Hsc70 chaperone activity underlies Trio GEF function in axon growth and guidance induced by netrin-1.

Abstract

During development, netrin-1 is both an attractive and repulsive axon guidance cue and mediates its attractive function through the receptor Deleted in Colorectal Cancer (DCC). The activation of Rho guanosine triphosphatases within the extending growth cone facilitates the dynamic reorganization of the cytoskeleton required to drive axon extension. The Rac1 guanine nucleotide exchange factor (GEF) Trio is essential for netrin-1-induced axon outgrowth and guidance. Here, we identify the molecular chaperone heat shock cognate protein 70 (Hsc70) as a novel Trio regulator. Hsc70 dynamically associated with the N-terminal region and Rac1 GEF domain of Trio. Whereas Hsc70 expression supported Trio-dependent Rac1 activation, adenosine triphosphatase-deficient Hsc70 (D10N) abrogated Trio Rac1 GEF activity and netrin-1-induced Rac1 activation. Hsc70 was required for netrin-1-mediated axon growth and attraction in vitro, whereas Hsc70 activity supported callosal projections and radial neuronal migration in the embryonic neocortex. These findings demonstrate that Hsc70 chaperone activity is required for Rac1 activation by Trio and this function underlies netrin-1/DCC-dependent axon outgrowth and guidance.

• Authors: Jonathan DeGeer, Andrew Kaplan, Pierre Mattar, Morgane Morabito, Ursula Stochaj, Timothy E Kennedy, Anne Debant, Michel Cayouette, Alyson E Fournier, Nathalie Lamarche-Vane
• Journal: The Journal of cell biology (J Cell Biol) Vol. 210 Issue 5 Pg. 817-32 (Aug 31 2015) ISSN: 1540-8140 [Electronic] United States
• PMID: 26323693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 DeGeer et al.

Chemical References

• DCC Receptor
• Dcc protein, rat
• Guanine Nucleotide Exchange Factors
• HSC70 Heat-Shock Proteins
• Hspa8 protein, rat
• NTN1 protein, human
• Nerve Growth Factors
• Nerve Tissue Proteins
• Ntn1 protein, mouse
• Ntn1 protein, rat
• RNA, Small Interfering
• Receptors, Cell Surface
• Trio protein, rat
• Tumor Suppressor Proteins
• Netrin-1
• Adenosine Triphosphatases
• Rac1 protein, rat
• rac1 GTP-Binding Protein

Topics

• Adenosine Triphosphatases (genetics)
• Animals
• Axons (physiology)
• Cell Line
• Cell Movement (genetics)
• Cell Proliferation
• DCC Receptor
• Enzyme Activation
• Guanine Nucleotide Exchange Factors (metabolism)
• HEK293 Cells
• HSC70 Heat-Shock Proteins (biosynthesis, genetics, metabolism)
• Humans
• Mice
• Neocortex (cytology, embryology, metabolism)
• Nerve Growth Factors (metabolism)
• Nerve Tissue Proteins (metabolism)
• Netrin-1
• Protein Structure, Tertiary
• RNA Interference
• RNA, Small Interfering
• Rats
• Receptors, Cell Surface (metabolism)
• Signal Transduction
• Tumor Suppressor Proteins (metabolism)
• rac1 GTP-Binding Protein (metabolism)