The Nuclear lamina, or the inner nuclear membrane (INM), is a scaffold-like network of protein filaments surrounding the nuclear periphery. This scaffold is made of mostly the type V intermediate filament proteins, lamin A/C and B, which together form a complex meshwork underneath the INM (reviewed in Foisner, 2001; and Wilson et al., 2001) . The lamins are coiled-coil structures that contain a small N-terminal head followed by a rod-like domain (coiled-coil) and a C-terminal globular tail. Via these coiled-coil regions lamins can form parallel dimers, which in turn form polymers with other lamin dimers in an anti-parallel manner (head-to-tail). Although quite resistant to biochemical extraction, the nuclear lamina is nonetheless dynamic and can depolymerise

during mitosis and reform upon re-entry into interphase following rounds of phosphorylation and dephosphorylation at residues flanking the coiled-coiled domain of the lamins (Wilson et al., 2001).

Various functions have been suggested for the nuclear lamina including: maintenance of nuclear shape; spatial organisation of nuclear pores within the nuclear membrane; regulation of transcription; anchoring of interphase heterochromatin; as well as, a role in DNA replication. Interestingly, lamins have also been reported within the nucleoplasm (Bridger et al., 1993) and these lamin foci are often associated with sites of DNA replication (Moir et al., 2000).

Formation of Lamin Polymers

B-type lamins are essential for development

B-type lamins are ubiquitously expressed and are essential, while the A-type lamins are believed to be non-essential and are only expressed in differentiated cells. There are two B-type lamins, B1 and B2, expressed from different genes; whereas, the A-type lamins, of which there are 4 isotypes (A and C being the most studied), are products of alternative mRNA splicing (Foisner, 2001) . Lamin depletion by RNA interference in C. elegans (which have only one B-type lamin) is lethal and associated with a number of phenotypic changes such as uneven clustering of nuclear pore complexes, irregularities in nuclear shape and defects in chromosomal organisation and segregation (Liu et al., 2000). In contrast, the lamin A knock-out mouse is born apparently normal, although by eight weeks most transgenic animals die from complications associated with muscular dystrophy and lipodystrophy (Sullivan et al., 1999). Thus, it appears that although A-type lamins are not required for development in mammals, they are required to maintain the integrity of a few specific tissues such as muscle and adipose tissue.

Other Inner nuclear membrane proteins

In addition to the lamins, vertebrates express several other INM proteins including: lamina-associated protein1 (LAP1, of which there are 3 isoforms (a, b and g)); LAP2 (six isoforms); emerin; MAN1; lamin B receptor (LBR); otefin; ring finger binding protein (RFBP); and nurim (Deschat et al., 2000; Cohen et al, 2001). Many of these proteins are integral to the inner nuclear membrane including: RFBP (9 transmembrane regions (TMRs)); LBR (8 TMRs); nurim (5 TMRs); and MAN1 (2 TMRs). Emerin, all LAP1 isoforms and 4 of the 6 LAP2 isoforms (b,e,d and g) have only one TMR. LAP2a and z do not have a TMR. All LAP1 isoforms and LAP2a interact preferentially with type A lamins, while LBR and LAP2b interact with the B-type lamins, and emerin interacts with both types of lamins (Foisner, 2001) .

Inner Nuclear Membrane Proteins
Click to enlarge
(Foisner, 2001)
Inner Nuclear Membrane Proteins and the Regulation of both Chromatin and Transcription

The lamins and the many of the other INM proteins have been implicated in both chromatin and transcriptional regulation (Foisner, 2001; Wilson et al., 2001). For instance, lamins have been implicated in transcriptional repression through both the interactions of lamin A/C with retinoblastoma protein (Rb) and LBR, which can bind heterochromatin protein 1 (HP1). In addition, both LBR and LAP2b can interact with the chromosomal protein HA95. Several other proteins, including all LAP2 isoforms, emerin and MAN1, contain a distinctive 43 amino acid region called the LEM domain in their N-terminus that can interact with a DNA-bridging protein called BAF. Furthermore, the lamins themselves can interact with core histones via their C-terminal tails (Taniura et al., 1995) . Recently, the first direct connection between the nuclear lamina and chromatin remodelling has been demonstrated by the discover of the INM protein RFBP, an atypical P-type ATPase that interacts directly with the RUSH family of SWI/SNF-like transcription factors (Mansharamani et al., 2001).

The Nuclear Lamina and Disease

Recently, two hereditary forms of Emery-Dreifuss muscular dystrophy (EDMD) have been linked to mutations in either lamins or lamin-associated proteins (reviewed in Morris, 2001). The X-linked recessive form of EDMD is caused by mutations in or the loss of emerin, while the autosomal dominant form of EDMD is caused by mutations in lamin A/C. Mutations in lamin A/C also cause one form of dilated cardiomyopathy (CMD1A), one form of limb-girdle muscular dystrophy (LGMD1B), and an unrelated form of lipodystrophy (FPLD). Confirming the role of lamin A/C in these diseases, the lamin A knock-out mouse exhibits both muscular dystrophy and lipodystrophy (Sullivan et al., 1999).

  • Nuclear Envelope from Gwen Child

  • EM images the nuclear lamina and lamins (University of Würzburg)
    -Image 1 (Human and Xenopus)
    -Image 2 (Drosophila)
    -Image 3 (Drosophila)
    -Immunofluorescence image of emerin

  • GFP-LBR movie--Jennifer Schwartz, Ph.D.

  • Published Movies of Nuclear Lamina dynamics
    Lamin B receptor Movies from the Ellenberg et al. 1997 paper (JCB on the dynamics of Lamin B receptor-GFP in interphase and mitosis.

    Broers et al., (1999) Dynamics of the nuclear lamina as monitored by GFP-tagged A-type lamins.JCS 112: 3463


    Bridger JM, Kill IR, O'Farrell M, Hutchison CJ. (1993) Internal lamin structures within G1 nuclei of human dermal fibroblasts. J. Cell Sci. 104(2):297-306.

    Cohen M, Lee KK, Wilson KL, Gruenbaum Y. (2001) Transcriptional repression, apoptosis, human disease and the functional evolution of the nuclear lamina. Trends Biochem. Sci. 26(1):41-47

    Dechat T, Korbei B, Vaughan OA, Vlcek S, Hutchison CJ, Foisner R. (2001) Lamina-associated polypeptide 2alpha binds intranuclear A-type lamins. J. Cell Sci. 113(19):3473-3484

    Foisner, R. (2001) Inner nuclear membrane proteins and the nuclear lamina. J. Cell Sci. 114(21):3791-3792.

    Liu J, Ben-Shahar TR, Riemer D, Treinin M, Spann P, Weber K, Fire A, Gruenbaum Y. (2000) Essential roles for Caenorhabditis elegans lamin gene in nuclear organization, cell cycle progression, and spatial organization of nuclear pore complexes. Mol. Biol. Cell 11(11):3937-3947

    Mansharamani M, Hewetson A, Chilton BS. (2001) Cloning and characterization of an atypical Type IV P-type ATPase that binds to the RING motif of RUSH transcription factors. J. Biol. Chem 276(5):3641-3649

    Moir RD, Spann TP, Herrmann H, Goldman RD. (2000) Disruption of nuclear lamin organization blocks the elongation phase of DNA replication. J. Cell Biol. 149(6):1179-1192.

    Morris, G.E. (2001) The role of the nuclear envelope in Emery-Dreifuss muscular dystrophy. Trends Mol Med 7(12):572-577

    Sullivan T, Escalante-Alcalde D, Bhatt H, Anver M, Bhat N, Nagashima K, Stewart CL, Burke B. (1999) Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J. Cell Biol. 147(5):913-920.

    Taniura H, Glass C, Gerace L. (1995) A chromatin binding site in the tail domain of nuclear lamins that interacts with core histones. J. Cell Biol. 131(1):33-44

    Wilson KL, Zastrow MS, Lee KK. (2001) Lamins and disease: insights into nuclear infrastructure. Cell 104(5):647-650