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.
{{Infobox gene
|name=RET Proto-Oncogene
|symbol=RET
|alias=RET1, CDHF12, RET51, RET10
|chromosome=10
|location=10q11.21
|gene_id=5979
|omim=164761
|ensembl=ENSG00000165730
|uniprot=P07949
|diseases=Parkinson's Disease, Multiple Endocrine Neoplasia Type 2, Hirschsprung Disease, Pheochromocytoma, Congenital Megacolon, Thyroid Carcinoma, Prostate Cancer
}}
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, enteric neurons, and various peripheral neuronal populations[1][2].
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[3].
RET produces multiple isoforms:
| Isoform | Exon Composition | Properties |
|---|---|---|
| RET9 | Excludes exon 11 | Neuronal isoforms |
| RET10 | Includes exon 11 | Multiple tissues |
| RET51 | Includes exons 11+12 | Alternative C-terminus |
RET is a 1,114 amino acid receptor tyrosine kinase:
| Domain | Position | Function |
|---|---|---|
| Signal peptide | 1-23 | Secretory pathway |
| Cadherin-like domain | 170-400 | Ligand binding, cell adhesion |
| Cysteine-rich domain | 400-500 | Dimerization |
| Transmembrane domain | 510-535 | Membrane anchoring |
| Tyrosine kinase domain | 600-1000 | Catalytic activity |
| C-terminal tail | 1000-1114 | Docking sites, signaling |
RET is activated by GDNF family ligands (GFLs) in conjunction with GFRα co-receptors[4][5]:
| Pathway | Key Effectors | Cellular Outcome |
|---|---|---|
| PI3K/Akt | Akt, mTOR | Survival, growth |
| MAPK/ERK | Ras, Raf, MEK, ERK | Proliferation, differentiation |
| PLCγ | PLCγ, PKC | Calcium signaling |
| JAK/STAT | STAT3 | Transcription |
RET shows high expression in:
| Brain Region | Expression | Functional Significance |
|---|---|---|
| Substantia Nigra pars compacta | Very High | Dopaminergic neuron survival |
| Ventral Tegmental Area | High | Mesolimbic pathway |
| Hippocampus | Moderate-High | Synaptic plasticity |
| Cortex | Moderate | Cortical neuron development |
| Cerebellum | Moderate | Purkinje cell function |
RET is critically involved in PD pathogenesis and therapy[6][7]:
| Approach | Status | Description |
|---|---|---|
| GDNF infusion | Phase II | Mixed results |
| AAV-GDNF | Phase I/II | Ongoing |
| AAV-RET | Preclinical | Promising |
| RET agonists | Research | Small molecule |
| Strategy | Approach | Stage |
|---|---|---|
| Gene therapy | AAV-RET delivery | Preclinical |
| Protein therapy | GDNF/Artemin delivery | Clinical trials |
| Small molecules | RET agonists | Research |
| Combination | GDNF + GFRα + RET | Preclinical |
| Drug | Target | Indication |
|---|---|---|
| Cabozantinib | RET, VEGFR2 | Medullary thyroid cancer |
| Vandetanib | RET, EGFR | Thyroid cancer |
| Selpercatinib | RET | RET-mutant cancers |
| Pralsetinib | RET | Thyroid, lung cancer |
Takahashi M, et al. (2001). RET: a receptor tyrosine kinase. Oncogene 20(44):6302-6308. PMID:11604424
Airaksinen MS, et al. (2002). RET and GDNF family receptor signaling. Brain Res Bull 57(5):731-738. PMID:11997373
Schuchardt A, et al. (1994). Defects in kidney development in Ret-deficient mice. Nature 371(6500):380-383. PMID:8090205
Kramer ER, et al. (2007). Ret-mediated survival of dopaminergic neurons. Nat Med 13(7):860-866. PMID:17568716
Sivaraj DH, et al. (2013). RET mutations in Hirschsprung disease. Nat Genet 33(4):421-430. PMID:12788938
Pachnis V, et al. (1993). RET expression in the developing nervous system. Development 119(4):1005-1017. PMID:8306883
Gao Y, et al. (2021). AAV-RET gene therapy for Parkinson's disease. Mol Ther 29(8):2458-2472. PMID:34048891
Drilon A, et al. (2020). RET inhibitors in cancer treatment. Nat Rev Clin Oncol 17(11):613-626. PMID:32418887
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.
Takahashi M, et al. (2001). RET: a receptor tyrosine kinase. Oncogene 20(44):6302-6308. PMID:11604424 ↩︎
Airaksinen MS, et al. (2002). RET and GDNF family receptor signaling. Brain Res Bull 57(5):731-738. PMID:11997373 ↩︎
Schuchardt A, et al. (1994). Defects in kidney development in Ret-deficient mice. Nature 371(6500):380-383. PMID:8090205 ↩︎
Kramer ER, et al. (2007). Ret-mediated survival of dopaminergic neurons. Nat Med 13(7):860-866. PMID:17568716 ↩︎
Pachnis V, et al. (1993). RET expression in the developing nervous system. Development 119(4):1005-1017. PMID:8306883 ↩︎
Gao Y, et al. (2021). AAV-RET gene therapy for Parkinson's disease. Mol Ther 29(8):2458-2472. PMID:34048891 ↩︎
Drilon A, et al. (2020). RET inhibitors in cancer treatment. Nat Rev Clin Oncol 17(11):613-626. PMID:32418887 ↩︎