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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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A genetic screen identifies Rab8 mutants as dominant enhancers of CHMP2BIntron5 toxicity. (A) Schematic representation of the genomic region uncovered by the Df(3L)ED228 deficiency. (B) Df(3L)ED228, Rab81/+, or Rab8-RNAi expression dominantly enhance the CHMP2BIntron5 mutant eye phenotype, with increased melanization. (C) Quantification of the eye phenotype in flies for genotypes in B. Numbers above bars = n. (D) Schematic representation of the Rab8 locus with location and nature of Rab8 mutant alleles used in this study. (E) Rab8 trans-heterozygote mutant combinations show pharate lethality.
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fig1: A genetic screen identifies Rab8 mutants as dominant enhancers of CHMP2BIntron5 toxicity. (A) Schematic representation of the genomic region uncovered by the Df(3L)ED228 deficiency. (B) Df(3L)ED228, Rab81/+, or Rab8-RNAi expression dominantly enhance the CHMP2BIntron5 mutant eye phenotype, with increased melanization. (C) Quantification of the eye phenotype in flies for genotypes in B. Numbers above bars = n. (D) Schematic representation of the Rab8 locus with location and nature of Rab8 mutant alleles used in this study. (E) Rab8 trans-heterozygote mutant combinations show pharate lethality.

Mentions: Expression of CHMP2BIntron5 in the Drosophila eye, under the control of the postmitotic eye-specific driver glass multimer reporter (GMR)-Gal4, leads to a mild phenotype characterized by melanotic deposits (Fig. 1 B; Ahmad et al., 2009; Lu et al., 2013). Loss of one copy of the deficiency allele Df(3L)ED228 (Fig. 1, A–C) potentiated this phenotype. To identify the genes responsible for this genetic interaction, mutant alleles of individual genes within this deficiency region were screened against the CHMP2BIntron5 eye phenotype. The Rab81 allele significantly potentiated CHMP2BIntron5 toxicity (Fig. 1, B and C). Enhancement was consistent for four additional identified Rab8 mutant alleles (Figs. 1 D and S1) as well as Rab8-RNAi expression (Fig. 1, B and C). In addition, coexpression of wild-type Rab8 with CHMP2BIntron5 could partially alleviate toxicity (Fig. S1 C). Sequencing of identified Rab8 alleles revealed missense mutations (Figs. 1 D and S1) affecting conserved residues essential for Rab8 GTPase function (Fig. S1; Giagtzoglou et al., 2012). Complementation analysis demonstrated that all Rab8 mutant combinations die at the pharate pupal stage (Figs. 1 E and S1 B).


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)

A genetic screen identifies Rab8 mutants as dominant enhancers of CHMP2BIntron5 toxicity. (A) Schematic representation of the genomic region uncovered by the Df(3L)ED228 deficiency. (B) Df(3L)ED228, Rab81/+, or Rab8-RNAi expression dominantly enhance the CHMP2BIntron5 mutant eye phenotype, with increased melanization. (C) Quantification of the eye phenotype in flies for genotypes in B. Numbers above bars = n. (D) Schematic representation of the Rab8 locus with location and nature of Rab8 mutant alleles used in this study. (E) Rab8 trans-heterozygote mutant combinations show pharate lethality.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384727&req=5

fig1: A genetic screen identifies Rab8 mutants as dominant enhancers of CHMP2BIntron5 toxicity. (A) Schematic representation of the genomic region uncovered by the Df(3L)ED228 deficiency. (B) Df(3L)ED228, Rab81/+, or Rab8-RNAi expression dominantly enhance the CHMP2BIntron5 mutant eye phenotype, with increased melanization. (C) Quantification of the eye phenotype in flies for genotypes in B. Numbers above bars = n. (D) Schematic representation of the Rab8 locus with location and nature of Rab8 mutant alleles used in this study. (E) Rab8 trans-heterozygote mutant combinations show pharate lethality.
Mentions: Expression of CHMP2BIntron5 in the Drosophila eye, under the control of the postmitotic eye-specific driver glass multimer reporter (GMR)-Gal4, leads to a mild phenotype characterized by melanotic deposits (Fig. 1 B; Ahmad et al., 2009; Lu et al., 2013). Loss of one copy of the deficiency allele Df(3L)ED228 (Fig. 1, A–C) potentiated this phenotype. To identify the genes responsible for this genetic interaction, mutant alleles of individual genes within this deficiency region were screened against the CHMP2BIntron5 eye phenotype. The Rab81 allele significantly potentiated CHMP2BIntron5 toxicity (Fig. 1, B and C). Enhancement was consistent for four additional identified Rab8 mutant alleles (Figs. 1 D and S1) as well as Rab8-RNAi expression (Fig. 1, B and C). In addition, coexpression of wild-type Rab8 with CHMP2BIntron5 could partially alleviate toxicity (Fig. S1 C). Sequencing of identified Rab8 alleles revealed missense mutations (Figs. 1 D and S1) affecting conserved residues essential for Rab8 GTPase function (Fig. S1; Giagtzoglou et al., 2012). Complementation analysis demonstrated that all Rab8 mutant combinations die at the pharate pupal stage (Figs. 1 E and S1 B).

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.

Show MeSH
Related in: MedlinePlus