Direct Synthesis of Lamin A, Bypassing Prelamin A Processing, Causes Misshapen Nuclei in Fibroblasts but No Detectable Pathology in Mice

Coffinier, Catherine; Jung, Hea-Jin; Li, Ziwei; Nobumori, Chika; Yun, Ui Jeong; Farber, Emily; Davies, Brandon S.J.; Weinstein, Michael M.; Yang, Shao Hua; Lammerding, Jan; Farahani, Javad N.; Bentolila, Laurent A.; Fong, Loren G.; Young, Stephen G.

doi:10.1074/jbc.m110.128835

Cited by 71 publications

(93 citation statements)

References 41 publications

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“…To test this idea, we examined lamin A expression in Lmna LAO/LAO mice in which all the output of the Lmna gene is channeled into the production of mutant prelamin A transcripts encoding mature lamin A (18). Because lamin C splicing is absent in these mice, we expected to find increased levels of lamin A in the brain (i.e., levels comparable to lamin C levels in the brain of wild-type mice).…”

Section: Resultsmentioning

confidence: 99%

“…The intensities of the lamin C bands in the brain were similar to those in the kidney, but the prelamin A bands were faint. We also examined transcripts in two Lmna knockin mice- Lmna LAO/LAO mice that express exclusively mutant prelamin A transcripts encoding mature lamin A (18) and Lmna nHG/nHG mice that express mutant prelamin A transcripts encoding nonfarnesylated progerin (Materials and Methods) (12). Lamin C transcripts were absent, as expected, in both knockin models, but, similar to wild-type mice, the levels of prelamin A transcripts were much lower in the brain than in the kidney (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Zmpste24 −/− mice have been described previously (14). Lmna LAO/LAO mice produce exclusively mutant prelamin A transcripts that yield mature lamin A (bypassing prelamin A synthesis and processing) (18). The production of mature lamin A from the Lmna LAO transcript, rather than from prelamin A, results from a deletion of the sequences encoding the last 18 amino acids of prelamin A (18).…”

Section: Methodsmentioning

confidence: 99%

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Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Jung¹,

Coffinier²,

Choe

et al. 2012

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

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Lamins A and C, alternatively spliced products of the LMNA gene, are key components of the nuclear lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpected pattern of expression in the brain. Western blot and immunohistochemistry studies showed that lamin C is abundant in the mouse brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and meningeal cells and are absent in neurons and glia. Prelamin A transcript levels were low in the brain, but this finding could not be explained by alternative splicing. In lamin Aonly knockin mice, where alternative splicing is absent and all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were found in peripheral tissues, but there was very little lamin A in the brain. Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that prelamin A expression, but not lamin C expression, is down-regulated by a brain-specific microRNA, miR-9. Expression of miR-9 in cultured cells reduced lamin A expression, and this effect was abolished when the miR-9-binding site in the prelamin A 3′ UTR was mutated. The down-regulation of prelamin A expression in the brain could explain why mouse models of Hutchinson-Gilford progeria syndrome are free of central nervous system pathology.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Jung¹,

Coffinier²,

Choe

et al. 2012

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

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195

217

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“…Earlier in vitro studies had suggested that prelamin A prenylation is important for lamin A function and its delivery to the nuclear rim (27)(28)(29), but recent studies with knock-in mouse models have suggested otherwise. Coffinier et al (30) created knock-in mice that produce mature lamin A directly, bypassing prelamin A synthesis and farnesylation. The "mature lamin A" mice were healthy and fertile, and the lamin A in their tissues was positioned normally along the rim of the cell nucleus, indistinguishable from lamin A in the tissues of wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of prelamin A, cell culture studies suggested that protein farnesylation plays a vital role in the targeting of prelamin A to the nuclear rim (27)(28)(29), but recent studies with gene-targeted mice have raised questions about the in vivo relevance of those findings. For example, knock-in mice that produce mature lamin A directly (bypassing prelamin A synthesis and protein farnesylation) are free of disease, and the nuclear rim positioning of lamin A in the tissues of mice is quite normal (30).…”

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confidence: 99%

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Jung¹,

Nobumori²,

Goulbourne³

et al. 2013

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

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The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1-but not lamin B2-is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.genetically modified mouse models T he nuclear lamina is an intermediate filament meshwork that lies beneath the inner nuclear membrane. This lamina provides structural support for the nucleus and also interacts with nuclear proteins and chromatin, thereby affecting many functions within the cell nucleus (1, 2). In mammals, the main protein components of the nuclear lamina are lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins).Both B-type lamins and prelamin A (the precursor of lamin A) terminate with a CaaX motif, which triggers three posttranslational modifications (3-5): farnesylation of the carboxyl-terminal cysteine (the "C" in the CaaX motif) (6), endoproteolytic cleavage of the last three amino acids (the -aaX) (7,8), and carboxyl methylation of the newly exposed farnesylcysteine (9, 10). Prelamin A undergoes a second endoproteolytic cleavage event, mediated by zinc metalloproteinase STE24 (ZMPSTE24), which removes 15 additional amino acids from the carboxyl terminus, including the farnesylcysteine methyl ester (11)(12)(13)(14). Lamins B1 and B2 do not undergo the second cleavage step and therefore retain their farnesyl lipid anchor.The discovery that Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation yielding an internally truncated farnesyl-prelamin A (15) has focused interest in the farnesylation of nuclear lamins. This interest has been fueled by the finding that disease phenotypes in mouse models of HGPS could be ameliorated by blocking protein farnesylation with a protein farnesyltransferase inhibitor (FTI) (16)(17)(18)(19). Most recently, children with HGPS seemed to show a positive response to FTI treatment (20).The prospect of using an FTI to treat children with HGPS naturally raises the issue of the importance of protein farnesylation for lamin B1 and lamin B2. The B-type lamins are expressed in all mammalian cells and have been h...

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Lamins in Inherited Disease

Comai

2017

Encyclopedia of Life Sciences

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Lamins are a family of intermediate filament proteins that establish a complex protein network on the inner side of the nuclear membrane and play a critical role in preserving the structural integrity of the nuclear envelope. They also contribute to the spatial organisation of the genome and influence nuclear processes through a multitude of interactions with proteins and DNA (deoxyribonucleic acid). A large number of mutations have been identified primarily in the gene that encodes for A‐type lamins that cause a group of diseases with a broad range of clinical phenotypes collectively known as laminopathies. Many of these disorders show tissue‐restricted pathologies, indicating that even though lamins are present in the vast majority of metazoan cells, the mutations differentially influence the physiology of distinct tissues. Important clues have emerged over the past decade on the impact of disease‐causing mutations on the processes that maintain the structural and functional integrity of the nucleus. Key Concepts Lamins are components of the nuclear lamina, a network of proteins that controls nuclear structure and stiffness. Lamins play critical roles in the spatial organisation of the nucleus, chromatin organisation, nucleocytoplasmic communication and mechanotransduction. Mutations in genes encoding lamins are associated with a wide range of human diseases known as laminopathies. Studies of lamins structure and function have shed light on the molecular mechanisms of disease pathogenesis. Insights into the molecular pathology of lamins‐associated diseases create opportunities for the development of novel therapeutic strategies.

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Direct Synthesis of Lamin A, Bypassing Prelamin A Processing, Causes Misshapen Nuclei in Fibroblasts but No Detectable Pathology in Mice

Cited by 71 publications

References 41 publications

Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Lamins in Inherited Disease

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