Prelamin A and lamin A appear to be dispensable in the nuclear lamina
Loren G. Fong, … , Martin O. Bergo, Stephen G. Young
Loren G. Fong, … , Martin O. Bergo, Stephen G. Young
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):743-752. https://doi.org/10.1172/JCI27125.
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Research Article Genetics

Prelamin A and lamin A appear to be dispensable in the nuclear lamina

Abstract

Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C–only mice (Lmna+/+), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna+/+ mice were entirely healthy, and Lmna+/+ cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl–prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A–related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single LmnaLCO allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24–/– mice. Moreover, treating Zmpste24–/– cells with a prelamin A–specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.

Authors

Loren G. Fong, Jennifer K. Ng, Jan Lammerding, Timothy A. Vickers, Margarita Meta, Nathan Coté, Bryant Gavino, Xin Qiao, Sandy Y. Chang, Stephanie R. Young, Shao H. Yang, Colin L. Stewart, Richard T. Lee, C. Frank Bennett, Martin O. Bergo, Stephen G. Young

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Figure 11

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Improved nuclear shape in immortalized Zmpste24 –/ – fibroblasts treated...
Improved nuclear shape in immortalized Zmpste24 –/ – fibroblasts treated with an antisense oligonucleotide specific for mouse prelamin A (ISIS 359445). Zmpste24 –/ – cells were treated with ISIS 359445; after 72 hours, the cells were stained with antibodies against lamin A/C and LAP2, and the number of cells with misshapen nuclei was scored by 3 trained observers blinded to genotype and treatment. Bars show the frequency of misshapen nuclei as a percentage of untreated Zmpste24 –/ – cells for each individual observer (observer 1, white bars; observer 2, black bars; observer 3, gray bars). There was a statistically significant decrease in the number of misshapen nuclei for cells treated with 12.5 and 25 nM oligonucleotide compared with untreated Zmpste24 –/ – cells for each observer (P < 0.001, χ2 test). The average number of cells with misshapen nuclei in the untreated Zmpste24 –/ – cells was 78.5 cells. The higher baseline level of misshapen nuclei in the Zmpste24 –/ – fibroblasts in this experiment compared with Figure 8 is likely due to the fact that the cells were immortalized. We have previously noted much higher levels of misshapen nuclei in immortalized Zmpste24 –/ – fibroblasts than in primary Zmpste24 –/ – fibroblasts (44).