The nuclear lamina is the structural scaffold of the nuclear envelope that plays multiple regulatory roles in chromatin organization and gene expression as well as a structural role in nuclear stability. The lamina proteins, also referred to as lamins, determine nuclear lamina organization and define the nuclear shape and the structural integrity of the cell nucleus. In addition, lamins are connected with both nuclear and cytoplasmic structures forming a dynamic cellular structure whose shape changes upon external and internal signals. When bound to the nuclear lamina, the lamins are mobile, have an impact on the nuclear envelop structure, and may induce changes in their regulatory functions. Changes in the nuclear lamina shape cause changes in cellular functions. A quantitative description of these structural changes could provide an unbiased description of changes in cellular function. In this review, we describe how changes in the nuclear lamina can be measured from three-dimensional images of lamins at the nuclear envelope, and we discuss how structural changes of the nuclear lamina can be used for cell classification. 1. Composition of the Nuclear Lamina The nuclear envelope (NE) is a biostructure, which separates the nuclear and cytoplasmic parts of eukaryotic cells. The NE is a dynamic structure composed of the outer nuclear membrane (ONM) and the inner nuclear membrane (INM). The NE is embedded with nuclear pore proteins, through which molecules selectively pass to move between the nucleus and the cytoplasm. The nuclear membranes are bilipid structures supported by a network of proteins. Within the nucleus, the INM is underlined by the nuclear lamina, a dynamic filamentous protein network. The nuclear lamina has both regulatory and structural roles. The nuclear lamina is predominantly composed of lamins, which are dynamically anchored to the INM via posttranslational modifications. The molecular composition of the nuclear lamina has been previously discussed in several reviews [1, 2]. In brief, lamins are divided into A- and B-types (LMNA and LMNB, resp.) and play a central role in the integrity of the nuclear lamina. Both proteins bind to the chromatin at highly defined regions, creating a regulatory role for lamina-chromatic interaction [3]. While LMNB is constitutively expressed, the expression of LMNA is developmentally regulated, and expression levels differ between cell types. It has, therefore, been suggested that LMNA also plays a regulatory role [1, 2]. Silencing of LMNB causes dramatic changes in the LMNA meshwork, while LMNA
References
[1]
T. Dechat, K. Pfleghaar, K. Sengupta et al., “Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin,” Genes & Development, vol. 22, no. 7, pp. 832–853, 2008.
[2]
B. Burke and C. L. Stewart, “The nuclear lamins: flexibility in function,” Nature Reviews Molecular Cell Biology, vol. 14, no. 1, pp. 13–24, 2013.
[3]
W. A. Bickmore and B. van Steensel, “Genome architecture: domain organization of interphase chromosomes,” Cell, vol. 152, no. 6, pp. 1270–1284, 2013.
[4]
V. K. Parnaik, “Role of nuclear lamins in nuclear organization, cellular signaling, and inherited diseases,” International Review of Cell and Molecular Biology, vol. 266, pp. 157–206, 2008.
[5]
R. D. Goldman, D. K. Shumaker, M. R. Erdos et al., “Accumulation of mutant lamin A progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 24, pp. 8963–8968, 2004.
[6]
P. Scaffidi and T. Misteli, “Lamin A-dependent nuclear defects in human aging,” Science, vol. 312, no. 5776, pp. 1059–1063, 2006.
[7]
K. Cao, C. D. Blair, D. A. Faddah et al., “Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts,” The Journal of Clinical Investigation, vol. 121, no. 7, pp. 2833–2844, 2011.
[8]
L. B. Gordon, W. T. Brown, and F. S. Collins, “Hutchinson-Gilford Progeria syndrome,” in GeneReviews, R. A. Pagon, Ed., Seattle, Wash, USA, 1993.
[9]
D. McClintock, D. Ratner, M. Lokuge et al., “The mutant form of Lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin,” PLoS ONE, vol. 2, no. 12, Article ID e1269, 2007.
[10]
R. B？kenkamp, V. Raz, A. Venema et al., “Differential temporal and spatial progerin expression during closure of the ductus arteriosus in neonates,” PloS One, vol. 6, no. 9, Article ID e23975, 2011.
[11]
V. Raz, F. Carlotti, B. J. Vermolen et al., “Changes in lamina structure are followed by spatial reorganization of heterochromatic regions in caspase-8-activated human mesenchymal stem cells,” Journal of Cell Science, vol. 119, part 20, pp. 4247–4256, 2006.
[12]
E. Haithcock, Y. Dayani, E. Neufeld et al., “Age-related changes of nuclear architecture in Caenorhabditis elegans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 46, pp. 16690–16695, 2005.
[13]
V. Raz, B. J. Vermolen, Y. Garini et al., “The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells,” Journal of Cell Science, vol. 121, part 24, pp. 4018–4028, 2008.
[14]
J. L. V. Broers, B. M. Machiels, G. J. J. M. Van Eys et al., “Dynamics of the nuclear lamina as monitored by GFP-tagged A-type lamins,” Journal of Cell Science, vol. 112, part 20, pp. 3463–3475, 1999.
[15]
C. H. Righolt, M. L. R. Van 't Hoff, B. J. Vermolen, I. T. Young, and V. Raz, “Robust nuclear lamina-based cell classification of aging and senescent cells,” Aging, vol. 3, no. 12, pp. 1192–1201, 2011.
[16]
T. Dechat, S. A. Adam, P. Taimen, T. Shimi, and R. D. Goldman, “Nuclear lamins,” Cold Spring Harbor Perspectives in Biology, vol. 2, no. 11, Article ID a000547, 2010.
[17]
B. Buendia, A. Santa-Maria, and J. C. Courvalin, “Caspase-dependent proteolysis of integral and peripheral proteins of nuclear membranes and nuclear pore complex proteins during apoptosis,” Journal of Cell Science, vol. 112, no. 11, pp. 1743–1753, 1999.
[18]
C. H. Righolt, V. Raz, B. J. Vermolen, R. W. Dirks, H. J. Tanke, and I. T. Young, “Molecular image analysis: quantitative description and classification of the nuclear lamina in human mesenchymal stem cells,” International Journal of Molecular Imaging, vol. 2011, Article ID 723283, 11 pages, 2011.
[19]
J. Lammerding, L. G. Fong, J. Y. Ji et al., “Lamins A and C but not lamin B1 regulate nuclear mechanics,” The Journal of Biological Chemistry, vol. 281, no. 35, pp. 25768–25780, 2006.
[20]
B. J. Vermolen, Y. Garini, I. T. Young, R. W. Dirks, and V. Raz, “Segmentation and analysis of the three-dimensional redistribution of nuclear components in human mesenchymal stem cells,” Cytometry A, vol. 73, no. 9, pp. 816–824, 2008.
[21]
E. A. J. Reits and J. J. Neefjes, “From fixed to FRAP: measuring protein mobility and activity in living cells,” Nature Cell Biology, vol. 3, no. 6, pp. E145–E147, 2001.
[22]
K. N. Dahl, P. Scaffidi, M. F. Islam, A. G. Yodh, K. L. Wilson, and T. Misteli, “Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 27, pp. 10271–10276, 2006.
[23]
S. Gilchrist, N. Gilbert, P. Perry, C. ？stlund, H. J. Worman, and W. A. Bickmore, “Altered protein dynamics of disease-associated lamin A mutants,” BMC Cell Biology, vol. 5, no. 1, article 46, 2004.
[24]
L. E. Finlan, D. Sproul, I. Thomson et al., “Recruitment to the nuclear periphery can alter expression of genes in human cells,” PLoS Genetics, vol. 4, no. 3, Article ID e1000039, 2008.
[25]
C. M. Funkhouser, R. Sknepnek, T. Shimi, A. E. Goldman, R. D. Goldman, and M. Olvera de la Cruz, “Mechanical model of blebbing in nuclear lamin meshworks,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 9, pp. 3248–3253, 2013.
[26]
J. Kind, L. Pagie, H. Ortabozkoyun, et al., “Single-cell dynamics of genome-nuclear lamina interactions,” Cell, vol. 153, no. 1, pp. 178–192, 2013.
