Evolutionary Conservation

Protein Structure

Structural Domains

Biochemical Properties

Molecular Functions

GDNF Family Ligand Signaling

Downstream Signaling Pathways

Biological Functions

Expression Pattern

Central Nervous System

Peripheral Tissues

Role in Neurodegeneration

Parkinson's Disease

Clinical Considerations

Other Neurodegenerative Conditions

Cancer (Oncogenic Mutations)

Therapeutic Implications

Neurodegeneration Therapy

Cancer Therapy

Challenges

Animal Models

Knockout Studies

Transgenic Models

Research Directions

Current Focus Areas

Emerging Areas

Key Publications

See Also

External Links

Background

References

Pathway Diagram

Disease Associations