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E3 ligase Nedd4 promotes axon branching by downregulating PTEN
Jovana Drinjakovic1, Hosung Jung, Douglas S Campbell
1Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
Neuron
|February 18, 2010
Summary
Regulated protein degradation controls synapse formation. Nedd4-regulated PTEN in retinal ganglion cells is crucial for axon terminal branching, not long-range navigation.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- The ubiquitin-proteasome system (UPS) is vital for synaptic connections.
- Specific UPS components and targets in neurons remain largely uncharacterized.
Purpose of the Study:
- To investigate the role of UPS in neuronal development, specifically in retinal ganglion cells (RGCs).
- To identify specific UPS E3 ligases and their targets involved in axon arborization.
Main Methods:
- Inhibition of the UPS in developing Xenopus RGCs using a dominant-negative ubiquitin mutant.
- Identification and functional analysis of E3 ligase Nedd4 in RGC axon growth cones.
- Investigation of PTEN as a downstream target of Nedd4 and its role in PI3K pathway regulation.
Main Results:
- UPS inhibition in RGCs impaired terminal branching but not long-range navigation.
- Nedd4 was identified as a key E3 ligase in RGC growth cones, with its disruption severely inhibiting branching.
- Nedd4 regulates PTEN levels in growth cones, and reduced PTEN levels rescued Nedd4 inhibition-induced branching defects.
Conclusions:
- Nedd4-regulated PTEN is a critical in vivo regulator of terminal arborization in RGCs.
- The UPS, through Nedd4 and PTEN, plays a specific role in refining synaptic connections at the terminal level.
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