The E3 Ubiquitin Ligase TRIM9 Is a Filopodia Off Switch Required for Netrin-Dependent Axon Guidance
2015
Summary Neuronal
growth cone
filopodiacontain guidance receptors and contribute to
axon guidance; however, the mechanism by which the guidance cue
netrinincreases
filopodiadensity is unknown. Here, we demonstrate that TRIM9, an E3
ubiquitin ligasethat localizes to
filopodiatips and binds the
netrin receptorDCC, interacts with and
ubiquitinatesthe
barbed-end polymerase VASP to modulate filopodial stability during
netrin-dependent
axon guidance. Studies with murine Trim9 +/+ and Trim9 −/− cortical neurons, along with a non-ubiquitinatable VASP mutant, demonstrate that TRIM9-mediated
ubiquitinationof VASP reduces VASP filopodial tip localization, VASP dynamics at tips, and filopodial stability. Upon
netrintreatment, VASP is deubiquitinated, which promotes VASP tip localization and filopodial stability. Trim9 deletion induces
axon guidancedefects in vitro and in vivo, whereas a gradient of deubiquitinase inhibition promotes
axonturning in vitro. We conclude that a gradient of TRIM9-mediated
ubiquitinationof VASP creates a filopodial stability gradient during
axonturning.
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