A nonsense mutation within the act88f actin gene disrupts myofibril formation in Drosophila indirect flight muscles

Karlik, C C; Coutu, Michelle D.; Fyrberg, Eric

doi:10.1016/0092-8674(84)90266-6

Cited by 103 publications

(51 citation statements)

References 21 publications

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“…In this case, a single base change in the actin coding sequence results in a modified actin protein which is probably significant in relation to the transformed phenotype of these cells. In invertebrates, such as Drosophila or the nematode, mutations which affect movement have been mapped to within tropomyosin (Karlik and Fyrberg, 1985), myosin (MacLeod et al, 1981;Mogami et al, 1986) and actin genes (Karlik et al, 1984). The mutation that we describe is not within the structural gene, but is a tandem duplication of the promoter and 5' exons of the cx-cardiac actin gene which is associated with abnormal levels of ae-cardiac actin mRNA.…”

Section: Discussionmentioning

confidence: 99%

A 5′ duplication of the alpha-cardiac actin gene in BALB/c mice is associated with abnormal levels of alpha-cardiac and alpha-skeletal actin mRNAs in adult cardiac tissue.

Garner¹,

Minty²,

Alonso³

et al. 1986

The EMBO Journal

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We describe the structure and transcriptional activity of the 5′ portion of the alpha‐cardiac actin gene of BALB/c mice. Southern blotting and DNA sequencing reveal that the promoter and first three exons of the gene are present as perfect repeats in a direct duplication of 9.5 kbp situated immediately upstream of the gene. Both promoters are active in adult cardiac tissue. Transcripts from the partial gene duplication give rise to novel RNAs that are spliced correctly in the actin region and polyadenylated. The level of mature alpha‐cardiac actin mRNA is only 16.5% that found in mice that do not possess the duplication. This is due, at least in part, to interference at the transcriptional level. Transcripts from the alpha‐skeletal actin gene accumulate to abnormally high levels in the hearts of such mutant mice. This result suggests tight regulatory coupling for this actin gene pair.

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Section: Discussionmentioning

confidence: 99%

A 5′ duplication of the alpha-cardiac actin gene in BALB/c mice is associated with abnormal levels of alpha-cardiac and alpha-skeletal actin mRNAs in adult cardiac tissue.

Garner¹,

Minty²,

Alonso³

et al. 1986

The EMBO Journal

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“…for the isoproteins of alpha-actinin (13) actin (38), myosin heavy chain (15,35), tubulin (16). In some cases, mutations in tissuespecific isoprotein genes led to severely damaged phenotypes (27,34) indicating the functional implications of defective isoproteins. These observations also are consistent with studies carried out on myogenic cells undergoing cytodifferentiation, in which stress fiber-like filaments (SFLS) have been observed consisting of nonmuscle contractile isoproteins that were the precursor structures for the myofibrils made up of muscle-specific contractile proteins (1, 12).…”

Section: Discussionmentioning

confidence: 99%

Intracellular targeting of isoproteins in muscle cytoarchitecture.

Schäfer

Perriard

1988

The Journal of Cell Biology

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Abstract. Part of the muscle creatine kinase (MM-CK) in skeletal muscle of chicken is localized in the M-band of myofibrils, while chicken heart cells containing myofibrils and BB-CK, but not expressing MM-CK, do not show this association. The specificity of the MM-CK interaction was tested using cultured chicken heart cells as "living test tubes" by microinjection of in vitro generated MM-CK and hybrid M-CK/B-CK mRNA with SP6 RNA polymerase. The resulting translation products were detected in injected cells with isoprotein-specific antibodies. M-CK molecules and translation products of chimeric cDNA molecules containing the head half of the B-CK and the tail half of the M-CK coding regions were localized in the M-band of the myofibrils. The tail, but not the head portion of M-CK is essential for the association of M-CK with the M-band of myofibrils. We conclude that gross biochemical properties do not always coincide with a molecule's specific functions like the participation in cell cytoarchitecture which may depend on molecular targeting even within the same cellular compartment. IN most cells of higher organisms isoforms, representing closely related proteins with conserved amino acid sequences and often similar functional properties are the products of multigene families. Distinct isoforms may exist as related proteins in different tissues, be developmentally regulated within a single tissue or even coexist within a single cytoplasmic compartment. In part divergence in protein sequence among isoforms may serve to target a given isoprotein to its appropriate compartment within the cell. Specific sequences, often located at the amino terminus, have been found to be responsible for the extracellular export of many secretory proteins (5) or the intracellular targeting of proteins destined for intracellular compartments like mitochondria, chloroplasts or the nucleus (11,17,26).Here we examine the molecular basis for the localization of muscle creatine kinase (MM-CK) ~ within the M-band of the muscle myofibril (50,54,55,56). Creatine kinase is the major enzyme ensuring energy production in the muscle cell. The enzyme is a dimer of two subunits which exist as a nonskeletal muscle form, brain creatine kinase (BB-CK), in embryonic muscle and in nonmuscle cells like brain. Upon muscle differentiation the synthesis of the M-CK subunit is induced and BB-CK is gradually replaced by the skeletal muscle-specific enzyme 14,40,41,51). Although myofibers that differentiate in culture have been shown to contain all three isoenzymes, MM-CK, MB-CK and BB-CK (40, 51) only MM-CK appears to be localized Beat W. Sch~ifer's present address is Department of Pharmacology, Stanford University, Stanford, CA 94305. Abbreviations used in this paper:B-CK, creatine kinase subunit; BB-CK, brain creatine kinase; CMF, calcium-and magnesium-free; MB-CK heterodimeric creatine kinase; M-CK, creatine kinase subunit; MM-CK, muscle creatine kinase. and specifically bound to the M-band of the myofibril (53). This result can be explained in two ways. ...

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“…We showed previously that two wild-type copies of the MHC gene are required for IFM and TDT function, whereas other muscles fimc tion adequately with a single copy (Mogami et al 1986;O'Donnell and Bemstein 1988). This sensitivity of IFM and TDT function to gene dosage extends to other muscle contractile protein genes as well and has per mitted the isolation of dominant flightless mutations in genes encoding actin and tropomyosin isoforms specific to the IFM (Karlik et al 1984;Hiromi and Hotta 1985;Karlik and Fyrberg 1985).…”

mentioning

confidence: 99%

Ultrastructural and molecular analyses of homozygous-viable Drosophila melanogaster muscle mutants indicate there is a complex pattern of myosin heavy-chain isoform distribution.

O'Donnell¹,

Collier²,

Mogami³

et al. 1989

Genes Dev.

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We describe the ultrastructural and initial molecular characterization of four homozygous-viable, dominantflightless mutants of Drosophila melanogaster. Genetic mapping indicates that these mutations are inseparable from the known muscle myosin heavy-chain (MHC) allele Mhc^, and each mutation results in a muscle-specific reduction in MHC protein accumulation. The indirect flight muscles (IFMs) of each of these homozygous mutants fail to accumulate MHC, lack thick filaments, and do not display normal cylindrical myofibrils. As opposed to the null phenotype observed in the IFM, normal amounts of MHC accumulate in the leg muscles of three of these mutants, whereas the fourth mutant shows a 45% reduction in leg muscle MHC. The ultrastructure of the tergal depressor of the trochanter muscle (TDT, or jump muscle] is normal in one mutant, completely lacks thick filaments in a second mutant, and displays a reduction of thick filaments in two mutants. The thick filament reduction in this latter class of mutants is limited to the four smaller anterior cells of the TDT, indicating that the TDT is a mixed fiber-type muscle. Because all isoforms of muscle MHC are encoded by alternative splicing of transcripts from a single gene, our results suggest that there is a complex pattern of MHC isoform accumulation in Drosophila, The phenotypes of the homozygous-viable mutants provide evidence for the differential localization of MHC isoforms in different muscles, within the same muscle, and even within a single muscle cell. The mutant characteristics also suggest that the use of some alternative exons is shared among the IFM, TDT, and additional muscles whereas the use of others is unique to the IFM.[Key Words: Drosophila-, muscle mutants; myosin heavy chain; alternative RNA splicing]

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A nonsense mutation within the act88f actin gene disrupts myofibril formation in Drosophila indirect flight muscles

Cited by 103 publications

References 21 publications

A 5′ duplication of the alpha-cardiac actin gene in BALB/c mice is associated with abnormal levels of alpha-cardiac and alpha-skeletal actin mRNAs in adult cardiac tissue.

A 5′ duplication of the alpha-cardiac actin gene in BALB/c mice is associated with abnormal levels of alpha-cardiac and alpha-skeletal actin mRNAs in adult cardiac tissue.

Intracellular targeting of isoproteins in muscle cytoarchitecture.

Ultrastructural and molecular analyses of homozygous-viable Drosophila melanogaster muscle mutants indicate there is a complex pattern of myosin heavy-chain isoform distribution.

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