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Increased apoptosis of myoblasts in Drosophila model for the Walker-Warburg syndrome.

Ueyama M, Akimoto Y, Ichimiya T, Ueda R, Kawakami H, Aigaki T, Nishihara S - PLoS ONE (2010)

Bottom Line: We demonstrated that expression of RNA interference (RNAi) for the rt gene and the tw mutant was almost completely lethal and semi-lethal, respectively.Flies expressing RNAi had reduced lifespans.We then observed a high density of myoblasts with an enhanced degree of apoptosis in the tw mutant, which completely lost enzymatic activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics, Soka University, Hachioji, Tokyo, Japan.

ABSTRACT
Walker-Warburg syndrome, a progressive muscular dystrophy, is a severe disease with various kinds of symptoms such as muscle weakness and occasional seizures. The genes of protein O-mannosyltransferases 1 and 2 (POMT1 and POMT2), fukutin, and fukutin-related protein are responsible for this syndrome. In our previous study, we cloned Drosophila orthologs of human POMT1 and POMT2 and identified their activity. However, the mechanism of onset of this syndrome is not well understood. Furthermore, little is known about the behavioral properties of the Drosophila POMT1 and POMT2 mutants, which are called rotated abdomen (rt) and twisted (tw), respectively. First, we performed various kinds of behavioral tests and described in detail the muscle structures by using these mutants. The mutant flies exhibited abnormalities in heavy exercises such as climbing or flight but not in light movements such as locomotion. Defective motor function in mutants appeared immediately after eclosion and was exaggerated with aging. Along with motor function, muscle ultrastructure in the tw mutant was altered, as seen in human patients. We demonstrated that expression of RNA interference (RNAi) for the rt gene and the tw mutant was almost completely lethal and semi-lethal, respectively. Flies expressing RNAi had reduced lifespans. These findings clearly demonstrate that Drosophila POMT mutants are models for human muscular dystrophy. We then observed a high density of myoblasts with an enhanced degree of apoptosis in the tw mutant, which completely lost enzymatic activity. In this paper, we propose a novel mechanism for the development of muscular dystrophy: POMT mutation causes high myoblast density and position derangement, which result in apoptosis, muscle disorganization, and muscle cell defects.

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Related in: MedlinePlus

Behavioral defects in rt and tw mutant flies.(A) Age-related change in climbing ability in rt mutants (A) and tw mutants (B). Age-related change in locomotive activity in rt mutants (C) and tw mutants (D). Flying ability in rt mutants (E) and tw mutants (F) at 30–35 days after eclosion. Rescue of flying ability in tw mutants (G). Error bars in all figures indicate standard error. Results of statistical analyses in (A) and (B) are shown in Tables 1 and 2, respectively. ***p<0.001 by Tukey test. n.s., not significant.
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pone-0011557-g001: Behavioral defects in rt and tw mutant flies.(A) Age-related change in climbing ability in rt mutants (A) and tw mutants (B). Age-related change in locomotive activity in rt mutants (C) and tw mutants (D). Flying ability in rt mutants (E) and tw mutants (F) at 30–35 days after eclosion. Rescue of flying ability in tw mutants (G). Error bars in all figures indicate standard error. Results of statistical analyses in (A) and (B) are shown in Tables 1 and 2, respectively. ***p<0.001 by Tukey test. n.s., not significant.

Mentions: Patients with progressive muscular dystrophy show muscle weakness and motor dysfunction with age. Therefore, we evaluated the motor function in rt and tw mutant flies. We first examined age-related changes in climbing activities. In rt mutants, which showed specific reduction of rt transcripts (Fig. S1), the climbing abilities of flies homozygous for rt were significantly decreased compared to those of flies heterozygous for rt at all ages (Fig. 1A, Table 1). In tw mutants, the climbing abilities of flies homozygous for tw were also significantly decreased compared to those of flies heterozygous for tw at all ages, except at the age of 41 days between Df(1)/+ and Df(1)/tw (Fig. 1B, Table 2). These data showed reduced climbing abilities in rt and tw mutants at almost all ages.


Increased apoptosis of myoblasts in Drosophila model for the Walker-Warburg syndrome.

Ueyama M, Akimoto Y, Ichimiya T, Ueda R, Kawakami H, Aigaki T, Nishihara S - PLoS ONE (2010)

Behavioral defects in rt and tw mutant flies.(A) Age-related change in climbing ability in rt mutants (A) and tw mutants (B). Age-related change in locomotive activity in rt mutants (C) and tw mutants (D). Flying ability in rt mutants (E) and tw mutants (F) at 30–35 days after eclosion. Rescue of flying ability in tw mutants (G). Error bars in all figures indicate standard error. Results of statistical analyses in (A) and (B) are shown in Tables 1 and 2, respectively. ***p<0.001 by Tukey test. n.s., not significant.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2903483&req=5

pone-0011557-g001: Behavioral defects in rt and tw mutant flies.(A) Age-related change in climbing ability in rt mutants (A) and tw mutants (B). Age-related change in locomotive activity in rt mutants (C) and tw mutants (D). Flying ability in rt mutants (E) and tw mutants (F) at 30–35 days after eclosion. Rescue of flying ability in tw mutants (G). Error bars in all figures indicate standard error. Results of statistical analyses in (A) and (B) are shown in Tables 1 and 2, respectively. ***p<0.001 by Tukey test. n.s., not significant.
Mentions: Patients with progressive muscular dystrophy show muscle weakness and motor dysfunction with age. Therefore, we evaluated the motor function in rt and tw mutant flies. We first examined age-related changes in climbing activities. In rt mutants, which showed specific reduction of rt transcripts (Fig. S1), the climbing abilities of flies homozygous for rt were significantly decreased compared to those of flies heterozygous for rt at all ages (Fig. 1A, Table 1). In tw mutants, the climbing abilities of flies homozygous for tw were also significantly decreased compared to those of flies heterozygous for tw at all ages, except at the age of 41 days between Df(1)/+ and Df(1)/tw (Fig. 1B, Table 2). These data showed reduced climbing abilities in rt and tw mutants at almost all ages.

Bottom Line: We demonstrated that expression of RNA interference (RNAi) for the rt gene and the tw mutant was almost completely lethal and semi-lethal, respectively.Flies expressing RNAi had reduced lifespans.We then observed a high density of myoblasts with an enhanced degree of apoptosis in the tw mutant, which completely lost enzymatic activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics, Soka University, Hachioji, Tokyo, Japan.

ABSTRACT
Walker-Warburg syndrome, a progressive muscular dystrophy, is a severe disease with various kinds of symptoms such as muscle weakness and occasional seizures. The genes of protein O-mannosyltransferases 1 and 2 (POMT1 and POMT2), fukutin, and fukutin-related protein are responsible for this syndrome. In our previous study, we cloned Drosophila orthologs of human POMT1 and POMT2 and identified their activity. However, the mechanism of onset of this syndrome is not well understood. Furthermore, little is known about the behavioral properties of the Drosophila POMT1 and POMT2 mutants, which are called rotated abdomen (rt) and twisted (tw), respectively. First, we performed various kinds of behavioral tests and described in detail the muscle structures by using these mutants. The mutant flies exhibited abnormalities in heavy exercises such as climbing or flight but not in light movements such as locomotion. Defective motor function in mutants appeared immediately after eclosion and was exaggerated with aging. Along with motor function, muscle ultrastructure in the tw mutant was altered, as seen in human patients. We demonstrated that expression of RNA interference (RNAi) for the rt gene and the tw mutant was almost completely lethal and semi-lethal, respectively. Flies expressing RNAi had reduced lifespans. These findings clearly demonstrate that Drosophila POMT mutants are models for human muscular dystrophy. We then observed a high density of myoblasts with an enhanced degree of apoptosis in the tw mutant, which completely lost enzymatic activity. In this paper, we propose a novel mechanism for the development of muscular dystrophy: POMT mutation causes high myoblast density and position derangement, which result in apoptosis, muscle disorganization, and muscle cell defects.

Show MeSH
Related in: MedlinePlus