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Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia.

West RJ, Lu Y, Marie B, Gao FB, Sweeney ST - J. Cell Biol. (2015)

Bottom Line: Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2B(Intron5).We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants.Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes.

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Affiliation: Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK.

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Rab8 mutants reveal a presynaptic role for Rab8 in the regulation of neuronal growth at the larval NMJ. (A) Rab8 is expressed in all Eve-positive motor neurons within the third instar larval VNC. Insets show magnification of four neurons showing coexpression of eve and Rab8 promoter–driven mCD8-GFP. Bar, 20 µm. (B) All trans-heterozygous Rab8 mutant combinations show significant synaptic overgrowth at the third instar larval NMJ (muscle 6/7, hemisegment A3). ANOVA: F(d.f. [degrees of freedom] 15) = 10.14; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control. (C) Overgrowth can be completely rescued by global (actin-Gal4) and neuronal (n-Syb–Gal4) expression of UAS-Rab8. Muscle (MHC-Gal4) expression of UAS-Rab8 partially rescues synaptic bouton number in Rab8 mutants. Bars, 10 µm. (D) Quantification of synaptic bouton number at muscle 6/7, hemisegment A3. ANOVA: F(d.f. 7) = 36.8975; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control, and post-hoc Student’s t test comparison between groups; ###, P < 0.001. (E) Quantification of synaptic bouton number at muscle 4, hemisegment A3. (ANOVA: F(d.f. 7) = 19.95; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control, and post-hoc Student’s t test comparison between groups; ###, P < 0.001; ##, P < 0.01. Numbers above bars = n. Error bars show SEM.
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fig2: Rab8 mutants reveal a presynaptic role for Rab8 in the regulation of neuronal growth at the larval NMJ. (A) Rab8 is expressed in all Eve-positive motor neurons within the third instar larval VNC. Insets show magnification of four neurons showing coexpression of eve and Rab8 promoter–driven mCD8-GFP. Bar, 20 µm. (B) All trans-heterozygous Rab8 mutant combinations show significant synaptic overgrowth at the third instar larval NMJ (muscle 6/7, hemisegment A3). ANOVA: F(d.f. [degrees of freedom] 15) = 10.14; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control. (C) Overgrowth can be completely rescued by global (actin-Gal4) and neuronal (n-Syb–Gal4) expression of UAS-Rab8. Muscle (MHC-Gal4) expression of UAS-Rab8 partially rescues synaptic bouton number in Rab8 mutants. Bars, 10 µm. (D) Quantification of synaptic bouton number at muscle 6/7, hemisegment A3. ANOVA: F(d.f. 7) = 36.8975; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control, and post-hoc Student’s t test comparison between groups; ###, P < 0.001. (E) Quantification of synaptic bouton number at muscle 4, hemisegment A3. (ANOVA: F(d.f. 7) = 19.95; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control, and post-hoc Student’s t test comparison between groups; ###, P < 0.001; ##, P < 0.01. Numbers above bars = n. Error bars show SEM.

Mentions: Rab8 function in Drosophila, and in neurons in general, is poorly understood. We first examined whether Rab8 is expressed in motor neurons. Expression of the membrane-associated GFP, mCD8-GFP, under the control of the Rab8-GAL4 driver (Chan et al., 2011) revealed Rab8 expressed throughout the Drosophila larval ventral nerve cord (VNC), with coexpression in all even-skipped (Eve)–positive cells (Fig. 2 A), indicating expression in all motor neurons.


Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia.

West RJ, Lu Y, Marie B, Gao FB, Sweeney ST - J. Cell Biol. (2015)

Rab8 mutants reveal a presynaptic role for Rab8 in the regulation of neuronal growth at the larval NMJ. (A) Rab8 is expressed in all Eve-positive motor neurons within the third instar larval VNC. Insets show magnification of four neurons showing coexpression of eve and Rab8 promoter–driven mCD8-GFP. Bar, 20 µm. (B) All trans-heterozygous Rab8 mutant combinations show significant synaptic overgrowth at the third instar larval NMJ (muscle 6/7, hemisegment A3). ANOVA: F(d.f. [degrees of freedom] 15) = 10.14; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control. (C) Overgrowth can be completely rescued by global (actin-Gal4) and neuronal (n-Syb–Gal4) expression of UAS-Rab8. Muscle (MHC-Gal4) expression of UAS-Rab8 partially rescues synaptic bouton number in Rab8 mutants. Bars, 10 µm. (D) Quantification of synaptic bouton number at muscle 6/7, hemisegment A3. ANOVA: F(d.f. 7) = 36.8975; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control, and post-hoc Student’s t test comparison between groups; ###, P < 0.001. (E) Quantification of synaptic bouton number at muscle 4, hemisegment A3. (ANOVA: F(d.f. 7) = 19.95; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control, and post-hoc Student’s t test comparison between groups; ###, P < 0.001; ##, P < 0.01. Numbers above bars = n. Error bars show SEM.
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fig2: Rab8 mutants reveal a presynaptic role for Rab8 in the regulation of neuronal growth at the larval NMJ. (A) Rab8 is expressed in all Eve-positive motor neurons within the third instar larval VNC. Insets show magnification of four neurons showing coexpression of eve and Rab8 promoter–driven mCD8-GFP. Bar, 20 µm. (B) All trans-heterozygous Rab8 mutant combinations show significant synaptic overgrowth at the third instar larval NMJ (muscle 6/7, hemisegment A3). ANOVA: F(d.f. [degrees of freedom] 15) = 10.14; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control. (C) Overgrowth can be completely rescued by global (actin-Gal4) and neuronal (n-Syb–Gal4) expression of UAS-Rab8. Muscle (MHC-Gal4) expression of UAS-Rab8 partially rescues synaptic bouton number in Rab8 mutants. Bars, 10 µm. (D) Quantification of synaptic bouton number at muscle 6/7, hemisegment A3. ANOVA: F(d.f. 7) = 36.8975; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control, and post-hoc Student’s t test comparison between groups; ###, P < 0.001. (E) Quantification of synaptic bouton number at muscle 4, hemisegment A3. (ANOVA: F(d.f. 7) = 19.95; ***, P < 0.001 with post-hoc Dunnett’s comparison to wild-type control, and post-hoc Student’s t test comparison between groups; ###, P < 0.001; ##, P < 0.01. Numbers above bars = n. Error bars show SEM.
Mentions: Rab8 function in Drosophila, and in neurons in general, is poorly understood. We first examined whether Rab8 is expressed in motor neurons. Expression of the membrane-associated GFP, mCD8-GFP, under the control of the Rab8-GAL4 driver (Chan et al., 2011) revealed Rab8 expressed throughout the Drosophila larval ventral nerve cord (VNC), with coexpression in all even-skipped (Eve)–positive cells (Fig. 2 A), indicating expression in all motor neurons.

Bottom Line: Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2B(Intron5).We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants.Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK.

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Related in: MedlinePlus