Decreased mechanical stiffness in LMNA−/− cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies

Broers, Jos L. V.; Peeters, Emiel A.G.; Kuijpers, Helma J.H.; Endert, J.; Bouten, Cvc Carlijn; Oomens, C.W.J.; Baaijens, F.P.T.; Ramaekers, Frans C. S.

doi:10.1093/hmg/ddh295

Cited by 325 publications

(329 citation statements)

References 58 publications

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“…The mechanical stress hypothesis proposes that alterations in A-type lamins compromise nuclear integrity in tissues susceptible to stress, such as striated muscle. This model is supported by findings that A-type lamin deficiency disrupts nuclear integrity in model systems (6,7). The second hypothesis postulates that LMNA mutations alter interactions of the nuclear lamina with chromatin, resulting in aberrant gene expression.…”

mentioning

confidence: 77%

Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement

Folker

Östlund

Luxton

et al. 2010

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

166

202

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Mutations in LMNA, which encodes A-type lamins, result in disparate diseases, known collectively as laminopathies, that affect distinct tissues, including striated muscle and adipose tissue. Lamins provide structural support for the nucleus and sites of attachment for chromatin, and defects in these functions may contribute to disease pathogenesis. Recent studies suggest that A-type lamins may facilitate connections between the nucleus and the cytoskeleton mediated by nuclear envelope nesprin and SUN proteins. In mammalian cells, however, interfering with A-type lamins does not affect the localization of these proteins. Here, we used centrosome orientation in fibroblasts, which requires separate nuclear and centrosome positioning pathways, as a model system to understand how LMNA mutations affect nucleus-cytoskeletal connections. We find that LMNA mutations causing striated muscle diseases block actin-dependent nuclear movement, whereas most that affect adipose tissue inhibit microtubule-dependent centrosome positioning. Genetic deletion or transient depletion of A-type lamins also blocked nuclear movement, showing that mutations affecting muscle exhibit the null phenotype. Lack of A-type lamins, or expression of variants that cause striated muscle disease, did not affect assembly of nesprin-2G and SUN2 into transmembrane actinassociated nuclear (TAN) lines that attach the nucleus to retrogradely moving actin cables. Nesprin-2G TAN lines were less stable, however, and slipped over the nucleus rather than moving with it, indicating that they were not anchored. Nesprin-2G TAN lines also slipped in SUN2-depleted cells. Our results establish A-type lamins as anchors for nesprin-2G-SUN2 TAN lines to allow productive movement and proper positioning of the nucleus by actin.nesprin SUN | linker of nucleoskeleton and cytoskeleton complex | muscular dystrophy L amin A and lamin C, the predominant A-type lamins, are expressed in most differentiated somatic cells. Yet, different mutations in the LMNA gene encoding these proteins result in a variety of diseases that affect specific tissues. LMNA mutations cause autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) and related diseases with dilated cardiomyopathy (DCM) that affect cardiac muscle and skeletal muscle to variable degrees (1). Other LMNA mutations cause Dunnigan-type familial partial lipodystrophy (FPLD) that affects adipose tissue (2), Charcot-Marie-Tooth type 2B1 disease that affects peripheral neurons (3), and progeroid syndromes with features of accelerated aging (4, 5). The mechanism whereby mutations in a single gene that is widely expressed cause such diverse diseases remains a puzzle.There are two prevailing hypotheses to explain the pathogenesis of laminopathies. The mechanical stress hypothesis proposes that alterations in A-type lamins compromise nuclear integrity in tissues susceptible to stress, such as striated muscle. This model is supported by findings that A-type lamin deficiency disrupts nuclear integrity in model systems (6, 7). The secon...

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mentioning

confidence: 77%

Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement

Folker

Östlund

Luxton

et al. 2010

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

166

202

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“…Polymorphisms in LMNA, encoding lamin A, a structural factor that lines the nucleus, have been linked to striated muscle wasting and muscular dystrophy. 44,45 Lamin A is also a relatively widely expressed protein, so the reasons for the tissue-selective effect of LMNA polymorphisms on striated muscle maintenance remain unclear. One theory is that the more fragile nucleus that results from lamin A loss is susceptible to rupture in muscle due to mechanical stress.…”

Section: Discussionmentioning

confidence: 99%

“…One theory is that the more fragile nucleus that results from lamin A loss is susceptible to rupture in muscle due to mechanical stress. 44,45 The subsequent loss of nuclear integrity is postulated to cause cell death. The NPC is known to associate with lamins, and interestingly a direct association between NUP35 and lamin B has been reported.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation in Nucleoporin 35 Causes Murine Degenerative Colonic Smooth Muscle Myopathy

Parish

Stamp

Lorenzo

et al. 2016

The American Journal of Pathology

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Chronic intestinal pseudo-obstruction (CIPO) is a rare but life-threatening disease characterized by severe intestinal dysmotility. Histopathologic studies in CIPO patients have identified several different mechanisms that appear to be involved in the dysmotility, including defects in neurons, smooth muscle, or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA recognition motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited a reduced lifespan. Histopathologic examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the subtype of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO. (Am J Pathol 2016 http://dx

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“…These changes make the cell susceptible to mechanical stress potentially leading to cell death, especially striated muscle or cardiomyocytes that are exposed to mechanical stress [64] . Embryonic fibroblasts obtained from Lmna knockout mice demonstrate the inability of the nuclear envelope to withstand physical force easily rupturing as compared to controls [65] . Skeletal muscle biopsies obtained from www.chinaphar.com Boudoulas KD et al Acta Pharmacologica Sinica npg patients with autosomal EDMD and cardiac biopsies from patients with dilated cardiomyopathies have shown physical damage to the cells including ruptured nuclear envelopes and localization of chromatin into the cytoplasm [66,67] .…”

Section: Structural Hypothesismentioning

confidence: 93%

Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

Boudoulas

Mohler

2011

Acta Pharmacol Sin

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Decreased mechanical stiffness in LMNA−/− cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies

Cited by 325 publications

References 58 publications

Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement

Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement

A Novel Mutation in Nucleoporin 35 Causes Murine Degenerative Colonic Smooth Muscle Myopathy

Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

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