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
Related in: MedlinePlus
License 1 - License 2
Mentions: Acetylation of α-tubulin at lysine 40 is a hallmark of stable neuronal MTs (Fukushima et al., 2009). foxO mutants were stained for acetylated α-tubulin (Ac-Tub) as a direct measure of synaptic MT stability. At a wild-type NMJ, the Ac-Tub signal is intense within the synaptic core and is much fainter or absent within terminal boutons, which contain a more dynamic MT pool (Fig. 4, A–B′; Viquez et al., 2006). Terminal boutons in foxO mutants display prominent anti–Ac-Tub staining (Fig. 4, C–D′). To enable quantification, we scored the proportion of terminal boutons at each NMJ with strong, weak, or undetectable Ac-Tub signals (Fig. 4 E). In foxO21 mutants, the mean fraction of terminal boutons/NMJ with strong anti–Ac-Tub staining is 0.53 ± 0.05 compared with 0.14 ± 0.03 in control (Fig. 4 E). foxOΔ94 and foxOΔ2 homozygotes display similarly expanded Ac-Tub distributions, demonstrating that the phenotype is not allele specific (Fig. 4 E and Table S2). Neuronal knockdown of FoxO likewise increased the proportion of terminal boutons/NMJ with strong Ac-Tub signal—the mean fraction of terminal boutons/NMJ with strong anti–Ac-Tub staining is 0.35 ± 0.05 in controls compared with 0.56 ± 0.03 in Elav>foxORNAi#1 mutants (Fig. 4 E). These findings support a neuronal role of FoxO in regulating synaptic MT stability. We next tested whether the phenotype is dominantly suppressed by Futsch. Indeed, the mean fraction of terminal boutons/NMJ with strong anti–Ac-Tub staining is reduced from 0.53 ± 0.05 in foxO21 homozygotes to 0.27 ± 0.05 in futschK68/+;; foxO21 animals (Fig. 4 E). In concert with the MT looping data, these findings demonstrate that foxO attenuates MT stability.
Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA.