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  • Review Article
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The nuclear lamina comes of age

Key Points

  • A- and B-type lamins form stable filaments in the nucleus, which anchor many nuclear-membrane proteins, soluble proteins and multiprotein complexes.

  • Lamins are needed directly or indirectly for many roles including the mechanical stability and shape of the nucleus, DNA replication and transcription, chromatin organization, cell-cycle regulation, cell development and differentiation, nuclear anchoring and migration, centrosome positioning and apoptosis. Each role probably involves one or more specific lamin-dependent complexes.

  • Mutations in A-type lamins (LMNA), or lamin-binding membrane proteins such as emerin or lamin-B receptor (LBR), cause heritable human diseases (laminopathies), which include muscular dystrophy, cardiomyopathy and accelerated ageing (progeria) syndromes. Diseases are proposed to arise from the defective assembly or function of the lamin-dependent protein complexes that are important for each affected tissue.

  • LBR, which is embedded in the inner nuclear membrane by eight transmembrane spans, binds lamins and has an essential sterol-reductase activity. LBR protein also functions as a scaffold for proteins (such as HP1) that are involved in chromatin silencing.

  • LEM-domain proteins (such as emerin, MAN1 and LAP2) bind lamins and function as scaffolds for various proteins including transcription regulators, such as germ cell-less (GCL) and BCL2-associated transcription factor (BTF); chromatin proteins, such as barrier-to-autointegration factor (BAF); and proteins that respond to TGFβ signalling, such as SMADs. Emerin also caps the pointed (minus) ends of filamentous (F)-actin in vitro, which indicates that it has roles in nuclear architecture.

  • Two emerging protein families, nesprins and SUN (Sad1/UNC-84 homology)-domain proteins, localize specifically to the inner or outer nuclear membrane, and interact with each other to form proposed 'bridging' complexes that span the nuclear envelope. These lamin-dependent complexes attach to cytoplasmic actin filaments, microtubules, or centrosomes, and mediate changes in nuclear position (for example, during development).

Abstract

Many nuclear proteins form lamin-dependent complexes, including LEM-domain proteins, nesprins and SUN-domain proteins. These complexes have roles in chromatin organization, gene regulation and signal transduction. Some link the nucleoskeleton to cytoskeletal structures, ensuring that the nucleus and centrosome assume appropriate intracellular positions. These complexes provide new insights into cell architecture, as well as a foundation for the understanding of the molecular mechanisms that underlie the human laminopathies — clinical disorders that range from Emery–Dreifuss muscular dystrophy to the accelerated ageing seen in Hutchinson–Gilford progeria syndrome.

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Figure 1: Schematic diagram of a human cell showing the nucleus and other selected structures (not to scale).
Figure 2: The lamin-B receptor is a membrane-embedded enzyme with an exposed domain that binds B-type lamins and other partners.
Figure 3: LAP2β mediates gene silencing and indirectly stabilizes pre-replication complexes.
Figure 4: Emerin binds many transcriptional regulators in vitro; models for in vivo function.
Figure 5: Proposed emerin-anchored actin cortical network at the nuclear envelope.
Figure 6: Man1 represses Smad signalling downstream of Bmp4 in Xenopus laevis embryos.
Figure 7: UNC-84-containing complexes are proposed to 'bridge' the nuclear envelope and link lamins to the cytoskeleton.
Figure 8: Summary of interactions between proteins of the nuclear lamina.

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References

  1. Stuurman, N., Heins, S. & Aebi, U. Nuclear lamins: their structure, assembly, and interactions. J. Struct. Biol. 122, 42–66 (1998).

    CAS  PubMed  Google Scholar 

  2. Schirmer, E. C., Florens, L., Guan, T., Yates, J. R. & Gerace, L. Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science 531, 1380–1382 (2003).

    Google Scholar 

  3. Weber, K., Plessmann, U. & Traub, P. Maturation of nuclear lamin A involves a specific carboxy-terminal trimming, which removes the polyisoprenylation site from the precursor; implications for the structure of the nuclear lamina. FEBS Lett. 257, 411–414 (1989).

    CAS  PubMed  Google Scholar 

  4. Leung, G. K. et al. Biochemical studies of Zmpste24-deficient mice. J. Biol. Chem. 276, 29051–29058 (2001).

    CAS  PubMed  Google Scholar 

  5. Herrmann, H. & Foisner, R. Intermediate filaments: novel assembly models and exciting new functions for nuclear lamins. Cell. Mol. Life Sci. 60, 1607–1612 (2003).

    CAS  PubMed  Google Scholar 

  6. Moir, R. D., Yoon, M., Khuon, S. & Goldman, R. D. Nuclear lamins A and B1. Different pathways of assembly during nuclear envelope formation in living cells. J. Cell Biol. 151, 1155–1168 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Karabinos, A., Schunemann, J., Meyer, M., Aebi, U. & Weber, K. The single nuclear lamin of Caenorhabditis elegans forms in vitro stable intermediate filaments and paracrystals with a reduced axial periodicity. J. Mol. Biol. 325, 241–247 (2003). The first study showing that lamin can form 10-nm filaments in vitro , similar to cytoplasmic intermediate filaments.

    CAS  PubMed  Google Scholar 

  8. Aebi, U., Cohn, J., Buhle, L. & Gerace, L. The nuclear lamina is a meshwork of intermediate-type filaments. Nature 323, 560–564 (1986).

    CAS  PubMed  Google Scholar 

  9. Gruenbaum Y. et al. The nuclear lamina and its functions in the nucleus. Int. Rev. Cyt. 226, 1–62 (2003).

    CAS  Google Scholar 

  10. Zastrow, M. S., Vlcek, S. & Wilson, K. L. Proteins that bind A-type lamins: integrating isolated clues. J. Cell Sci. 117, 979–987 (2004).

    CAS  PubMed  Google Scholar 

  11. Liu, J. et al. Essential roles for Caenorhabditis elegans lamin gene in nuclear organization, cell cycle progression, and spatial organization of nuclear pore complexes. Mol. Biol. Cell 11, 3937–3947 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu, J. et al. MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in C. elegans. Proc. Natl Acad. Sci. USA 100, 4598–4603 (2003). LEM-domain proteins have redundant functions in regulating mitosis and chromatin organization. This functional overlap might explain why loss of emerin, which is expressed in nearly all tissues, has no phenotype in C. elegans , and affects only three human tissues.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sullivan, T. et al. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J. Cell Biol. 147, 913–920 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Guillemin, K., Williams, T. & Krasnow, M. A. A nuclear lamin is required for cytoplasmic organization and egg polarity in Drosophila. Nature Cell Biol. 3, 848–851 (2001).

    CAS  PubMed  Google Scholar 

  15. Schirmer, E. C., Guan, T. & Gerace, L. Involvement of the lamin rod domain in heterotypic lamin interactions important for nuclear organization. J. Cell Biol. 153, 479–490 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Starr, D. A. et al. unc-83 encodes a novel component of the nuclear envelope and is essential for proper nuclear migration. Development 128, 5039–5050 (2001).

    CAS  PubMed  Google Scholar 

  17. Starr, D. A. & Han, M. Role of ANC-1 in tethering nuclei to the actin cytoskeleton. Science 11, 406–409 (2002). Evidence that the C. elegans nesprin homologue, ANC-1, is localized in the ONM and anchors the nucleus by binding both UNC-84 (at the nuclear envelope) and actin (in the cytoplasm).

    Google Scholar 

  18. Lopez-Soler, R. I., Moir, R. D., Spann, T. P., Stick, R. & Goldman, R. D. A role for nuclear lamins in nuclear envelope assembly. J. Cell Biol. 154, 61–70 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Spann, T. P., Moir, R. D., Goldman, A. E., Stick, R. & Goldman, R. D. Disruption of nuclear lamin organization alters the distribution of replication factors and inhibits DNA synthesis. J. Cell Biol. 136, 1201–1212 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Spann, T. P., Goldman, A. E., Wang, C., Huang, S. & Goldman, R. D. Alteration of nuclear lamin organization inhibits RNA polymerase II-dependent transcription. J. Cell Biol. 156, 603–608 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee, K. K. et al. Lamin-dependent localization of UNC-84, a protein required for nuclear migration in C. elegans. Mol. Biol. Cell 13, 892–901 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Malone, C. J. et al. The C. elegans Hook protein, ZYG-12, mediates the essential attachment between the centrosome and nucleus. Cell 115, 825–836 (2003). Evidence that ZYG-12 homodimers attach C. elegans centrosomes to the outer nuclear membrane, and to the nuclear lamina through direct or indirect binding to SUN1/matefin, an inner-nuclear-membrane protein.

    CAS  PubMed  Google Scholar 

  23. Zhen, Y. Y., Libotte, T., Munck, M., Noegel, A. A. & Korenbaum, E. NUANCE, a giant protein connecting the nucleus and actin cytoskeleton. J. Cell Sci. 115, 3207–3222 (2002).

    CAS  PubMed  Google Scholar 

  24. Croft, J. A. et al. Differences in the localization and morphology of chromosomes in the human nucleus. J. Cell Biol. 145, 1119–1131 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Nikolova, V. et al. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 113, 357–369 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Goldman, R. D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 101, 8963–8968 (2004). Fibroblasts from Hutchinson–Gilford progeria patients show dramatic changes in nuclear structure, loss of peripheral heterochromatin and changes in nuclear-envelope composition.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Waterham, H. R. et al. Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3β-hydroxysterol Δ14-reductase deficiency due to mutations in the Lamin B receptor gene. Am. J. Hum. Genet. 72, 1013–1017 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Holmer, L. & Worman, H. J. Inner nuclear membrane proteins: functions and targeting. Cell. Mol. Life Sci. 58, 1741–1747 (2001).

    CAS  PubMed  Google Scholar 

  29. Hoffmann, K. et al. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huet anomaly). Nature Genet. 31, 410–414 (2002). Evidence that LBR influences chromatin organization and nuclear shape during white-blood-cell differentiation.

    CAS  PubMed  Google Scholar 

  30. Lin, F. et al. MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin. J. Biol. Chem. 275, 4840–4847 (2000).

    CAS  PubMed  Google Scholar 

  31. Lee, K. K. & Wilson, K. L. The Nuclear Envelope (eds Evans, D. E., Hutchinson, C. & Bryant, J.) 331–341 (BIOS Scientific Publishers, Abingdon, UK, 2004).

    Google Scholar 

  32. Shumaker, D. K., Lee, K. K., Tanhehco, Y. C., Craigie, R. & Wilson, K. L. LAP2 binds to BAF–DNA complexes: requirement for the LEM domain and modulation by variable regions. EMBO J. 20, 1754–1764 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lee, K. K. et al. Distinct functional domains in emerin bind lamin A and DNA-bridging protein BAF. J. Cell Sci. 114, 4567–4573 (2001).

    CAS  PubMed  Google Scholar 

  34. Dechat, T. et al. Lamina-associated polypeptide 2α binds intranuclear A-type lamins. J. Cell Sci. 19, 3473–3484 (2000).

    Google Scholar 

  35. Goldberg, M. et al. Interactions among Drosophila nuclear envelope proteins lamin, otefin, and YA. Mol. Cell. Biol. 18, 4315–4323 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wagner, N., Schmitt, J. & Krohne, G. Two novel LEM-domain proteins are splice products of the annotated Drosophila melanogaster gene CG9424 (Bocksbeutel). Euro. J. Cell Biol. 82, 605–616 (2004).

    CAS  Google Scholar 

  37. Furukawa, K. LAP2 binding protein 1 (L2BP1/BAF) is a candidate mediator of LAP2- chromatin interaction. J. Cell Sci. 112, 2485–2492 (1999).

    CAS  PubMed  Google Scholar 

  38. Segura-Totten, M. & Wilson, K. L. BAF: roles in chromatin, nuclear structure and retrovirus integration. Trends Cell Biol. 14, 261–266 (2004).

    CAS  PubMed  Google Scholar 

  39. Zheng, R. et al. Barrier-to-autointegration factor (BAF) bridges DNA in a discrete, higher-order nucleoprotein complex. Proc. Natl Acad. Sci. USA 97, 8997–9002 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, X. et al. Barrier to autointegration factor interacts with the cone-rod homeobox and represses its transactivation function. J. Biol. Chem. 277, 43288–43300 (2002).

    CAS  PubMed  Google Scholar 

  41. Furukawa, K. et al. Barrier-to-autointegration factor plays crucial roles in cell cycle progression and nuclear organization in Drosophila. J. Cell Sci. 116, 3811–3823 (2003).

    CAS  PubMed  Google Scholar 

  42. Vlcek, S., Korbei, B. & Foisner, R. Distinct functions of LAP2α's unique C-terminus in cell proliferation and nuclear assembly. J. Biol. Chem. 277, 18898–18907 (2002).

    CAS  PubMed  Google Scholar 

  43. Johnson et al. A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation. Proc. Natl Acad. Sci. USA 101, 9677–9682 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Haraguchi, T. et al. BAF is required for emerin assembly into the reforming nuclear envelope. J. Cell Sci. 114, 4575–4585 (2001).

    CAS  PubMed  Google Scholar 

  45. Cohen, M., Lee, K., Wilson, K. W. & Gruenbaum, Y. Transcriptional repression, apoptosis, human disease and the functional evolution of the nuclear lamina. Trends Biochem. Sci 26, 41–47 (2001).

    CAS  PubMed  Google Scholar 

  46. Nili, E. et al. Nuclear membrane protein, LAP2β, mediates transcriptional repression alone and together with its binding partner GCL (germ cell-less). J. Cell Sci. 114, 3297–3307 (2001).

    CAS  PubMed  Google Scholar 

  47. Jongens, T. A., Ackerman, L. D., Swedlow, J. R., Jan, L. Y. & Jan, Y. N. Germ cell-less encodes a cell type-specific nuclear pore-associated protein and functions early in the germ-cell specification pathway of Drosophila. Genes Dev. 8, 2123–2136 (1994).

    CAS  PubMed  Google Scholar 

  48. de la Luna, S., Allen, K. E., Mason, S. L. & La Thangue, N. B. Integration of a growth-suppressing BTB/POZ domain protein with the DP component of the E2F transcription factor. EMBO J. 18, 212–228 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Martins, S., Eikvar, S., Furukawa, K. & Collas, P. HA95 and LAP2β mediate a novel chromatin-nuclear envelope interaction implicated in initiation of DNA replication. J. Cell Biol. 160, 177–188. (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Holaska, J. M., Lee, K. K., Kowalski, A. K. & Wilson, K. L. Transcriptional repressor germ cell-less (GCL) and barrier-to-autointegration factor (BAF) compete for binding to emerin in vitro. J. Biol. Chem. 278, 6969–6975 (2003).

    CAS  PubMed  Google Scholar 

  51. Bengtsson, L. & Wilson, K. L. Multiple and surprising new functions for emerin, a nuclear membrane protein. Curr. Opin. Cell Biol. 16, 73–79 (2004).

    CAS  PubMed  Google Scholar 

  52. Haraguchi, T. et al. Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery–Dreifuss muscular dystrophy. Eur. J. Biochem. 271, 1035–1045 (2004).

    CAS  PubMed  Google Scholar 

  53. Pederson, T. & Aebi, U. Actin in the nucleus: what form and what for? J. Struct. Biol. 140, 3–9 (2002).

    CAS  PubMed  Google Scholar 

  54. Pestic-Dragovich, L. et al. A myosin I isoform in the nucleus. Science 290, 337–342 (2000).

    CAS  PubMed  Google Scholar 

  55. Bettinger, B. T., Gilbert, D. M. & Amberg, D. C. Actin up in the nucleus. Nature Rev. Mol. Cell Biol. 5, 410–415 (2004).

    CAS  Google Scholar 

  56. Sasseville, A. M. & Langelier, Y. In vitro interaction of the carboxy-terminal domain of lamin A with actin. FEBS Lett. 425, 485–489 (1998).

    CAS  PubMed  Google Scholar 

  57. Fairley, E. A., Kendrick-Jones, J. & Ellis, J. A. The Emery–Dreifuss muscular dystrophy phenotype arises from aberrant targeting and binding of emerin at the inner nuclear membrane. J. Cell Sci. 112, 2571–2582 (1999).

    CAS  PubMed  Google Scholar 

  58. Lattanzi, G. et al. Association of emerin with nuclear and cytoplasmic actin is regulated in differentiating myoblasts. Biochem. Biophys. Res. Commun. 303, 764–770 (2003).

    CAS  PubMed  Google Scholar 

  59. Mattioli, E. et al. Nuclear AKAPs in muscle differentiation: redistribution of PKA in myotubes and regulation of AKAP149 expression by MAPK/ERK pathway. FEBS Lett. (in the press).

  60. Holaska, J. M., Kowalski, A. K. & Wilson, K. L. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane. PLoS Biol. 2, E231 (2004). Evidence that emerin caps the pointed end of F-actin and thereby indirectly enhances actin polymerization rates in vitro . Emerin also affinity-purifies nuclear-enriched αII-spectrin from HeLa-cell nuclear lysates, indicating that emerin anchors a spectrin- and actin-containing cortical network at the NE.

    PubMed  PubMed Central  Google Scholar 

  61. Luque, C. M. et al. An alternative domain containing a leucine-rich sequence regulates nuclear cytoplasmic localization of protein 4.1R. J. Biol. Chem. 278, 2686–2691 (2003).

    CAS  PubMed  Google Scholar 

  62. Sridharan, D., Brown, M., Lambert, W. C., McMahon, L. W. & Lambert, M. W. Nonerythroid αII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links. J. Cell Sci. 116, 823–835 (2003).

    CAS  PubMed  Google Scholar 

  63. Krauss, S. W., Chen, C., Penman, S. & Heald, R. Nuclear actin and protein 4.1: essential interactions during nuclear assembly in vitro. Proc. Natl Acad. Sci. USA 100, 10752–10757 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lammerding, J. et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J. Clin. Invest. 113, 370–378 (2004). Evidence that lmna -null mouse embryo fibroblasts have deformed nuclei, impaired viability under mechanical stress, defective mechanotransduction and attenuated gene-expression responses to mechanical stress via the NFκB signalling pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Dahl, K. N., Kahn, S. M., Wilson, K. L. & Discher, D. E. The nuclear envelope lamina network has elasticity and a compressibility limit suggestive of a molecular shock absorber. J. Cell Sci. 15, 4779–4786 (2004).

    Google Scholar 

  66. Osada, S., Ohmori, S. Y. & Taira, M. XMAN1, an inner nuclear membrane protein, antagonizes BMP signaling by interacting with Smad1 in Xenopus embryos. Development 130, 1783–1794 (2003). Evidence that X. laevis Man1 is a neuralizing factor that blocks Bmp signalling by direct binding to Smad proteins. Similar results were reported by Raju et al . (2003).

    CAS  PubMed  Google Scholar 

  67. ten Dijke, P. & Hill, C. S. New insights into TGF-β-Smad signalling. Trends Biochem. Sci. 29, 265–273 (2004).

    CAS  PubMed  Google Scholar 

  68. Nakayama, T., Cui, Y. & Christian, J. L. Regulation of BMP/Dpp signaling during embryonic development. Cell. Mol. Life Sci. 57, 943–956 (2000).

    CAS  PubMed  Google Scholar 

  69. Lee, H., Habas, R. & Abate-Shen, C. Msx1 cooperates with histone H1b for inhibition of transcription and myogenesis. Science 304, 1675–1678 (2004).

    CAS  PubMed  Google Scholar 

  70. Fainsod, A., Steinbeisser, H. & De Robertis, E. M. On the function of BMP-4 in patterning the marginal zone of the Xenopus embryo. EMBO J. 13, 5015–5025 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Malone, C. J., Fixsen, W. D., Horvitz, H. R. & Han, M. UNC-84 localizes to the nuclear envelope and is required for nuclear migration and anchoring during C. elegans development. Development 126, 3171–3181 (1999).

    CAS  PubMed  Google Scholar 

  72. Hedgecock, E. M. & Thomson, J. N. A gene required for nuclear and mitochondrial attachment in the nematode Caenorhabditis elegans. Cell 30, 321–330 (1982).

    CAS  PubMed  Google Scholar 

  73. Hodzic, D. M., Yeater, D. B., Bengtsson, L., Otto, H. & Stahl, P. D. Sun2 is a novel mammalian inner nuclear membrane protein. J. Biol. Chem. 279, 25805–25812 (2004).

    CAS  PubMed  Google Scholar 

  74. Fridkin, A. et al. Matefin, a C. elegans germ-line specific SUN-domain nuclear membrane protein, is essential for early embryonic and germ cell development. Proc. Natl Acad. Sci. USA 101, 6987–6992 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang, Q., Ragnauth, C., Greener, J. M., Shanahan, C. M. & Roberts, R. G. The nesprins are giant actin-binding proteins, orthologous to Drosophila muscle protein MSP-300. Genomics 80, 473–481 (2002).

    CAS  PubMed  Google Scholar 

  76. Padmakumar, V. C. et al. Enaptin, a giant actin-binding protein, is an element of the nuclear membrane and the actin cytoskeleton. Exp. Cell Res. 295, 330–339 (2004).

    CAS  PubMed  Google Scholar 

  77. Starr, D. A. & Han, M. ANChors away: an actin based mechanism of nuclear positioning. J. Cell Sci. 116, 211–216 (2003).

    CAS  PubMed  Google Scholar 

  78. Mislow, M. K. J. et al. Nesprin-1α self-associates and binds directly to emerin and lamin A in vitro. FEBS Lett. 525, 135–140 (2002).

    CAS  PubMed  Google Scholar 

  79. Muchir, A. et al. Nuclear envelope alterations in fibroblasts from LGMD1B patients carrying nonsense Y259X heterozygous or homozygous mutation in lamin A/C gene. Exp. Cell Res. 291, 352–362 (2003). Homozygous-null lmna fibroblasts were derived from a 30-week-old human fetus that was born prematurely to consanguineous parents. The infant had severe muscle defects and fibrosis, joint contractures and missing diaphragm muscles, and died after birth. The fibroblast nuclei were highly lobulated; lamin B and LAP2β were not detected at the NE; and emerin and nesprin-1α both mislocalized to the ER.

    CAS  PubMed  Google Scholar 

  80. Paddock, S. W. & Albrecht-Buehler, G. Rigidity of the nucleus during nuclear rotation in 3T3 cells. Exp. Cell Res. 175, 409–413 (1988).

    CAS  PubMed  Google Scholar 

  81. Gonczy, P., Pichler, S., Kirkham, M. & Hyman, A. A. Cytoplasmic dynein is required for distinct aspects of MTOC positioning, including centrosome separation, in the one cell stage Caenorhabditis elegans embryo. J. Cell Biol. 147, 135–150 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Yoder, J. H. & Han, M. Cytoplasmic dynein light intermediate chain is required for discrete aspects of mitosis in Caenorhabditis elegans. Mol. Biol. Cell 12, 2921–2933 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Walenta, J. H., Didier, A. J., Liu, X. & Kramer, H. The Golgi-associated hook3 protein is a member of a novel family of microtubule-binding proteins. J. Cell Biol. 152, 923–934 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Worman, H. J. & Courvalin, J. C. How do mutations in lamins A and C cause disease? J. Clin. Invest. 113, 349–351 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Mounkes, L., Kozlov, S., Burke, B. & Stewart, C. L. The laminopathies: nuclear structure meets disease. Curr. Opin. Genet. Dev. 213, 223–230 (2003).

    Google Scholar 

  86. Navarro, C. et al. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganisation and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum. Mol. Genet. 13, 2493–2503 (2004).

    CAS  PubMed  Google Scholar 

  87. Vigouroux, C. et al. Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene. J. Cell Sci. 114, 4459–4468 (2001).

    CAS  PubMed  Google Scholar 

  88. Markiewicz, E. et al. Increased solubility of lamins and redistribution of lamin C in X-linked Emery–Dreifuss muscular dystrophy fibroblasts. J. Struct. Biol. 140, 241–253 (2002).

    CAS  PubMed  Google Scholar 

  89. Broers, J. L. et al. Decreased mechanical stiffness in LMNA−/− cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies. Hum. Mol. Genet. 13, 2567–2580 (2004).

    CAS  PubMed  Google Scholar 

  90. Morris, G. E. in The Nuclear Envelope (eds Evans, D. E., Hutchinson, C. & Bryant, J.) (BIOS Scientific Publishers, Abingdon, UK, 2004).

    Google Scholar 

  91. Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114–10118 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sarkar, P. K. & Shinton, R. A. Hutchinson–Gilford progeria syndrome. Postgrad. Med. J. 77, 312–317 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Mukherjee, A. B. & Costello, C. Aneuploidy analysis in fibroblasts of human premature aging syndromes by FISH during in vitro cellular aging. Mech. Ageing Dev. 103, 209–222 (1998).

    CAS  PubMed  Google Scholar 

  94. Morris, G. E. The role of the nuclear envelope in Emery–Dreifuss muscular dystrophy. Trends. Mol. Med. 7, 572–577 (2001).

    CAS  PubMed  Google Scholar 

  95. Chen, L. et al. LMNA mutations in atypical Werner's syndrome. Lancet 362, 440–445 (2003).

    CAS  PubMed  Google Scholar 

  96. Brodsky, G. L. et al. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation 101, 473–476 (2000).

    CAS  PubMed  Google Scholar 

  97. Garg, A., Speckman, R. A. & Bowcock, A. M. Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and α-helical rod domains of the lamin A/C gene. Am. J. Med. 112, 549–555 (2002).

    CAS  PubMed  Google Scholar 

  98. Zhang, Q. et al. Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues. J. Cell Sci. 114, 4485–4498 (2001).

    CAS  PubMed  Google Scholar 

  99. Nedivi, E., Fieldust, S., Theill, L. E. & Hevron, D. A set of genes expressed in response to light in the adult cerebral cortex and regulated during development. Proc. Natl Acad. Sci. USA 93, 2048–2053 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Apel, E. D., Lewis, R. M., Grady, R. M. & Sanesi, J. R. Syne-1, a dystrophin-and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction. J. Biol. Chem. 275, 31986–31995 (2000).

    CAS  PubMed  Google Scholar 

  101. Mislow, J. M., Kim, M. S., Davis, D. B. & McNally, E. M. Myne-1, a spectrin repeat transmembrane protein of the myocyte inner nuclear membrane, interacts with lamin A/C. J. Cell Sci. 115, 61–70 (2002).

    CAS  PubMed  Google Scholar 

  102. Rosenberg-Hasson, Y., Renert-Pasca, M. & Volk, T. A Drosophila dystrophin-related protein, MSP-300, is required for embryonic muscle morphogenesis. Mech. Dev. 60, 83–94 (1996).

    CAS  PubMed  Google Scholar 

  103. Patterson, K. et al. The functions of Klarsicht and nuclear lamin in developmentally regulated nuclear migrations of photoreceptor cells in the Drosophila eye. Mol. Biol. Cell 15, 600–610 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Gough, L. L., Fan, J., Chu, S., Winnick, S. & Beck, K. A. Golgi localization of syne-1. Mol. Biol. Cell 14, 2410–2424 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Vlcek, S., Dechat, T. & Foisner, R. Nuclear envelope and nuclear matrix: interactions and dynamics. Cell. Mol. Life Sci. 58, 1758–1765 (2001).

    CAS  PubMed  Google Scholar 

  106. Tsukahara, T., Tsujino, S. & Arahata, K. cDNA microarray analysis of gene expression in fibroblasts of patients with X-linked Emery–Dreifuss muscular dystrophy. Muscle Nerve 25, 898–901 (2002).

    CAS  PubMed  Google Scholar 

  107. Shimi, T. et al. Dynamic interaction between BAF and emerin revealed by FRAP, FLIP, and FRET analyses in living HeLa cells. J. Struct. Biol. 147, 31–41 (2004).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Fainsod, P. Collas, M. Taira, H. Worman, J. Holaska and M. Mansharamani for comments. We apologize to authors whose work was not cited directly due to space limitations. We gratefully acknowledge support from the Israel Science Foundation and the German Cancer Research Center to Y.G., and the National Institutes of Health to K.L.W.

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Correspondence to Yosef Gruenbaum.

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DATABASES

Entrez

LMNA

Flybase

Bocksbeutel

Otefin

OMIM

EDMD

HGPS

PHA

Swiss-Prot

BAF

BTF

CDC6

Ce-lamin

CRX

emerin

GCL

HA95

LAP1

LAP2β

LAP2α

LBR

MAN1

MOK2

UNC-83

UNC-84

ZYG-12

FURTHER INFORMATION

Leiden Muscular Dystrophy pages

Glossary

INTERMEDIATE-FILAMENT PROTEINS

A large family of proteins with a central coiled-coil 'rod' domain that polymerize into stable 10-nm-diameter filaments in cells. These filaments are thicker than actin ('thin') filaments but thinner than microtubules, hence 'intermediate'. Lamins (type-V intermediate-filament proteins) are found only in the nucleus.

ISOPRENYLATION

Enzyme-mediated post-translational covalent attachment of a hydrophobic isoprenyl moiety to proteins.

FLUORESCENCE RECOVERY AFTER PHOTOBLEACHING

(FRAP). A microscope technique used to measure the movement (for example, diffusion rates) of fluorescently tagged molecules over time in vivo. Specific regions in a cell are irreversibly photobleached using a laser; fluorescence is restored by diffusion of fluorescently tagged unbleached molecules into the bleached area.

HETEROCHROMATIN

Highly compacted chromatin that is transcriptionally inactive. Includes structural regions of the chromosome that lack genes (for example, centromeres; 'constitutive' heterochromatin) as well as genes that are silenced in a given cell type ('facultative' heterochromatin).

CARDIOMYOPATHY

Weakening of the heart muscle that results in a decreased cardiac pumping force.

CHONDRODYSTROPHY

Inherited skeletal disorders in which cartilage is prematurely or inappropriately converted to bone. Non-lethal forms can cause dwarfism.

HETEROCHROMATIN PROTEIN-1

(HP1). Originally identified in D. melanogaster, HP1 is a protein that silences chromatin by binding histone H3 when the H3 tail is methylated at amino-acid residue Lys9 (Me-H3K9).

ANEUPLOIDY

Having an abnormal number of chromosomes (too many or too few).

α-ACTIN, β-ACTIN AND γ-ACTIN

In higher eukaryotes there are three actin isoforms; α-actin is specific to muscle cells, whereas β-actin and γ-actin are present in all cells.

SPECTRIN

A family of tetrameric, actin-binding proteins. The functional molecule consists of two α/β heterodimers.

VENTRALIZATION

Loss of dorsal-axis specification during early development, which produces embryos with ventral-only fates.

SPEMANN ORGANIZER

Specialized tissue at the dorsal lip of the blastopore in amphibian embryos, which directs formation of the embryonic body axis.

P CELLS

Ventral cord blast cells in C. elegans.

SYNCYTIAL HYPODERMAL CELLS

Many of the hypodermal cells that establish the basic body shape of C. elegans form multinucleate syncytia by cell fusion during development.

CALPONIN-HOMOLOGY DOMAIN

A 110-residue, actin-binding domain that is common to many actin-binding proteins, including cytoskeletal and signal-transduction proteins.

CENTROSOME

The microtubule-organizing center, an organelle that contains the centrioles and that anchors the 'minus' ends of microtubules.

DYNEIN

A microtubule-dependent motor protein that is powered by ATP hydrolysis.

NFκB PATHWAY

A signal-transduction pathway with central roles in immune and stress responses, inflammation, cell adhesion and protection against apoptosis.

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Gruenbaum, Y., Margalit, A., Goldman, R. et al. The nuclear lamina comes of age. Nat Rev Mol Cell Biol 6, 21–31 (2005). https://doi.org/10.1038/nrm1550

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