Function of an axonal chemoattractant modulated by metalloprotease activity
1Department of Anatomy, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
Science (New York, N.Y.)
|August 26, 2000
Summary
Metalloprotease inhibitors enhance netrin-1 axon guidance by stabilizing its receptor, DCC (Deleted in Colorectal Cancer). This stabilization increases DCC protein levels on axons, regulating axon migration during neural development.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Netrin-1 is a key axonal chemoattractant guiding spinal commissural axons.
- Netrin-1 exerts its function by binding to its receptor, DCC (Deleted in Colorectal Cancer).
- Extracellular matrix proteases can influence axon guidance signaling pathways.
Purpose of the Study:
- To investigate the role of metalloproteases in netrin-1-mediated axon outgrowth.
- To determine if DCC is a substrate for metalloprotease activity.
- To elucidate the mechanism by which metalloprotease inhibitors affect DCC levels and axon guidance.
Main Methods:
- In vitro axon outgrowth assays using netrin-1.
- Treatment with chemical inhibitors of metalloproteases.
- Analysis of DCC protein levels in spinal cord explants.
- Assessment of DCC ectodomain shedding.
Main Results:
- Metalloprotease inhibitors potentiate netrin-1-mediated axon outgrowth in vitro.
- DCC undergoes metalloprotease-dependent ectodomain shedding.
- Inhibitors block DCC proteolytic processing, increasing DCC protein levels on axons.
- Increased DCC levels correlate with enhanced netrin-1 signaling.
Conclusions:
- Metalloprotease activity regulates axon guidance by controlling the availability of functional DCC receptors.
- Inhibiting metalloproteases stabilizes DCC on axons, enhancing netrin-1 signaling.
- Proteolytic processing of DCC is a critical mechanism for modulating axon migration.
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