Mutations in the rotated abdomen locus affect muscle development and reveal an intrinsic asymmetry in Drosophila.

Martı́n-Blanco, Enrique; Garcı́a-Bellido, Antonio

doi:10.1073/pnas.93.12.6048

Cited by 98 publications

(94 citation statements)

References 25 publications

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“…The dPOMT2 RNAi mutant flies, in addition to the dPOMT1 mutant, showed the twisted abdomen phenotype, as previously reported for the dPOMT1 classical mutant, rt (10). RNAi knockdown was performed with a heritable and inducible RNAi system using the GAL4-UAS-IR system (23,24).…”

Section: Discussionmentioning

confidence: 92%

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The Twisted Abdomen Phenotype of Drosophila POMT1 and POMT2 Mutants Coincides with Their Heterophilic Protein O-Mannosyltransferase Activity

Ichimiya

Manya

Ohmae

et al. 2004

Journal of Biological Chemistry

110

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Walker-Warburg syndrome, caused by mutations in protein O-mannosyltransferase-1 (POMT1), is an autosomal recessive disorder characterized by severe brain malformation, muscular dystrophy, and structural eye abnormalities. As humans have a second POMT, POMT2, we cloned each Drosophila ortholog of the human POMT genes and carried out RNA interference (RNAi) knockdown to investigate the function of these proteins in vivo. Drosophila POMT2 (dPOMT2) RNAi mutant flies showed a "twisted abdomen phenotype," in which the abdomen is twisted 30 -60°, similar to the dPOMT1 mutant. Moreover, dPOMT2 interacted genetically with dPOMT1, suggesting that the dPOMTs function in collaboration with each other in vivo. We expressed dPOMTs in Sf21 cells and measured POMT activity. dPOMT2 transferred a mannose to the dystroglycan protein only when it was coexpressed with dPOMT1. Likewise, dPOMT1 showed POMT activity only when coexpressed with dPOMT2, and neither dPOMT showed any activity by itself. Each dPOMT RNAi fly totally reduced POMT activity, despite the specific reduction in the level of each dPOMT mRNA. The expression pattern of dPOMT2 mRNA was found to be similar to that of dPOMT1 mRNA using whole mount in situ hybridization. These results demonstrate that the two dPOMTs function as a protein O-mannosyltransferase in association with each other, in vitro and in vivo, to generate and maintain normal muscle development.

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Section: Discussionmentioning

confidence: 92%

“…The dPOMT1 mutants are known to have reduced viability, whereas escaper flies show the so-called twisted abdomen phenotype that is caused by pronounced de-fects in muscle development (10). The dPOMT1 gene was named after this phenotype as rotated abdomen (rt) (19).…”

mentioning

confidence: 99%

The Twisted Abdomen Phenotype of Drosophila POMT1 and POMT2 Mutants Coincides with Their Heterophilic Protein O-Mannosyltransferase Activity

Ichimiya

Manya

Ohmae

et al. 2004

Journal of Biological Chemistry

110

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“…These asymmetries may also rely on positional signals from a left^right axis, but they do not provide unambiguous evidence because alternative mechanisms are conceivable. For instance, mutations at the rotated abdomen locus in Drosophila cause abdominal torsion; Mart|¨n-Blanco & Garc|¨a-Bellido (1996) hypothesized that an intrinsic torque of muscle ¢bres leads to asymmetry in the overall structure of muscles of the body wall, causing them to exert force in an oblique direction, which ultimately generates the clockwise staggered arrangement of adult abdominal segments characteristic of the mutant phenotype. Yet, because the wings develop from imaginal discs that are physically separated, such a mechanism without left^right signalling cannot account for wing asymmetry.…”

Section: Discussionmentioning

confidence: 99%

Left–right asymmetry of fly wings and the evolution of body axes

Klingenberg

McIntyre

Zaklan

1998

Proc. R. Soc. Lond. B

123

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The body plan of Drosophila, and presumably that of other insects, develops under the control of anteriorp osterior and dorsal^ventral axes, but no evidence for a left^right axis has yet been found. We used geometric morphometrics to study the wings in three species of £ies: Drosophila melanogaster, Musca domestica and Glossina palpalis gambiensis. In all three species, we found that both size and shape showed subtle, but statistically signi¢cant directional asymmetry. For size, these asymmetries were somewhat inconsistent within and between species, but for shape, highly signi¢cant directional asymmetry was found in all samples examined. These systematic left^right di¡erences imply the existence of a left^right axis that conveys distinct positional identities to the wing imaginal discs on either body side. Hence, the wing discs of Drosophila may be a new model to study the developmental genetics of left^right asymmetry. The asymmetries of shape were similar among species, suggesting that directional asymmetry has been evolutionarily conserved since the three lineages diverged. We discuss the implications of this evolutionary conservatism in conjunction with results from earlier studies that showed a lack of genetic variation for directional asymmetry in Drosophila.

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“…3 and 4). 2 Moreover, PMT homologues have been also identified in many multicellular eukaryotes such as Drosophila melanogaster, mouse and, humans (15)(16)(17). Despite their evolutionarily conservation in fungi and throughout the animal kingdom (with the exception of Caenorhabditis elegans), PMTs are not present in green plants.…”

mentioning

confidence: 99%

Members of the Evolutionarily Conserved PMT Family of ProteinO-Mannosyltransferases Form Distinct Protein Complexes among Themselves

Girrbach

Strahl

2003

Journal of Biological Chemistry

134

153

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Protein O-mannosyltransferases (PMTs) initiate the assembly of O-mannosyl glycans, an essential protein modification. Since PMTs are evolutionarily conserved in fungi but are absent in green plants, the PMT family is a putative target for new antifungal drugs, particularly in fighting the threat of phytopathogenic fungi. The PMT family is phylogenetically classified into PMT1, PMT2, and PMT4 subfamilies, which differ in protein substrate specificity. In the model organism Saccharomyces cerevisiae as well as in many other fungi the PMT family is highly redundant, and only the simultaneous deletion of PMT1/PMT2 and PMT4 subfamily members is lethal. In this study we analyzed the molecular organization of PMT family members in S. cerevisiae. We show that members of the PMT1 subfamily (Pmt1p and Pmt5p) interact in pairs with members of the PMT2 subfamily (Pmt2p and Pmt3p) and that Pmt1p-Pmt2p and Pmt5p-Pmt3p complexes represent the predominant forms. Under certain physiological conditions, however, Pmt1p interacts also with Pmt3p, and Pmt5p with Pmt2p, suggesting a compensatory cooperation that guarantees the maintenance of O-mannosylation. Unlike the PMT1/PMT2 subfamily members, the single member of the PMT4 subfamily (Pmt4p) acts as a homomeric complex. Using mutational analyses we demonstrate that the same conserved protein domains underlie both heteromeric and homomeric interactions, and we identify an invariant arginine residue of transmembrane domain two as essential for the formation and/or stability of PMT complexes in general. Our data suggest that protein-protein interactions between the PMT family members offer a point of attack to shut down overall protein O-mannosylation in fungi.Protein O-mannosylation is an evolutionarily conserved protein modification of fundamental importance in many eukaryotes. In yeasts and fungi, the attachment of O-linked mannosyl residues to proteins of the secretory pathway is essential for cell viability (1). In particular it is indispensable for cell wall integrity and normal cellular morphogenesis (2-4). Impairment of O-mannosylation also affects the stability, localization, and/or proper function of individual proteins (5-10). Furthermore, aberrant O-mannosylation can interfere with the retrograde transport of misfolded proteins across the membrane of the endoplasmic reticulum (ER) 1 (11). O-mannosylation is not only important in yeast, but also in mammals. It was recently shown that in humans, O-mannosyl glycosylation represents a new pathomechanism for muscular dystrophy and neuronal migration disorders (12, 13).In yeast and fungi, O-mannosylation is initiated in the lumen of the ER by an essential family of protein O-mannosyltransferases (PMTs). These enzymes catalyze the transfer of mannose from dolichyl phosphate-activated mannose (Dol-PMan) to serine or threonine residues of secretory proteins (2). In Saccharomyces cerevisiae, a total of seven PMT family members (Pmt1-7p) have been identified, which share almost identical hydropathy profiles that predict the PMTs to b...

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Mutations in the rotated abdomen locus affect muscle development and reveal an intrinsic asymmetry in Drosophila.

Abstract: In bilateral animals, the left and right sides of the body usually present asymmetric structures, the genetic bases of whose generation are still largely unknown [CIBA Foundation (1991)

Cited by 98 publications

References 25 publications

The Twisted Abdomen Phenotype of Drosophila POMT1 and POMT2 Mutants Coincides with Their Heterophilic Protein O-Mannosyltransferase Activity

The Twisted Abdomen Phenotype of Drosophila POMT1 and POMT2 Mutants Coincides with Their Heterophilic Protein O-Mannosyltransferase Activity

Left–right asymmetry of fly wings and the evolution of body axes

Members of the Evolutionarily Conserved PMT Family of ProteinO-Mannosyltransferases Form Distinct Protein Complexes among Themselves

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