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Neogenin regulates neuronal survival through DAP kinase
Y Fujita1, J Taniguchi, M Uchikawa
1Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Cell Death and Differentiation
|June 28, 2008
Summary
Repulsive guidance molecule (RGM) and neogenin signaling regulate cell fate by controlling death-associated protein kinase (DAPK) activity. This interaction is crucial for cell death during central nervous system development.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Repulsive guidance molecule (RGM) is a membrane protein with diverse functions in the developing central nervous system.
- Neogenin, a receptor for RGM, has cell death-inducing activity independent of RGM.
Purpose of the Study:
- To investigate the role of death-associated protein kinase (DAPK) in neogenin-mediated signal transduction.
- To elucidate the mechanism by which RGM/neogenin signaling regulates cell fate.
Main Methods:
- In vitro interaction studies between neogenin and DAPK.
- Analysis of DAPK autophosphorylation at Ser308.
- In vivo studies using chick neural tube models with neogenin overexpression or RGM downregulation.
- Assessment of apoptosis using dominant-negative DAPK mutants and small-interference RNA (siRNA).
Main Results:
- Neogenin interacts with DAPK and reduces its autophosphorylation on Ser308 in vitro.
- Neogenin-induced cell death is blocked by RGM or DAPK inhibition.
- Neogenin overexpression or RGM downregulation induces apoptosis in the chick neural tube.
- DAPK inhibition attenuates neogenin/RGM-induced proapoptotic activity in vivo.
Conclusions:
- Death-associated protein kinase (DAPK) is a key component in neogenin's signal transduction pathway.
- RGM/neogenin signaling regulates cell fate decisions by modulating DAPK activity.
- This pathway is critical for controlling apoptosis during central nervous system development.
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