Structural and physiological phenotypes of disease-linked lamin mutations in C. elegans

Bank, Erin M.; Ben‐Harush, Kfir; Feinstein, Naomi; Medalia, Ohad; Gruenbaum, Yosef

doi:10.1016/j.jsb.2011.10.009

Cited by 28 publications

(23 citation statements)

References 37 publications

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“…3C-E). In contrast, animals expressing the L535P lamin mutation, in addition to their muscle phenotypes, show reduced motility (Bank et al, 2012) (Fig. 3F).…”

Section: Loss Of Prenylation Rescues Muscle Structure and Motility Inmentioning

confidence: 97%

“…Approximately 85% of L535P-expressing animals treated with fdps-1 (RNAi) demonstrated wild-type actin filament organization, as compared to 95% in wild-type animals and only 15% in L535P animals treated with an empty vector ( Fig. 3C,D; Bank et al, 2012). The rescue of the muscle phenotype was further analyzed in late L4 animals by thin-section transmission electron microscopy ( Fig.…”

Section: Loss Of Prenylation Rescues Muscle Structure and Motility Inmentioning

confidence: 99%

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Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation

Zuela

Zwerger

Levin

et al. 2016

Journal of Cell Science

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There are roughly 14 distinct heritable autosomal dominant diseases associated with mutations in lamins A/C, including Emery-Dreifuss muscular dystrophy (EDMD). The mechanical model proposes that the lamin mutations change the mechanical properties of muscle nuclei, leading to cell death and tissue deterioration. Here, we developed an experimental protocol that analyzes the effect of disease-linked lamin mutations on the response of nuclei to mechanical strain in living Caenorhabditis elegans. We found that the EDMD mutation L535P disrupts the nuclear mechanical response specifically in muscle nuclei. Inhibiting lamin prenylation rescued the mechanical response of the EDMD nuclei, reversed the muscle phenotypes and led to normal motility. The LINC complex and emerin were also required to regulate the mechanical response of C. elegans nuclei. This study provides evidence to support the mechanical model and offers a potential future therapeutic approach towards curing EDMD.

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“…3C-E). In contrast, animals expressing the L535P lamin mutation, in addition to their muscle phenotypes, show reduced motility (Bank et al, 2012) (Fig. 3F).…”

Section: Loss Of Prenylation Rescues Muscle Structure and Motility Inmentioning

confidence: 97%

Section: Loss Of Prenylation Rescues Muscle Structure and Motility Inmentioning

confidence: 99%

Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation

Zuela

Zwerger

Levin

et al. 2016

Journal of Cell Science

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“…In an effort to understand the underlying mechanism of various laminopathies, a number of disease-related lamin mutations have been introduced into C. elegans. Many of these mutations disrupted C. elegans LMN-1 oligomerization in vitro and lamin function in vivo (Wiesel et al 2008;Bank et al 2011Bank et al , 2012Mattout et al 2011;Zuela et al 2016). For example, LMN-1DK46, which corresponds to the deletion of lysine 32 in the rod domain of lamin A/C in Emery-Dreifuss muscular dystrophy patients, causes defects in the lateral assembly of LMN-1 dimers and results in abnormal muscle structure and motility in the worm .…”

Section: Components Of the Nementioning

confidence: 99%

Cell Biology of theCaenorhabditis elegansNucleus

Cohen-Fix

Askjaer

2017

Genetics

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Studies on the Caenorhabditis elegans nucleus have provided fascinating insight to the organization and activities of eukaryotic cells. Being the organelle that holds the genetic blueprint of the cell, the nucleus is critical for basically every aspect of cell biology. The stereotypical development of C. elegans from a one cell-stage embryo to a fertile hermaphrodite with 959 somatic nuclei has allowed the identification of mutants with specific alterations in gene expression programs, nuclear morphology, or nuclear positioning. Moreover, the early C. elegans embryo is an excellent model to dissect the mitotic processes of nuclear disassembly and reformation with high spatiotemporal resolution. We review here several features of the C. elegans nucleus, including its composition, structure, and dynamics. We also discuss the spatial organization of chromatin and regulation of gene expression and how this depends on tight control of nucleocytoplasmic transport. Finally, the extensive connections of the nucleus with the cytoskeleton and their implications during development are described. Most processes of the C. elegans nucleus are evolutionarily conserved, highlighting the relevance of this powerful and versatile model organism to human biology.KEYWORDS Caenorhabditis elegans; chromatin; gene expression; lamin; LEM-domain proteins; LINC; P granule; nuclear pore complex; nuclear envelope; nucleocytoplasmic transport; nucleolus; WormBook TABLE OF CONTENTSAbstract 25 C. elegans as a model system to study cell biology of the nucleus 26 Structural components of the nucleus 27

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“…27 Our transcriptional changes in the locomotion cluster (Table 1) correlate with the impaired motility observed in L535P animals. 20,24 Many of the lamin based muscle diseases have impaired ability to transmit forces from the cytoplasm to the nucleus and vice versa.…”

Section: Down Regulation Of Pharyngeal Muscle Genes Correlates With Amentioning

confidence: 63%

“…27 In order to gain better understanding of these EDMD disease-like phenotypes and to study changes in nuclear mechanical response, we analyzed the early transcription changes resulting from the dominant expression of the L535P EDMD mutation in C. elegans. mRNA of wild-type (N2)-, and L535P-animals at the fourth larval stage were extracted from roughly 3 hundred animals and these mRNA samples were used to prepare cDNA libraries that were subjected to deep sequencing analysis.…”

Section: Resultsmentioning

confidence: 99%

Global transcriptional changes caused by an EDMD mutation correlate to tissue specific disease phenotypes inC. elegans

Zuela

Dorfman

Gruenbaum

2016

Nucleus

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There are numerous heritable diseases associated with mutations in the LMNA gene. Most of these laminopathic diseases, including several muscular dystrophies, are autosomal dominant and have tissue-specific phenotypes. Our previous studies have shown that the globally expressed EmeryDreifuss muscular dystrophy (EDMD)-linked lamin mutation, L535P, disrupts nuclear mechanical response specifically in muscle nuclei of C. elegans leading to atrophy of the body muscle cells and to reduced motility. Here we used RNA sequencing to analyze the global changes in gene expression caused by the L535P EDMD lamin mutation in order to gain better understanding of disease mechanisms and the correlation between transcription and phenotype. Our results show changes in key genes and biological pathways that can help explain the muscle specific phenotypes. In addition, the differential gene expression between wild-type and L535P mutant animals suggests that the pharynx function in the L535P mutant animals is affected by this lamin mutation. Moreover, these transcriptional changes were then correlated with reduced pharynx activity and abnormal pharynx muscle structure. Understanding disease mechanisms will potentially lead to new therapeutic approaches toward curing EDMD.

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Structural and physiological phenotypes of disease-linked lamin mutations in C. elegans

Cited by 28 publications

References 37 publications

Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation

Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation

Cell Biology of theCaenorhabditis elegansNucleus

Global transcriptional changes caused by an EDMD mutation correlate to tissue specific disease phenotypes inC. elegans

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