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Functional receptor for GDNF encoded by the c-ret proto-oncogene
M Trupp1, E Arenas, M Fainzilber
1Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Nature
|June 27, 1996
Summary
Glial-cell-line-derived neutrophic factor (GDNF) binds to the Ret receptor tyrosine kinase, mediating neurotrophic effects. This identifies Ret as a functional GDNF receptor, crucial for motor and dopaminergic neuron survival.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Glial-cell-line-derived neutrophic factor (GDNF) supports survival of various neurons, including dopaminergic and motor neurons.
- Despite its neurotrophic roles, GDNF receptors remained unidentified.
- GDNF shares structural similarities with the TGF-beta superfamily, suggesting a receptor system.
Purpose of the Study:
- To identify the functional receptor for Glial-cell-line-derived neutrophic factor (GDNF).
- To investigate the role of the c-ret proto-oncogene product in mediating GDNF's neurotrophic effects.
Main Methods:
- Binding assays and tyrosine phosphorylation studies using a GDNF-responsive motor neuron cell line.
- Transfection of naive fibroblasts with Ret to assess GDNF-mediated responses.
- Analysis of c-ret mRNA expression in adult substantia nigra and GDNF's protective effects on Ret-positive neurons.
Main Results:
- GDNF directly binds to and induces tyrosine phosphorylation of the Ret proto-oncogene product, a receptor tyrosine kinase.
- Ret mediates GDNF-induced survival and growth signals when expressed in naive cells.
- c-ret mRNA is highly expressed in dopaminergic neurons, and GDNF protects these Ret-positive neurons from cell death.
Conclusions:
- The c-ret proto-oncogene product functions as a GDNF receptor.
- Ret mediates the neurotrophic effects of GDNF on motor and dopaminergic neurons.
- This discovery provides a molecular target for understanding and potentially treating neurodegenerative conditions affecting these neuronal populations.