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

The Journal of Cell Biology
Jonathan DeGeerNathalie Lamarche-Vane

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.

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Citations

Jun 1, 2017·The Journal of Cell Biology·Archan GangulySubhojit Roy
Feb 9, 2018·International Journal of Molecular Sciences·Mirela MaierTomoko Takano
Jun 3, 2016·Journal of Cell Science·Milan PatraMalini Sen
Sep 5, 2018·Development·Stéphanie BackerEvelyne Bloch-Gallego
Apr 3, 2019·International Journal of Molecular Sciences·Sadig Niftullayev, Nathalie Lamarche-Vane
Jun 5, 2020·The Journal of Cell Biology·Carlos Sánchez-HuertasJérôme Boudeau
Aug 21, 2020·Calcified Tissue International·Virginia M StiffelKin-Hing William Lau
Nov 30, 2018·Frontiers in Neuroscience·David J Miller, Patrice E Fort
Jun 22, 2018·International Journal of Molecular Sciences·Valentina ZamboniGiorgio R Merlo
Aug 16, 2018·Frontiers in Cellular Neuroscience·Nicholas P Boyer, Stephanie L Gupton
Dec 31, 2020·Cells·Ray Yueh Ku, Masaaki Torii

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Methods Mentioned

BETA
GTPases
GTPase
nucleotide
coIP
confocal microscopy
immunoprecipitation
pull-down
pull-downs
transfection
fluorescence microscopy

Software Mentioned

GraphPad
Photoshop
MetaMorph
Zen2009
GraphPad Prism
Mascot
Zen
Adobe
Quantity One

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