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Drosophila GGA model: an ultimate gateway to GGA analysis.

ABSTRACT: Golgi-localized, ?-ear-containing, ADP ribosylation factor-binding (GGA) proteins are monomeric adaptors implicated in clathrin-mediated vesicular transport between the trans Golgi network and endosomes, characterized mainly from cell culture analysis of lysosomal sorting. To provide the first demonstration of GGA's role in vivo, we used Drosophila which has a single GGA and a single lysosomal sorting receptor, lysosomal enzyme receptor protein (LERP). Using RNAi knockdowns, we show that the Drosophila GGA is required for lysosomal sorting. We further identified authentic components of the Drosophila lysosomal sorting system--the sorting receptor LERP, the sorting adaptor GGA and the lysosomal cargo cathepsins B1, D and L--to show that GGA depletion results in lysosomal dysfunction. Abnormal lysosomal morphology, missorting of lysosomal cathepsins and impaired lysosomal proteolysis show disturbed LERP trafficking after GGA depletion. GGA is highly expressed in the mushroom bodies and the pigment cells of the retina, and increasing or decreasing the levels of GGA in the eyes leads to retinal defects. Reduced GGA levels also enhance an eye defect caused by overexpression of the autophagy-associated protein Blue cheese (Bchs), implicating GGA in autophagic processes. This shows that Drosophila provides an excellent whole-animal model to gain new insights into the function of GGA in the physiological environment of a multicellular organism.

SUBMITTER: Eissenberg JC

PROVIDER: S-EPMC3601743 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Drosophila GGA model: an ultimate gateway to GGA analysis.

Eissenberg Joel C JC Ilvarsonn Anne M AM Sly William S WS Waheed Abdul A Krzyzanek Vladislav V Pohlmann Regina R Waschkau Daniela D Kretzschmar Doris D Dennes André C AC

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Golgi-localized, γ-ear-containing, ADP ribosylation factor-binding (GGA) proteins are monomeric adaptors implicated in clathrin-mediated vesicular transport between the trans Golgi network and endosomes, characterized mainly from cell culture analysis of lysosomal sorting. To provide the first demonstration of GGA's role in vivo, we used Drosophila which has a single GGA and a single lysosomal sorting receptor, lysosomal enzyme receptor protein (LERP). Using RNAi knockdowns, we show that the Dro ...[more]

PMID: 21923734

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Project description:GGAs (Golgi-localised, ?-ear containing, ADP ribosylation factor-binding) are a family of clathrin adaptors that sort a number of biologically important transmembrane proteins into clathrin-coated vesicles. Knockout and knockdown studies to determine GGA function are confounded by the fact that there are 3 GGA genes in mammalian cells. Thus Drosophila melanogaster is a useful model system to study tissue expression profiles and knockdown phenotypes as there is a single GGA ortholog.Here we have quantified protein expression in Drosophila and show that there is >3-fold higher expression of GGA in male flies relative to female flies. In female flies the majority of GGA expression is in the head. In male flies GGA is not only expressed at high levels in the head but there is a gender specific increased expression which is due to the abundant expression of GGA in the testes. Using a highly specific antibody we have localised endogenous GGA protein in testes squashes, and visualised it in somatic and germ line cells. We show that GGA is expressed during multiple stages of sperm development, and co-stains with a marker of the trans-Golgi Network. This is most striking at the acroblast of early spermatids. In spite of the high expression of GGA in testes, knocking down its expression by >95% using transgenic RNAi fly lines did not affect male fertility. Therefore spermatogenesis in the male flies appears to progress normally with <5% GGA, most likely because alternative adaptors may be able to substitute partially or completely for the function of GGA. We also identify 'cueball' as a novel cargo for GGA, and mutants of cueball have been shown to have a male sterility phenotype.In Drosophila we have uncovered a potential role for GGA in the testes of male flies. The gender specific higher expression of GGA, its specific enrichment in testes and its localisation to developing spermatocytes and at the acroblast of spermatids supports a role for GGA function in Drosophila spermatogenesis, even though spermatogenesis still occurs when GGA expression is depleted to <5% of control.

Project description:ObjectiveTo identify potential gateway factors and behaviors that are associated with infant and young child feeding (IYCF) practices in the Maradi and Zinder regions of Niger through application of the Integrated Gateway Model.MethodsWe analyzed data from 2,727 married women of reproductive age including details on child feeding practices for their 2,551 children between the ages of 0 to 23 months. We assessed the association of three gateway behaviors (i.e., any antenatal care, facility delivery, and communication on nutrition practices) and gateway factors (i.e., behavioral determinants, exposure to information, decision-making agency, and woman's group participation) on four IYCF practices (i.e., early initiation of breastfeeding, exclusive breastfeeding, minimum meal frequency, and minimum dietary diversity) while controlling for age, parity, educational attainment, and household wealth.ResultsWe found antenatal care was associated with exclusive breastfeeding of children 0-5 months [adjusted odds ratio (aOR): 1.17 (95% confidence interval (CI): 1.03-1.33)], and minimum meal frequency of children 6-23 months [aOR: 1.10 (95% CI: 1.03-1.17)], and facility delivery was associated with early initiation of breastfeeding among children 0-5 months [aOR: 2.08 (95% CI: 1.39-3.12)]. We found negative associations with exclusive breastfeeding and communication on nutrition practices with husbands, family/friends, and health workers. Exposure to nutrition messages through radio, women's groups participation, and with health workers was positively associated with minimum dietary diversity. Self-efficacy was positively associated with both early initiation of breastfeeding, exclusive breastfeeding among children 0-5 months and minimum dietary diversity among children 6-23 months. Women's agency was positively associated with early initiation of breastfeeding.ConclusionThe association of antenatal care and facility delivery with child nutrition outcomes suggest intervening before a woman becomes pregnant or early in her pregnancy could improve nutrition outcomes. Programs strengthening the continuum of care should identify gateway behaviors to maximize adoption of priority health behaviors.

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Drosophila GGA model: an ultimate gateway to GGA analysis.

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Drosophila GGA model: an ultimate gateway to GGA analysis.

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