Limits...
FoxO limits microtubule stability and is itself negatively regulated by microtubule disruption.

Nechipurenko IV, Broihier HT - J. Cell Biol. (2012)

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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA.

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foxO is required for synaptic vesicle cycling. (A–C) Representative images of FM 1-43 dye uptake by NMJs 6/7 of the indicated genotypes after 90 mM K+ stimulation. Bar, 20 µm. (D) Quantification of FM 1-43 labeling intensity at NMJs 6/7 of listed genotypes after 90 mM K+ stimulation. Anterior is up. Data represent means ± SEM normalized to wild type; n = 9 for ElavGal4/CS, n = 6 for foxO21, and n = 7 for futschK68/+;; foxO21, in which n is the number of animals (≥15 NMJs/genotype). *, P < 0.05; **, P < 0.01.
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fig5: foxO is required for synaptic vesicle cycling. (A–C) Representative images of FM 1-43 dye uptake by NMJs 6/7 of the indicated genotypes after 90 mM K+ stimulation. Bar, 20 µm. (D) Quantification of FM 1-43 labeling intensity at NMJs 6/7 of listed genotypes after 90 mM K+ stimulation. Anterior is up. Data represent means ± SEM normalized to wild type; n = 9 for ElavGal4/CS, n = 6 for foxO21, and n = 7 for futschK68/+;; foxO21, in which n is the number of animals (≥15 NMJs/genotype). *, P < 0.05; **, P < 0.01.

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.


FoxO limits microtubule stability and is itself negatively regulated by microtubule disruption.

Nechipurenko IV, Broihier HT - J. Cell Biol. (2012)

foxO is required for synaptic vesicle cycling. (A–C) Representative images of FM 1-43 dye uptake by NMJs 6/7 of the indicated genotypes after 90 mM K+ stimulation. Bar, 20 µm. (D) Quantification of FM 1-43 labeling intensity at NMJs 6/7 of listed genotypes after 90 mM K+ stimulation. Anterior is up. Data represent means ± SEM normalized to wild type; n = 9 for ElavGal4/CS, n = 6 for foxO21, and n = 7 for futschK68/+;; foxO21, in which n is the number of animals (≥15 NMJs/genotype). *, P < 0.05; **, P < 0.01.
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fig5: foxO is required for synaptic vesicle cycling. (A–C) Representative images of FM 1-43 dye uptake by NMJs 6/7 of the indicated genotypes after 90 mM K+ stimulation. Bar, 20 µm. (D) Quantification of FM 1-43 labeling intensity at NMJs 6/7 of listed genotypes after 90 mM K+ stimulation. Anterior is up. Data represent means ± SEM normalized to wild type; n = 9 for ElavGal4/CS, n = 6 for foxO21, and n = 7 for futschK68/+;; foxO21, in which n is the number of animals (≥15 NMJs/genotype). *, P < 0.05; **, P < 0.01.
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.

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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA.

Show MeSH
Related in: MedlinePlus