Mouse models of the laminopathies

Abstract

The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the A type lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.

Figure 1. Immunofluoresence images showing the distribution of progerin in untreated and FTI-treated Lmna^HG/HG cells

DNA was visualized with DAPI (blue), and progerin was visualized with an antibody against lamin A (red). A and B, Untreated Lmna^HG/HG cells, showing progerin along the nuclear envelope. Misshapen nuclei were common (white arrow). C and D, FTI-treated Lmna^HG/HG cells, revealing intensely staining progerin aggregates (white arrowheads) in the nucleoplasm. Reproduced, with permission, from The Proceedings of the National Academy of Science USA [55].

Figure 2. A positive effect of FTIs on disease phenotypes in Lmna^HG/+ mice

A, μCT scans illustrating reduced numbers of rib fractures in FTI-treated Lmna^HG/+ mice. Red arrowheads indicate rib fractures and surrounding callus. In the FTI-treated mouse, there is thinning of one rib along with a small amount of callus. B, Reduced number of rib fractures in FTI-treated Lmna^HG/+ mice. After 24 weeks, surviving mice were euthanized, and the number of rib fractures was counted. The number of rib fractures in the FTI-treated Lmna^HG/+ mice was lower than in vehicle-treated Lmna^HG/+ mice (P < 0.0001). Reproduced, with permission, from The Journal of Clinical Investigation [56].