RRC ID 46164
著者 Mattout A, Pike BL, Towbin BD, Bank EM, Gonzalez-Sandoval A, Stadler MB, Meister P, Gruenbaum Y, Gasser SM.
タイトル An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity.
ジャーナル Curr Biol
Abstract BACKGROUND:In worms, as in other organisms, many tissue-specific promoters are sequestered at the nuclear periphery when repressed and shift inward when activated. It has remained unresolved, however, whether the association of facultative heterochromatin with the nuclear periphery, or its release, has functional relevance for cell or tissue integrity.
RESULTS:Using ablation of the unique lamin gene in C. elegans, we show that lamin is necessary for the perinuclear positioning of heterochromatin. We then express at low levels in otherwise wild-type worms a lamin carrying a point mutation, Y59C, which in humans is linked to an autosomal-dominant form of Emery-Dreifuss muscular dystrophy. Using embryos and differentiated tissues, we track the subnuclear position of integrated heterochromatic arrays and their expression. In LMN-1 Y59C-expressing worms, we see abnormal retention at the nuclear envelope of a gene array bearing a muscle-specific promoter. This correlates with impaired activation of the array-borne myo-3 promoter and altered expression of a number of muscle-specific genes. However, an equivalent array carrying the intestine-specific pha-4 promoter is expressed normally and shifts inward when activated in gut cells of LMN-1 Y59C worms. Remarkably, adult LMN-1 Y59C animals have selectively perturbed body muscle ultrastructure and reduced muscle function.
CONCLUSION:Lamin helps sequester heterochromatin at the nuclear envelope, and wild-type lamin permits promoter release following tissue-specific activation. A disease-linked point mutation in lamin impairs muscle-specific reorganization of a heterochromatic array during tissue-specific promoter activation in a dominant manner. This dominance and the correlated muscle dysfunction in LMN-1 Y59C worms phenocopies Emery-Dreifuss muscular dystrophy.
巻・号 21(19)
ページ 1603-14
公開日 2011-10-11
DOI 10.1016/j.cub.2011.08.030
PII S0960-9822(11)00936-5
PMID 21962710
MeSH Animals Caenorhabditis elegans / embryology Caenorhabditis elegans / genetics* Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Disease Models, Animal Heterochromatin / metabolism Humans Laminin / genetics Laminin / metabolism* Locomotion Microscopy Muscle Development Muscles / embryology Muscular Dystrophy, Emery-Dreifuss / genetics* Muscular Dystrophy, Emery-Dreifuss / physiopathology Nuclear Envelope / metabolism Point Mutation* RNA Interference Real-Time Polymerase Chain Reaction Trans-Activators / genetics Trans-Activators / metabolism
IF 9.601
引用数 88
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
リソース情報
線虫 tm1582 tm1502