Conservation of components of the dystrophin complex in <i>Drosophila</i><sup>1</sup>

Greener, Marc; Roberts, Roland G.

doi:10.1016/s0014-5793(00)02018-4

Cited by 81 publications

(78 citation statements)

References 43 publications

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“…10 We have previously noted the conservation of this shifted ORF in Xenopus and dogfish. 8 The recent description of C-terminal dystrophin sequence from invertebrates such as sea urchin, 11 nematode 12 and (to a lesser extent) fruitfly 13 shows the D78 sequence to be the ancestral one, retained in embryonic dystrophin ( Figure 1B), but not in the adult muscle isoform or the two paralogous proteins utrophin and DRP2.…”

Section: Resultsmentioning

confidence: 99%

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

et al. 2002

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The 3'-untranslated region (3'UTR) of some vertebrate dystrophin genes shows an extraordinary degree and extent of conservation (better than that of many coding regions), a phenomenon that remains unexplained. We examine novel sequence and mutational data to explore the possible reasons for this. We show that loss of the human dystrophin 3'UTR is sufficient to cause Becker muscular dystrophy with pronounced reduction in dystrophin protein levels. The acquisition of dystrophin 3'UTR sequence from an amphibian and a cartilaginous fish allows us to refine previously identified functionally constrained regions which might account for the observed phenotype. These comprise (a) the open reading frame encoding the ancestral 'alternative' amphipathic C-terminal a-helix, normally removed from adult dystrophin by inclusion of a poorly conserved frameshifting penultimate exon, and (b) two highly conserved untranslated regions ('Lemaire A', 350 nucleotides and 'Lemaire D', 250 nucleotides) separated by a non-conserved 700 -2000-nucleotide spacer. We consider the possibility that the 3'UTR may represent a significant target for pathogenic mutations.

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Section: Resultsmentioning

confidence: 99%

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

et al. 2002

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“…1) (Greener and Roberts, 2000;Neuman et al, 2001). The three large isoforms DLP1, DLP2, and DLP3 have an N-terminal actinbinding domain, spectrin repeats, and a C-terminal cysteine-rich domain, which in mammals has been shown to interact with other DGC proteins.…”

Section: The Large Dystrophin Isoform Dlp2 Is Expressed At the Nmj Pomentioning

confidence: 99%

“…These and other data suggest that dystrophin and utrophin likely play partially redundant and subtle roles at the mammalian NMJ (Lyons and Slater, 1991;Deconinck et al, 1997b). A single dystrophin ortholog exists in Drosophila (Greener and Roberts, 2000); its isoforms are predominantly expressed in the muscle and nervous system (Neuman et al, 2001;Dekkers et al, 2004). In this study, we investigate the role of the postsynaptically localized dystrophinlike protein 2 (DLP2) Dystrophin isoform at the Drosophila NMJ.…”

Section: Introductionmentioning

confidence: 95%

Dystrophin Is Required for Appropriate Retrograde Control of Neurotransmitter Release at theDrosophilaNeuromuscular Junction

Plas¹,

Pilgram²,

Plomp³

et al. 2006

J. Neurosci.

112

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Mutations in the human dystrophin gene cause the Duchenne and Becker muscular dystrophies. The Dystrophin protein provides a structural link between the muscle cytoskeleton and extracellular matrix to maintain muscle integrity. Recently, Dystrophin has also been found to act as a scaffold for several signaling molecules, but the roles of dystrophin-mediated signaling pathways remain unknown. To further our understanding of this aspect of the function of dystrophin, we have generated Drosophila mutants that lack the large dystrophin isoforms and analyzed their role in synapse function at the neuromuscular junction. In expression and rescue studies, we show that lack of the large dystrophin isoforms in the postsynaptic muscle cell leads to elevated evoked neurotransmitter release from the presynaptic apparatus. Overall synapse size, the size of the readily releasable vesicle pool as assessed with hypertonic shock, and the number of presynaptic neurotransmitter release sites (active zones) are not changed in the mutants. Short-term synaptic facilitation of evoked transmitter release is decreased in the mutants, suggesting that the absence of dystrophin results in increased probability of release. Absence of the large dystrophin isoforms does not lead to changes in muscle cell morphology or alterations in the postsynaptic electrical response to spontaneously released neurotransmitter. Therefore, postsynaptic glutamate receptor function does not appear to be affected. Our results indicate that the postsynaptically localized scaffolding protein Dystrophin is required for appropriate control of neuromuscular synaptic homeostasis.

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“…Drosophila Dystroglycan (Dg) is a fly homolog of the vertebrate Dystroglycan gene (Greener and Roberts 2000;Deng et al 2003). The predicted product of this gene, Drosophila DG protein, is structurally related to its vertebrate counterpart (Deng et al 2003), thus representing a potential molecular target of RT/TW O-mannosyltransferase activity.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, the Drosophila genome encodes homologs of all essential components necessary for the formation of DGC but with substantially less diversity (Greener and Roberts 2000;Dekkers et al 2004), which presents an attractive possibility for using fruit flies as a model system for studying the biology of DGC and several human congenital neuromuscular diseases.…”

mentioning

confidence: 99%

The twisted Gene Encodes Drosophila Protein O-Mannosyltransferase 2 and Genetically Interacts With the rotated abdomen Gene Encoding Drosophila Protein O-Mannosyltransferase 1

Lyalin

Koles

Roosendaal³

et al. 2006

Genetics

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The family of mammalian O-mannosyltransferases includes two enzymes, POMT1 and POMT2, which are thought to be essential for muscle and neural development. Similar to mammalian organisms, Drosophila has two O-mannosyltransferase genes, rotated abdomen (rt) and DmPOMT2, encoding proteins with high homology to their mammalian counterparts. The previously reported mutant phenotype of the rt gene includes a clockwise rotation of the abdomen and defects in embryonic muscle development. No mutants have been described so far for the DmPOMT2 locus. In this study, we determined that the mutation in the twisted (tw) locus, tw 1 , corresponds to a DmPOMT2 mutant. The twisted alleles represent a complementation group of recessive mutations that, similar to the rt mutants, exhibit a clockwise abdomen rotation phenotype. Several tw alleles were isolated in the past; however, none of them was molecularly characterized. We used an expression rescue approach to confirm that tw locus represents DmPOMT2 gene. We found that the tw 1 allele represents an amino acid substitution within the conserved PMT domain of DmPOMT2 (TW) protein. Immunostaining experiments revealed that the protein products of both rt and tw genes colocalize within Drosophila cells where they reside in the ER subcellular compartment. In situ hybridization analysis showed that both genes have essentially overlapping patterns of expression throughout most of embryogenesis (stages 8-17), while only the rt transcript is present at early embryonic stages (5 and 6), suggesting its maternal origin. Finally, we analyzed the genetic interactions between rt and tw using several mutant alleles, RNAi, and ectopic expression approaches. Our data suggest that the two Drosophila O-mannosyltransferase genes, rt and tw, have nonredundant functions within the same developmental cascade and that their activities are required simultaneously for possibly the same biochemical process. Our results establish the possibility of using Drosophila as a model system for studying molecular and genetic mechanisms of protein O-mannosylation during development.

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Conservation of components of the dystrophin complex in Drosophila¹

Cited by 81 publications

References 43 publications

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

Dystrophin Is Required for Appropriate Retrograde Control of Neurotransmitter Release at theDrosophilaNeuromuscular Junction

The twisted Gene Encodes Drosophila Protein O-Mannosyltransferase 2 and Genetically Interacts With the rotated abdomen Gene Encoding Drosophila Protein O-Mannosyltransferase 1

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Conservation of components of the dystrophin complex in Drosophila1

Cited by 81 publications

References 43 publications

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

Dystrophin Is Required for Appropriate Retrograde Control of Neurotransmitter Release at theDrosophilaNeuromuscular Junction

The twisted Gene Encodes Drosophila Protein O-Mannosyltransferase 2 and Genetically Interacts With the rotated abdomen Gene Encoding Drosophila Protein O-Mannosyltransferase 1

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Conservation of components of the dystrophin complex in Drosophila¹