A Series of Mutations in the D-MEF2 Transcription Factor Reveal Multiple Functions in Larval and Adult Myogenesis in Drosophila

Ranganayakulu, Gogineni; Zhao, Bin; Dokidis, Anthea; Molkentin, Jeffery D.; Olson, Eric N.; Schulz, Robert A.

doi:10.1006/dbio.1995.1269

Cited by 209 publications

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“…The allelic series extends from a null mutation, mef2 22.21 , through to the wild type via three hypomorphic alleles, mef2 113 , mef2 424 , and mef2 65 (10). The phenotype of each hypomorph corresponds to different levels of Mef2, because these phenotypes can be recapitulated by direct manipulation of Mef2 levels (32).…”

Section: Resultsmentioning

confidence: 99%

“…The phenotypes of the mef2 hypomorphs in this allelic series correspond to different levels of Mef2 protein (32). Moreover, Western and immunohistochemistry analyses show that these alleles actually express different levels of the Mef2 protein, although there may also be additional effects on its activity (10). We have therefore referred to ''levels of mef2 activity'' to include both of these aspects.…”

Section: Discussionmentioning

confidence: 98%

“…Mef2 was first identified in mammalian cell culture (5-7), but because mammals possess four closely related mef2 genes functional analyses during development are complicated. In contrast, Drosophila has a single mef2 gene and was the first organism to be used to show that mef2 is required for muscle development in vivo (8)(9)(10). This highlighted that the analysis of how mef2 functions is central to understanding how muscle is made.…”

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mef2 activity levels differentially affect gene expression during Drosophila muscle development

Elgar

Han

Taylor

2008

Proc. Natl. Acad. Sci. U.S.A.

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Cell differentiation is controlled by key transcription factors, and a major question is how they orchestrate cell-type-specific genetic programs. Muscle differentiation is a well studied paradigm in which the conserved Mef2 transcription factor plays a pivotal role. Recent genomic studies have identified a large number of mef2-regulated target genes with distinct temporal expression profiles during Drosophila myogenesis. However, the question remains as to how a single transcription factor can control such diverse patterns of gene expression. In this study we used a strategy combining genomics and developmental genetics to address this issue in vivo during Drosophila muscle development. We found that groups of mef2-regulated genes respond differently to changes in mef2 activity levels: some require higher levels for their expression than others. Furthermore, this differential requirement correlates with when the gene is first expressed during the muscle differentiation program. Genes that require higher levels are activated later. These results implicate mef2 in the temporal regulation of muscle gene expression, and, consistent with this, we show that changes in mef2 activity levels can alter the start of gene expression in a predictable manner. Together these results indicate that Mef2 is not an all-or-none regulator; rather, its action is more subtle, and levels of its activity are important in the differential expression of muscle genes. This suggests a route by which mef2 can orchestrate the muscle differentiation program and contribute to the stringent regulation of gene expression during myogenesis. muscle differentiation program ͉ transcription factor levels F or several decades it has been appreciated that the controlled regulation of gene expression, including the coordinated activation of batteries of genes, lies behind cell differentiation programs (1-3). It is now clear that a principle tier of control of cell differentiation is through key transcription factors, and an important general question is how these factors coordinate the genetic program of such complex processes. A classic paradigm is muscle, in which the conserved Mef2 transcription factor is a major regulator of gene expression and differentiation (4). Mef2 was first identified in mammalian cell culture (5-7), but because mammals possess four closely related mef2 genes functional analyses during development are complicated. In contrast, Drosophila has a single mef2 gene and was the first organism to be used to show that mef2 is required for muscle development in vivo (8)(9)(10). This highlighted that the analysis of how mef2 functions is central to understanding how muscle is made. Important characteristics of the underlying genetic program include the temporal coordination of muscle gene expression (11-13) and the regulation of levels and relative stoichiometries of gene expression during myogenesis (14-19). Although these basic features have been known for many years, much remains to be understood about them. However, the identificati...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

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confidence: 99%

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mef2 activity levels differentially affect gene expression during Drosophila muscle development

Elgar

Han

Taylor

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The fruit fly Drosophila has only one MEF2 gene. Loss of its expression eliminates expression of contractile proteins in muscle cells 68,69 . In vertebrates, there are four MEF2 duplicates showing partially redundancy 70 , a remnant of the robustness caused by their ancient duplication.…”

Section: Heart Evolutionmentioning

confidence: 99%

Gene duplications, robustness and evolutionary innovations

Wagner

2008

BioEssays

118

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Gene duplications, robustness and evolutionary innovations Gene duplications, robustness and evolutionary innovations AbstractMutational robustness facilitates evolutionary innovations. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation is thus a special case of a general mechanism linking innovation to robustness. The potential power of this mechanism to promote evolutionary innovations on large time scales is illustrated here with several examples. These include the role of gene duplications in the vertebrate radiation, flowering plant evolution and heart development, which encompass some of the most striking innovations in the evolution of life. Gene duplications, robustness, and evolutionary innovationsAndreas Wagner AbstractMutational robustness facilitates evolutionary innovations in biological systems. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation thus exemplifies a general mechanism linking innovation to robustness. I illustrate the potential power of this mechanism on large time scales with the role of gene duplications in the vertebrate radiation, flowering plant evolution, and heart development, which encompass some of the most striking innovations in the evolution of life. Mutational robustnessMutational robustness is a biological's system ability to withstand mutations. Such robustness exists on multiple levels of biological organization. A case in point are random mutagenesis experiments of various proteins. They suggest that only a small fraction of mutations affect protein function adversely. For instance, a study of the bacteriophage T4 lysozyme generated more than 2000 random amino acid changes in the protein. Only 16% of them affected lysozyme function 1 . Other examples come from regulatory gene networks, such as the molecular network specifying fruit fly segments. Such networks may tolerate much quantitative variation in interactions among network genes 2-5 . Examples at the highest level of organization include macroscopic traits. Even substantial genetic variation -ultimately caused by mutations -may leave such traits unchanged. Take the vulva of the nematode worms Caenorhabditis elegans and Pristionchus pacificus 6 . These organisms shared a common ancestor 200-300 million years ago. Their vulvae are very similar, yet the genetic and cellular networks producing them have diverged greatly. For example, whereas in C. elegans one specific cell -the anchor cell -induces vulva development, multiple gonadal cells are responsible for this induction in P. pacificus 7 . Similarly, the same key signaling molecules, such as Wnt, may play a positive role in the network for vulval induction in C. elegans, but a negative role in P. pacificus 8,9 . In sum, mutational robustness is everywhere, from proteins to or...

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“…To determine the status of IFM formation, thoraces from pupal or adult animals were embedded and processed as described (18). Images of hematoxylin-and eosin-stained sections were captured with a Zeiss Axioplan 2 microscope and digital camera using AXIOVISION V.3.1 software.…”

Section: Suppressor Screen Using Drosophila Chromosome 2 and 3 Deficimentioning

confidence: 99%

Requirement of the calcineurin subunit gene canB2 for indirect flight muscle formation in Drosophila

Gajewski

Wang

Molkentin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Calcineurin is a calcium-activated protein phosphatase involved in multiple aspects of cardiac and skeletal muscle development and disease. Genes encoding calcineurin subunit proteins are highly conserved among animal species. Toward the goal of identifying new calcineurin-interacting loci that function in myogenic processes, we expressed an activated form of mouse calcineurin A in Drosophila and screened for suppressors of the phosphataseinduced lethality. Here, we demonstrate that a mutation in the canB2 gene, which encodes a regulatory subunit of Drosophila calcineurin, can suppress a pupal developmental arrest phenotype to adult viability. As canB2 is an essential gene and rare homozygous escapers are flightless, we further analyzed canB2 expression and function in pupae and adults. The gene is expressed in the forming indirect flight muscles and central nervous system during pupal development. A canA gene is comparably expressed in these tissues. Consistent with the observed muscle expression, canB2 mutants exhibit severe defects in the organization of their indirect flight muscles, a phenotype that is likely caused by muscle hypercontractility. Together, these findings demonstrate a vital role for the phosphatase in this specific facet of Drosophila myogenesis and show conserved fly and vertebrate calcineurin genes contribute prominently to fundamental processes of muscle formation and function.

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A Series of Mutations in the D-MEF2 Transcription Factor Reveal Multiple Functions in Larval and Adult Myogenesis in Drosophila

Cited by 209 publications

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mef2 activity levels differentially affect gene expression during Drosophila muscle development

mef2 activity levels differentially affect gene expression during Drosophila muscle development

Gene duplications, robustness and evolutionary innovations

Requirement of the calcineurin subunit gene canB2 for indirect flight muscle formation in Drosophila

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