Loss of Drosophila A-type lamin C initially causes tendon abnormality including disintegration of cytoskeleton and nuclear lamina in muscular defects

Uchino, Ryo; Nonaka, Yuki; Horigome, Tuneyoshi; Sugiyama, Shin

doi:10.1016/j.ydbio.2012.08.001

Cited by 25 publications

(22 citation statements)

References 56 publications

(114 reference statements)

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“…The limited number of available human samples and inherent genomic heterogeneity, however, limits the conclusions that can be made. Our results are consistent with previous reports of NE damage and intrusion of cytoplasmic organelles into the nucleoplasm in skeletal muscle fibers of patients with EDMD [64][65][66][67] , cardiac myocytes in LMNA-dilated cardiomyopathy patients 68,69 , lamin A/Cdeficient mice 13,70 , and muscle and tendons of lamin-deficient fruit flies 71,72 . Unlike those previous reports, however, we now provide detailed information on the extent, timing, and cause of the NE damage, revealing a striking correlation of NE rupture and disease severity.…”

Section: Discussionsupporting

confidence: 93%

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Earle

Kirby

Fedorchak

et al. 2018

Preprint

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Mutations in the human LMNA gene, which encodes the nuclear envelope proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found that Lmna mutations caused extensive nuclear envelope damage, consisting of chromatin protrusions and transient rupture of the nuclear envelope, in skeletal muscle cells in vitro and in vivo. The nuclear envelope damage was associated with progressive DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, nuclear envelope damage resulted from nuclear movement in maturing skeletal muscle cells, rather than actomyosin contractility, and was reversed by either depletion of kinesin-1 or stabilization of microtubules. Depletion of kinesin-1 also rescued DNA damage, indicating that DNA damage is the result of nuclear envelope damage. The extent of nuclear envelope damage and DNA damage in the different Lmna mouse models strongly correlated with the disease onset and severity in vivo, and inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients with LMNA associated muscular dystrophy similarly revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor for these skeletal muscle diseases.

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Section: Discussionsupporting

confidence: 93%

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Earle

Kirby

Fedorchak

et al. 2018

Preprint

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“…Remarkably, the critical function of lamin C is exerted in tendon cells, not muscle, and involves the spectraplakin-dependent stabilization of the cytoskeleton (Uchino et al, 2013). Mammalian tendons are maintained by fibroblasts, which actively migrate and proliferate in response to injury (Arnesen & Lawson, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest Lmo7 activity is regulated by p130Cas-dependent association with focal adhesions. These findings are discussed in the light of a Drosophila study that showed A-type lamins exert their critical function in tendon cells (Uchino et al, 2013), which connect to muscle cells via the extracellular matrix, and evidence that integrin-dependent signaling is important for cells to respond to and withstand mechanical stress (Pines et al, 2012). …”

Section: Introductionmentioning

confidence: 98%

The emerin-binding transcription factor Lmo7 is regulated by association with p130Cas at focal adhesions

Wozniak

Baker

Chen

et al. 2013

PeerJ

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Loss of function mutations in the nuclear inner membrane protein, emerin, cause X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). X-EDMD is characterized by contractures of major tendons, skeletal muscle weakening and wasting, and cardiac conduction system defects. The transcription factor Lmo7 regulates muscle- and heart-relevant genes and is inhibited by binding to emerin, suggesting Lmo7 misregulation contributes to EDMD disease. Lmo7 associates with cell adhesions and shuttles between the plasma membrane and nucleus, but the regulation and biological consequences of this dual localization were unknown. We report endogenous Lmo7 also associates with focal adhesions in cells, and both co-localizes and co-immunoprecipitates with p130Cas, a key signaling component of focal adhesions. Lmo7 nuclear localization and transcriptional activity increased significantly in p130Cas-null MEFs, suggesting Lmo7 is negatively regulated by p130Cas-dependent association with focal adhesions. These results support EDMD models in which Lmo7 is a downstream mediator of integrin-dependent signaling that allows tendon cells and muscles to adapt to and withstand mechanical stress.

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“…Drosophila lamin C, which is the homolog of mammalian A/C type lamin, displays tissuespecific expression levels in fully differentiated cells 39,40 . Mutations in lamin A/C have been associated with aberrant chromatin organization and global detachment of chromatin from the nuclear lamina in a wide range of model organisms and tissues 15,18,19 .…”

Section: Lamin C Over-expression Disrupts Chromatin Localization At Tmentioning

confidence: 99%

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Pavlov¹,

Lorber²,

Bajpai³

et al. 2020

Preprint

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Packaging of the chromatin within the nucleus serves as an important factor in the regulation of transcriptional output. However, information on chromatin architecture on nuclear scale in fully differentiated cells, under physiological conditions and in live organisms, is largely unavailable. Here, we imaged nuclei and chromatin in muscle fibers of live, intact Drosophila larvae. In contrast to the common view that chromatin is distributed throughout the nuclear volume, we show that the entire chromatin, including active and repressed regions, forms a peripheral layer underneath the nuclear lamina, leaving a chromatin-devoid compartment at the nucleus center. Importantly, visualization of nuclear compartmentalization required imaging of un-fixed nuclei embedded within their intrinsic tissue environment, with preserved nuclear volume. Upon fixation of similar muscle nuclei, we observed an average of three-fold reduction in nuclear volume caused by dehydration and evidenced by nuclear flattening. In these conditions, the peripheral chromatin layer was not detected anymore, demonstrating the importance of preserving native biophysical tissue environment. We further show that nuclear compartmentalization is sensitive to the levels of lamin C, since over-expression of lamin C-GFP in muscle nuclei resulted in detachment of the peripheral chromatin layer from the lamina and its collapse into the nuclear center. Computer simulations of chromatin distribution recapitulated the peripheral chromatin organization observed experimentally, when binding of lamina associated domains (LADs) was incorporated with chromatin selfattractive interactions. Reducing the number of LADs led to collapse of the chromatin, similarly to our observations following lamin C over-expression. Taken together, our findings reveal a novel mode of mesoscale organization of chromatin within the nucleus in a live organism, in which the chromatin forms a peripheral layer separated from the nuclear interior.This architecture may be essential for robust transcriptional regulation in fully differentiated cells.

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Loss of Drosophila A-type lamin C initially causes tendon abnormality including disintegration of cytoskeleton and nuclear lamina in muscular defects

Cited by 25 publications

References 56 publications

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

The emerin-binding transcription factor Lmo7 is regulated by association with p130Cas at focal adhesions

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

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