FoxO limits microtubule stability and is itself negatively regulated by microtubule disruption.
Bottom Line: Indeed, levels of neuronal FoxO were strongly reduced after acute pharmacological MT disruption as well as sustained genetic disruption of the neuronal cytoskeleton.This decrease was independent of the dual leucine zipper kinase-Wallenda pathway and required function of Akt kinase.We present a model wherein FoxO degradation is a component of a stabilizing, protective response to cytoskeletal insult.
Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA.Show MeSH
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Mentions: To expand upon the role of FoxO in synaptic function, we performed live imaging of NMJs with fluorescent FM 1-43 dye. Upon stimulation, FM 1-43 dye is taken up by synaptic vesicles and labels newly endocytosed vesicles within the nerve terminal. Thus, defects in synaptic labeling with FM 1-43 dye are indicative of compromised vesicle cycling (Kuromi and Kidokoro, 2005; Verstreken et al., 2008). Stimulation with 90 mM KCl caused robust labeling of synaptic boutons in wild-type larvae (Fig. 5, A and D). In contrast, synaptic terminals in foxO21 animals were labeled ∼50% less efficiently than in controls (Fig. 5, B and D), indicating impaired synaptic vesicle dynamics. We next asked whether the defects in FM 1-43 uptake observed in foxO mutants are directly linked to the activity of foxO in regulating MT dynamics or whether they are incident to its function in a different cellular context. If elevated synaptic MT stability is behind the aberrant vesicle cycling in foxO animals, the FM 1-43 loading defects should be suppressed by futsch. Remarkably, the FM 1-43 loading defects in foxO21 homozygotes are fully suppressed in futschK68/+;; foxO21 animals (Fig. 5, C and D). We interpret this result to indicate that the MT defects at foxO NMJs are primarily responsible for dysfunction in synaptic vesicle cycling.
Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA.