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Abstract
Lamin A and lamin C isoforms of the gene LMNA are major structural and mechanotransductive components of the nuclear lamina. Previous reports have proposed lamin A as the isoform with the most dominant contributions to cellular mechanophenotype. Recently, expression of lamin C has also been shown to strongly correlate to cellular elastic and viscoelastic properties. Nevertheless, LMNA isoforms exist as part of a network that collectively provides structural integrity to the nucleus and their expression is ultimately regulated in a cell-specific manner. Thus, they have importance in mechanotransduction and structural integrity of the nucleus as well as potential candidates for biomarkers of whole-cell mechanophenotype. Therefore, a fuller discussion of lamin isoforms as mechanophenotypic biomarkers should compare both individual and ratiometric isoform contributions toward whole-cell mechanophenotype across different cell types. In this perspective, we discuss the distinctions between the mechanophenotypic correlations of individual and ratiometric lamins A:B1, C:B1, (A + C):B1, and C:A across cells from different lineages, demonstrating that the collective contribution of ratiometric lamin (A + C):B1 isoforms exhibited the strongest correlation to whole-cell stiffness. Additionally, we highlight the potential roles of lamin isoform ratios as indicators of mechanophenotypic change in differentiation and disease to demonstrate that the contributions of individual and collective lamin isoforms can occur as both static and dynamic biomarkers of mechanophenotype.
Highlights
Nuclear lamina proteins are type V intermediate filament proteins that exhibit important nuclear roles by contributing to structural integrity and regulating transcriptional activities (Dechat et al, 2010)
B-type lamins, such as lamin B1 and lamin B2, are differentially expressed by LMNB1 and LMNB2 and can be readily imaged together or separately. These proteins include lamin isoforms A, B1, B2, and C and are expressed at variable levels in all mammalian cells (Lin and Worman, 1993, 1995). These isoforms interact with several nuclear membrane proteins to form the nuclear lamina, LMNA Isoforms in Mechanophenotype the A-type and B-type proteins form independent filaments, and filament networks are spatially segregated within the nuclear lamina (Shimi et al, 2008)
We have found that individual lamin C to correlate better with mechanical properties than lamin A (Gonzalez-Cruz et al, 2018)
Summary
Nuclear lamina proteins are type V intermediate filament proteins that exhibit important nuclear roles by contributing to structural integrity and regulating transcriptional activities (Dechat et al, 2010). B-type lamins, such as lamin B1 and lamin B2, are differentially expressed by LMNB1 and LMNB2 and can be readily imaged together or separately These proteins include lamin isoforms A, B1, B2, and C and are expressed at variable levels in all mammalian cells (Lin and Worman, 1993, 1995). Lamins are connected to a network of intermembrane proteins that form the linker of the nucleus to cytoskeleton (LINC) protein complex, which is itself connected to the actomyosin cytoskeleton (Lombardi et al, 2011). Lamin proteins relay physical cues from the external microenvironment to the nucleus to induce physical chromatin rearrangement and influence gene expression and associate with perinuclear actin-LINC supramolecular complexes to prevent nuclear deformation upon exposure to these mechanical cues (Dahl et al, 2008; Osmanagic-Myers et al, 2015; Alam et al, 2016; Kim et al, 2017)
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