Differential control of tropomyosin mRNA levels during myogenesis suggests the existence of an isoform competition-autoregulatory compensation control mechanism

Gunning, Peter W.; Gordon, Monica L.; Wade, Robert; Gahlmann, Reinhold; Lin, Chen; Hardeman, Edna C.

doi:10.1016/0012-1606(90)90210-a

Cited by 73 publications

(61 citation statements)

References 35 publications

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“…10). This result is consistent with the pattern of expression of the endogenous gene (16). In contrast to the result seen with construct ASK-6 in COS cells, no products including both exons NM and SK were detected, which suggests that ASK-6 did not mimic the events determining exon SK incorporation in muscle cells.…”

Section: Methodssupporting

confidence: 85%

“…The organization of the central mutually exclusive exons is very similar to that of the ,B-tropomyosin genes, with a skeletal muscle-specific exon. However, the developmental profile of expression of the two isoforms is quite distinct from that of a-and ,B-tropomyosins (16), suggesting that the mechanism of the switch between the two central exons might be different. We report here that a systematic mutational analysis in nonmuscle cells shows that the muscle exon does not compete for splicing, and that this arises because of a novel combination of poor branch site signals and specific exon elements.…”

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confidence: 95%

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Alternative splicing of a human alpha-tropomyosin muscle-specific exon: identification of determining sequences.

Graham¹,

Hamshere²,

Eperon³

1992

Mol. Cell. Biol.

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The human ac-tropomyosin gene hTM.m has two mutually exclusive versions of exon 5 (NM and SK), one of which is expressed specifically in skeletal muscle (exon SK). A minigene construct expresses only the nonmuscle (NM) isoform when transfected into COS-1 cells and both forms when transfected into myoblasts. Twenty-four mutants were produced to determine why the SK exon is not expressed in COS cells. The results showed that exons NM and SK are not in competition for splicing to the flanking exons and that there is no intrinsic barrier to splicing between the exons. Instead, exon SK is skipped whenever there are flanking introns. Splicing of exon SK was induced when the branch site sequence 70 nucleotides upstream of the exon was mutated to resemble the consensus and when the extremities of the exon itself were changed to the corresponding NM sequence. Precise swaps of the NM and SK exon sequences showed that the exon sequence effect was dominant to that of intron sequences. The mechanism of regulation appears to be unlike that of other tropomyosin genes. We propose that exclusion of exon SK arises because its 3' splicing signals are weak and are prevented by an exon-specific repressor from competing for splice site recognition.Alternative splicing of pre-mRNA produces different isoforms of mRNA from a single gene, often resulting in the production of multiple protein isoforms. In many cases, the proportions of the various isoforms alter during cell differentiation or development. Mutually exclusive splicing, whereby only one of two adjacent exons is incorporated between common flanking exons, is associated particularly with transcripts which are expressed primarily in muscle cells or which exhibit muscle-specific switches in the exon selected. This pattern of splicing raises three principal problems: (i) the two alternative exons are not usually spliced to each other, and where the process appears to be regulated, (ii) one exon is preferred in most cell types but (iii) the alternative exon is incorporated in the specific tissue.This pattern of splicing has been studied most intensively in two tropomyosin gene systems: the 5'-proximal exons 2 and 3 of rat a-tropomyosin, in which exon 2 is incorporated specifically in smooth muscle (39), and the more central exons 6 and 7 (or 6A and 6B) of the 3-tropomyosin homologs in rats and chickens, in which the 3' most of the two exons is incorporated in skeletal muscle (19,24,26). The results of these studies do not address all of the issues described above, but perhaps surprisingly, it is clear that mutually exclusive splicing is not determined by a common mechanism. In the case of the rat a-tropomyosin gene, it appears that exons 2 and 3 do not splice together because the long polypyrimidine tract of exon 3 forces the branch site too close to the 5' splice site of exon 2 (39). The default exon 3 appears to be selected because both exons are in competition for splicing to exon 1, but exon 3 is preceded by a more favorable polypyrimidine tract (32); sequences near or within ...

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Section: Methodssupporting

confidence: 85%

mentioning

confidence: 95%

Alternative splicing of a human alpha-tropomyosin muscle-specific exon: identification of determining sequences.

Graham¹,

Hamshere²,

Eperon³

1992

Mol. Cell. Biol.

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“…The striated muscle-specific a-TM isoform is the major TM isoform present in adult rodent cardiac tissue (17,25). Recent studies suggest that striated ,B-TM may also be expressed in adult murine hearts (52).…”

Section: Materuils and Methodsmentioning

confidence: 99%

Developmental analysis of tropomyosin gene expression in embryonic stem cells and mouse embryos.

et al. 1993

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Tropomyosins (TMs) comprise a family of actin-binding proteins which play an important role in the regulation of contractility in muscle (cardiac, skeletal, and smooth) and nonmuscle cells. Although they are present in all cells, different isoforms are characteristic of specific cell types. In vertebrates, there are four different TM genes (a-TM, 1s-TM, TM30, and TM4), three of which generate alternatively spliced isoforms.This study defines the expression patterns of these isoforms during murine embryogenesis, using both in vivo and in vitro conditions. The embryonic stem cell culture system, which has been shown to mimic different stages of mouse embryonic development, including the differentiation of primitive organ systems such as the myocardium, is used for our in vitro analysis. Our results demonstrate that several TM isoforms are expressed in specific developmental patterns, often correlated with the differentiation of particular tissues or organs.Surprisingly, other TMs, such as the striated muscle 13-TM and smooth muscle a-TM, are expressed constitutively. This study also demonstrates that there is an excellent correlation between the expression patterns of the TM isoforms observed in developing embryonic stem cells and mouse embryos. In addition, a quantitative molecular analysis of TM isoforms was conducted in embryonic, neonatal, and adult cardiac tissue. Our results show for the first time that the a-and 1-TM striated muscle transcripts are present in the earliest functional stages of the heart, and these TM isoforms are identical to those present throughout cardiac development.

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“…TPM1 and TPM2 show high expression levels in adult skeletal muscle. 39) TPM1 is an -helical, coiled-coil homodimeric thin filament protein that takes part in the process of muscle contraction. Mutation of TPM1 can decrease the affinity of Ca 2þ with troponin and affects contraction force of muscle.…”

Section: Analysis Of Time-series Expression Patternsmentioning

confidence: 99%

Identification and Characterization of Genes Related to the Development of Skeletal Muscle in the Hainan Black Goat

Zhang

et al. 2012

Bioscience, Biotechnology, and Biochemistry

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Differential control of tropomyosin mRNA levels during myogenesis suggests the existence of an isoform competition-autoregulatory compensation control mechanism

Cited by 73 publications

References 35 publications

Alternative splicing of a human alpha-tropomyosin muscle-specific exon: identification of determining sequences.

Alternative splicing of a human alpha-tropomyosin muscle-specific exon: identification of determining sequences.

Developmental analysis of tropomyosin gene expression in embryonic stem cells and mouse embryos.

Identification and Characterization of Genes Related to the Development of Skeletal Muscle in the Hainan Black Goat

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