The Nuclear Lamina

Wong, Xianrong; Melendez-Perez, Ashley J.; Reddy, Karen L.

doi:10.1101/cshperspect.a040113

Cited by 51 publications

(40 citation statements)

References 211 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that the lamin meshwork forms a scaffold for the attachment of genomic DNA packaged into chromatin, it is possible that substitutions at R264 disrupt such contacts [19,[23][24][25]. To test for this, we analyzed the degree to which the fluorescent DAPI signal colocalized with the fluorescent signal from antibodies to LamC and lamDm 0 using the JACoP plugin for Fiji [68,69].…”

Section: Larval Body Wall Muscle-specific Expression Of R264q and R264w Did Not Affect Motility But Caused Pupal Lethalitymentioning

confidence: 99%

“…Lamins serve multiple functions in the cell. They provide structural support for the nucleus and ensure the integrity of the nuclear envelope [19,20]. Support for this statement comes from studies showing that transient nuclear rupture and increased DNA damage are observed in skeletal muscle nuclei, which experience mechanical stress [21,22].…”

Section: Introductionmentioning

confidence: 99%

“…Support for this statement comes from studies showing that transient nuclear rupture and increased DNA damage are observed in skeletal muscle nuclei, which experience mechanical stress [21,22]. Lamins provide a scaffold for attachment of chromatin to the nuclear envelope at specific genomic locations called lamin-associated domains (LADs), which play a role in the orchestration of proper gene expression [19,[23][24][25]. LADs attract specific non-histone chromosomal proteins and are enriched for histone H3K9 tri-methylation, an epigenetic gene silencing mark [23].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

Hinz

Walker

Xiong

et al. 2021

IJMS

View full text Add to dashboard Cite

Mutations in the LMNA gene cause diseases called laminopathies. LMNA encodes lamins A and C, intermediate filaments with multiple roles at the nuclear envelope. LMNA mutations are frequently single base changes that cause diverse disease phenotypes affecting muscles, nerves, and fat. Disease-associated amino acid substitutions were mapped in silico onto three-dimensional structures of lamin A/C, revealing no apparent genotype–phenotype connections. In silico analyses revealed that seven of nine predicted partner protein binding pockets in the Ig-like fold domain correspond to sites of disease-associated amino acid substitutions. Different amino acid substitutions at the same position within lamin A/C cause distinct diseases, raising the question of whether the nature of the amino acid replacement or genetic background differences contribute to disease phenotypes. Substitutions at R249 in the rod domain cause muscular dystrophies with varying severity. To address this variability, we modeled R249Q and R249W in Drosophila Lamin C, an orthologue of LMNA. Larval body wall muscles expressing mutant Lamin C caused abnormal nuclear morphology and premature death. When expressed in indirect flight muscles, R249W caused a greater number of adults with wing posturing defects than R249Q, consistent with observations that R249W and R249Q cause distinct muscular dystrophies, with R249W more severe. In this case, the nature of the amino acid replacement appears to dictate muscle disease severity. Together, our findings illustrate the utility of Drosophila for predicting muscle disease severity and pathogenicity of variants of unknown significance.

show abstract

Section: Larval Body Wall Muscle-specific Expression Of R264q and R264w Did Not Affect Motility But Caused Pupal Lethalitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

Hinz

Walker

Xiong

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Muscle cells possess structural components to withstand such force, including high expression levels of A-type lamins, lamins A and C ( Swift et al, 2013 ; Cho et al, 2017 ). Lamins, intermediate filaments that line the inner nuclear membrane, provide structural support for the nucleus, determine the nuclear shape, and organize genomic DNA for proper gene expression ( Goldman et al, 2004 ; Burke & Stewart, 2006 ; Swift et al, 2013 ; Zwerger et al, 2013 ; Camozzi et al, 2014 ; Dialynas et al, 2015 ; Kim et al, 2017 ; Wong et al, 2022 ). Dominant mutations in the LMNA gene encoding the A-type lamins, A and C, cause Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B, and congenital muscular dystrophy ( Bonne et al, 1999 ; Rankin & Ellard, 2006 ; Astejada et al, 2007 ; Worman & Bonne, 2007 ; Lu et al, 2011 ; Maggi et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of mutant lamins on nucleo-cytoskeletal coupling in Drosophila models of LMNA muscular dystrophy

Shaw

Rios-Monterrosa

Fedorchak

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The nuclei of multinucleated skeletal muscles experience substantial external force during development and muscle contraction. Protection from such forces is partly provided by lamins, intermediate filaments that form a scaffold lining the inner nuclear membrane. Lamins play a myriad of roles, including maintenance of nuclear shape and stability, mediation of nuclear mechanoresponses, and nucleo-cytoskeletal coupling. Herein, we investigate how disease-causing mutant lamins alter myonuclear properties in response to mechanical force. This was accomplished via a novel application of a micropipette harpooning assay applied to larval body wall muscles of Drosophila models of lamin-associated muscular dystrophy. The assay enables the measurement of both nuclear deformability and intracellular force transmission between the cytoskeleton and nuclear interior in intact muscle fibers. Our studies revealed that specific mutant lamins increase nuclear deformability while other mutant lamins cause nucleo-cytoskeletal coupling defects, which were associated with loss of microtubular nuclear caging. We found that microtubule caging of the nucleus depended on Msp300, a KASH domain protein that is a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Taken together, these findings identified residues in lamins required for connecting the nucleus to the cytoskeleton and suggest that not all muscle disease-causing mutant lamins produce similar defects in subcellular mechanics.

show abstract

“…In higher eukaryotes, the most prominent structural component of the INM is the nuclear lamina (NL), a protein meshwork lining the NE (Burke and Stewart, 2013; Dobrzynska et al, 2016; Gruenbaum and Foisner, 2015; Wong et al, 2021). The backbone of the NL comprises polymers of nuclear lamins, type V intermediate filament proteins (de Leeuw et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Shared and distinctive neighborhoods of emerin and LBR revealed by proximity labeling and quantitative proteomics

Cheng

Zhang

Abhinav

et al. 2022

Preprint

View full text Add to dashboard Cite

Emerin and LBR are abundant transmembrane proteins of the nuclear envelope (NE) that are concentrated at the inner nuclear membrane (INM). Although both proteins interact with chromatin and nuclear lamins, they have distinctive biochemical and functional properties. Here we have deployed proximity labeling using the engineered biotin ligase TurboID (TbID) and quantitative proteomics to compare the neighborhoods of emerin and LBR in cultured mouse embryonic fibroblasts (MEFs). Our analysis revealed 232 high confidence proximity partners (HCPP) that interact selectively with emerin and/or LBR, 49 of which are shared by both. These included previously characterized NE-concentrated proteins, as well as a host of additional proteins not previously linked to emerin or LBR functions. Many of these are TM proteins of the ER and include two E3 ubiquitin ligases. Using the proximity ligation assay as an orthogonal approach, we validated the interactions described by proximity labeling for 11/12 proteins analyzed, supporting the robustness of our analysis. Overall, this work presents methodology that may be used for large-scale mapping of the landscape of the INM and reveals a group of new proteins with potential functional connections to emerin and LBR.

show abstract

The Nuclear Lamina

Cited by 51 publications

References 211 publications

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

Effects of mutant lamins on nucleo-cytoskeletal coupling in Drosophila models of LMNA muscular dystrophy

Shared and distinctive neighborhoods of emerin and LBR revealed by proximity labeling and quantitative proteomics

Contact Info

Product

Resources

About