Glycobiology on the fly: Developmental and mechanistic insights from Drosophila

Hagen, Karl S.; Zhang, Liping; Tian, E; Zhang, Ying

doi:10.1093/glycob/cwn096

Cited by 70 publications

(50 citation statements)

References 92 publications

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“…Here, we provide direct evidence for the role of mucin-type O-glycans in modulating proper secretion to this basal region in vivo by examining a specific substrate in a glycosyltransferase mutant background. Given that the multiple pgant genes responsible for initiating mucin-type O-glycosylation (22,39) have unique tissue-and stage-specific patterns of expression (23,(51)(52)(53), it is likely that specific pgant family members may be playing unique roles in the secretion and localization of proteins within diverse cell types.…”

Section: Discussionmentioning

confidence: 99%

“…This type of evolutionarily conserved protein modification, known as mucin-type O-glycosylation (21)(22)(23), was shown to be required for proper cell adhesion between the epithelial cell layers comprising the Drosophila wing blade. Loss of the gene encoding the enzyme responsible for glycosylating Tiggrin (pgant3) resulted in the formation of wing blisters in adult flies (similar to those seen in homozygous tiggrin mutant escapers (3)), which could be rescued upon expression of wild type pgant3 (20).…”

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confidence: 99%

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An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand

Zhang

Tran

Hagen

2010

Journal of Biological Chemistry

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Protein secretion and localization are crucial during eukaryotic development, establishing local cell environments as well as mediating cell interactions, signaling, and adhesion. In this study, we demonstrate that the glycosyltransferase, pgant3, specifically modulates integrin-mediated cell adhesion by influencing the secretion and localization of the integrin ligand, Tiggrin. We demonstrate that Tiggrin is normally O-glycosylated and localized to the basal matrix where the dorsal and ventral cell layers adhere in wild type Drosophila wings. In pgant3 mutants, Tiggrin is no longer O-glycosylated and fails to be properly secreted to this basal cell layer interface, resulting in disruption of integrin-mediated cell adhesion in the wing. pgant3-mediated effects are dependent on enzymatic activity, as mutations that form a stable protein yet abrogate O-glycosyltransferase activity result in Tiggrin accumulation within the dorsal and ventral cells comprising the wing. Our results provide the first in vivo evidence for the role of O-glycosylation in the secretion of specific extracellular matrix proteins, thus altering the composition of the cellular "microenvironment" and thereby modulating developmentally regulated cell adhesion events. As alterations in cell adhesion are a hallmark of cancer progression, this work provides insight into the long-standing association between aberrant O-glycosylation and tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand

Zhang

Tran

Hagen

2010

Journal of Biological Chemistry

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“…Of particular relevance to galactosemia, the complexity of N-and O-linked glycans in Drosophila and the organismal effects of loss of specific enzymes in the glycosylation pathway have recently been reported (for a review, see Ten Hagen et al, 2009). Further, we recently confirmed GALE is essential for fly development RESEARCH ARTICLE that D. melanogaster encode (http://superfly.ucsd.edu/ homophila) and express functional orthologs of all three Leloir enzymes, designated dGALK (CG5288), dGALT (CG9232) and dGALE (CG12030) (Kushner et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

UDP-galactose 4′ epimerase (GALE) is essential for development ofDrosophila melanogaster

Sanders¹,

Sefton

Moberg

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARYUDP-galactose 4' epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose in the final step of the Leloir pathway; human GALE (hGALE) also interconverts UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. GALE therefore plays key roles in the metabolism of dietary galactose, in the production of endogenous galactose, and in maintaining the ratios of key substrates for glycoprotein and glycolipid biosynthesis. Partial impairment of hGALE results in the potentially lethal disorder epimerase-deficiency galactosemia. We report here the generation and initial characterization of a first whole-animal model of GALE deficiency using the fruit fly Drosophila melanogaster. Our results confirm that GALE function is essential in developing animals; Drosophila lacking GALE die as embryos but are rescued by the expression of a human GALE transgene. Larvae in which GALE has been conditionally knocked down die within days of GALE loss. Conditional knockdown and transgene expression studies further demonstrate that GALE expression in the gut primordium and Malpighian tubules is both necessary and sufficient for survival. Finally, like patients with generalized epimerase deficiency galactosemia, Drosophila with partial GALE loss survive in the absence of galactose but succumb in development if exposed to dietary galactose. These data establish the utility of the fly model of GALE deficiency and set the stage for future studies to define the mechanism(s) and modifiers of outcome in epimerase deficiency galactosemia.

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“…Although the enzymes required for the biosyntheses of various nucleotide sugars have been elucidated (30), very few studies have examined whether nucleotide sugars are exchanged intercellularly (31), and none have investigated such exchanges in vivo. To address these issues, we next examined whether Gmd and Gmer function cell-autonomously or cell-nonautonomously in vivo, because these mutants should behave cell-nonautonomously if GDP-Lfucose is transferred intercellularly.…”

Section: Resultsmentioning

confidence: 99%

Rescue of Notch signaling in cells incapable of GDP- l -fucose synthesis by gap junction transfer of GDP- l -fucose in Drosophila

Ayukawa¹,

Matsumoto

Ishikawa

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Notch (N) is a transmembrane receptor that mediates cell-cell interactions to determine many cell-fate decisions. N contains EGF-like repeats, many of which have an O-fucose glycan modification that regulates N-ligand binding. This modification requires GDP-L-fucose as a donor of fucose. The GDP-L-fucose biosynthetic pathways are well understood, including the de novo pathway, which depends on GDP-mannose 4,6 dehydratase (Gmd) and GDP-4-keto-6-deoxy-D-mannose 3,5-epimerase/4-reductase (Gmer). However, the potential for intercellularly supplied GDP-L-fucose and the molecular basis of such transportation have not been explored in depth. To address these points, we studied the genetic effects of mutating Gmd and Gmer on fucose modifications in Drosophila. We found that these mutants functioned cell-nonautonomously, and that GDP-L-fucose was supplied intercellularly through gap junctions composed of Innexin-2. GDP-L-fucose was not supplied through body fluids from different isolated organs, indicating that the intercellular distribution of GDP-L-fucose is restricted within a given organ. Moreover, the gap junction-mediated supply of GDP-L-fucose was sufficient to support the fucosylation of N-glycans and the O-fucosylation of the N EGF-like repeats. Our results indicate that intercellular delivery is a metabolic pathway for nucleotide sugars in live animals under certain circumstances.sugar metabolism | intercellular transport

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Glycobiology on the fly: Developmental and mechanistic insights from Drosophila

Cited by 70 publications

References 92 publications

An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand

An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand

UDP-galactose 4′ epimerase (GALE) is essential for development ofDrosophila melanogaster

Rescue of Notch signaling in cells incapable of GDP- l -fucose synthesis by gap junction transfer of GDP- l -fucose in Drosophila

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