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MINIREVIEW
The nuclear lamina
Both a structural framework and a platform for genome
organization
Joanna M. Bridger
1
, Nicole Foeger
2
, Ian R. Kill
1
and Harald Herrmann
3
1 Centre for Cell and Chromosome Biology, Division of Biosciences, Brunel University, London, UK
2 Institute for Medical Biochemistry, Vienna Biocenter, Austria
3 Functional Architecture of the Cell, German Cancer Research Center (DKFZ), Heidelberg, Germany
Evolution of the intermediate filament
protein family
The nuclear lamina is a complex ensemble of proteins
that connects the inner nuclear membrane to chroma-
tin, and thus creates a link from the cytoplasm to the
genome. The nuclear lamina has received much atten-
tion recently, because presently 220 mutations have
been discovered within one of the constituent polypep-
tides, lamin A ⁄ C, and these have been demonstrated
to be the cause of a number of severe human diseases,
termed laminopathies (for a recent review see [1]).
Moreover, their down-regulation is associated with
specific cancers, such as lymphoma and leukaemia [2],
and lung cancer [3].
In contemporary metazoan cells the lamina is com-
prised of fibrous polypeptides of the intermediate

filament (IF) protein family, one type in lower phyla
like cnidaria or nematodes and four major forms in
mammals, designated A-type (lamin A and lamin C)
and B-type (lamin B1 and lamin B2), in addition to an
increasing number of associated proteins [4]. Lamins
were originally isolated from the high salt ⁄ detergent-
insoluble fractions of nuclear envelopes derived from
rat liver and named according to their apparent
molecular mass during SDS ⁄ PAGE [5]. Moreover,
B-type lamins are acidic and A-type lamins are basic,
as revealed by isoelectric focusing in conventional two-
dimensional polyacrylamide gel electrophoresis [6].
Molecular cloning as well as their appearance in the
Keywords
chromosomal organization; fluorescence
in situ hybridization; intermediate filaments;
lamins; nuclear envelope
Correspondence
H. Herrmann, B065 Functional Architecture
of the Cell, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 580,
D-69120 Heidelberg, Germany
Fax: +49 62214 23519
Tel: +49 62214 23512
E-mail:
(Received 26 February 2006, accepted 8
January 2007)
doi:10.1111/j.1742-4658.2007.05694.x
The inner face of the nuclear envelope of metazoan cells is covered by a thin
lamina consisting of a one-layered network of intermediate filaments inter-

connecting with a complex set of transmembrane proteins and chromatin
associating factors. The constituent proteins, the lamins, have recently gained
tremendous recognition, because mutations in the lamin A gene, LMNA, are
the cause of a complex group of at least 10 different diseases in human, inclu-
ding the Hutchinson–Gilford progeria syndrome. The analysis of these dis-
ease entities has made it clear that besides cytoskeletal functions, the lamina
has an important role in the ‘behaviour’ of the genome and is, probably as a
consequence of this function, intimately involved in cell fate decisions. Fur-
thermore, these functions are related to the involvement of lamins in organ-
izing the position and functional state of interphase chromosomes as well as
to the occurrence of lamins and lamina-associated proteins within the nucleo-
plasm. However, the structural features of these lamins and the nature of the
factors that assist them in genome organization present an exciting challenge
to modern biochemistry and cell biology.
Abbreviations
IF, intermediate filament; LAP, lamina-associated protein; LBR, lamin B receptor.
1354 FEBS Journal 274 (2007) 1354–1361 ª 2007 The Authors Journal compilation ª 2007 FEBS
electron microscope indicated that they are bona fide
IF proteins, although distinct differences became clear
both from the amino acid sequences and electron
microscopic images [7–9]. With the availability of
increasing sequence data for the IF multigene family,
they were grouped into the so-called sequence
homology class V, thereby distinguishing them from
the cytoplasmic class I acidic keratins, the class II basic
keratins, the class III desmin-like proteins and the class
IV neuronal IF proteins [10,11]. In addition to carrying
a conventional nuclear localization signal, lamins differ
from the cytoplasmic IF proteins with respect to the
structural organization in the first half of their central

a-helical rod, which is 42 amino acids longer than that
of cytoplasmic IF proteins (for review see [12]). This
longer ‘rod’-version is also found in the cytoplasmic IF
proteins of lower invertebrates and this led, together
with data for the gene structure of various genes, to the
concept that lamins, though they were detected last,
were very probably the primordial IF proteins [13].
Hence, a speculative ancestral lamin gene stands at the
origin of the 65 IF genes that we know for human at
present [14]. The fact that human harbours only three
genes for lamins – lamin A and C are derived by
splicing from one gene – in contrast to more than 50
genes for keratins, may indicate that they are conserved
with respect to the amino acid sequence for functional
reasons and so their number did not increase in a
corresponding fashion. Only in the germ cells of several
vertebrates are additional spliced versions such as lamin
C2 and lamin B3 are found. The fact that these special
lamins are expressed in spermatocytes and oocytes
possibly reflects the distinct organization of the nuclei
of these cells in general and chromatin in particular in
germ cells. Indeed, alteration of chromosome position-
ing and reorganization of the genome is very noticeable
during porcine spermatogenesis [15], with spermatogen-
esis being perturbed in mice lacking A-type lamins [16].
A modulation of function, as required in various
differentiated cells, may therefore be accomplished
by a combination of various, differentially expressed
associated proteins within or near the inner nuclear
membrane [17]. Nevertheless, complex multicellular

organisms such as Caenorhabditis elegans develop with
one B-type lamin in their various differentiated cells [1].
Fibrous proteins: Structural properties
and implications for function
Lamins contain a central, mainly a-helical rod of 350
amino acids with four subsegments able to form coiled-
coils with a like molecule in parallel orientation. These
individual a-helical segments, coils 1A, 1B, 2A and 2B,
are separated from each other by short ‘linkers’. The first
(L1) and the third (L2) linker are probably a-helical
whereas the second, longer one (L12) is unstructured
[18]. Two such molecules are able to associate into an
extended rod-like dimeric coiled-coil molecule of
 50 nm length, and their formation has been demon-
strated by glycerol spraying⁄ metal rotary shadowing EM
techniques (for review see [19]). These experiments
revealed also that the C-terminal domains of lamins form
globular structures, which have recently been demonstra-
ted by X-ray crystallography and NMR to be compact
Ig folds [20,21]. Lamin dimers are stable under high pH
and elevated salt conditions and this distinguishes them
from cytoplasmic IF proteins such as vimentin, which
form soluble, tetrameric complexes under low salt condi-
tions, both at physiological and high pH. At higher salt
concentration, i.e., 150–250 mm, vimentin will, however,
associate into higher assemblies and eventually filaments
[22,23]. Between the end of the a-helical rod and the Ig
fold domain, a multitude of basic amino acids including
a conventional nuclear localization signal is found,
which may interact with the acidic patches of the rod

domain. The non a-helical tail domain subsequent to the
Ig fold domain has been demonstrated to harbour chro-
matin-binding activity in a short glycine-serine-threonine
rich element near the carboxy-terminus [24].
Assembly, topogenesis and interaction
partners
Assembly of intermediate filaments starts with the
formation of coiled-coil dimers, which in the case of
lamins preferentially associate head-to-tail to form
extended threads of dimers [12,19]. Whether this
occurs during translation or post-translationally is
unknown. Moreover, it is completely unclear whether
lamin B1 and lamin B2 associate into homodimers
exclusively or if they are able – or even prefer – to
form heterodimers. With respect to the behaviour of
lamins during mitosis, i.e., A-type lamins being found
in a soluble and B-type lamins in a membrane-bound
form, it is rather safe to postulate that A- and B-type
lamins segregate completely within the cell, at least at
the dimeric level (Fig. 1; see Fig. 4 in [25]). Moreover,
during embryogenesis B-type lamins suffice to facilitate
proper development as demonstrated by gene targeting
of lamin A in mice [26]. At what level lamin B1 and
lamin B2 interact, is presently not known. Due to the
high sequence identity within the coiled-coil forming
domain of both lamins, it may be safe to speculate
that they are able to associate into mixed dimers. With
the onset of mitosis, the lamina is disassembled due
to specific phosphorylation reactions, and is, upon
J. M. Bridger et al. The nuclear lamina

FEBS Journal 274 (2007) 1354–1361 ª 2007 The Authors Journal compilation ª 2007 FEBS 1355
completion of mitosis, reorganized on the surface of
individual chromosomes together with inner nuclear
membrane proteins such as lamin B receptor (LBR),
emerin and lamina-associated protein (LAP)s ([27], for
review see [28,29]). Their function during this period of
the cell cycle is elusive. It may be that this cell cycle
stage provides the cell with a possibility to reorganize
the nucleus, allowing genome organization within nuc-
lei to be drastically altered. It is interesting to note that
if a quiescent state of chromosome positioning within
nuclei is enforced by serum starvation, it is not until
the next postmitotic G1 phase that the chromosomes
are found repositioned in a proliferating organization
[30].
Genome organization and the nuclear
lamina
One of the enigmatic suggested roles for lamins is
in genome organization, which could impact on
regulation of genome function, i.e., gene expression
[31]. Indeed, all the lamin subtypes have affinity for
chromosomes, chromatin and ⁄ or DNA [24,32–35].
Because chromatin and the nuclear lamina exhibit an
intimate spatial relationship, it has been suggested that
chromosomes are anchored, at least to some extent, by
the nuclear lamina [31,36]. Chromosome positioning
within nuclei is nonrandom and in human lympho-
blasts and fibroblasts chromosomes are positioning
according to their gene-density [37,38], with the most
gene-poor chromosomes found at the nuclear periph-

ery abutting the nuclear lamina (Fig. 2). It is as yet
unclear whether the nonrandom spatial positioning of
the genome within nuclei is involved in controlling
gene expression, but alterations in the level of tran-
scription have been observed when specific loci change
position within nuclei [39]. On the other hand it may
be that chromosomes themselves do not move much
within nuclei once they are positioned but specific gene
sequences may be looped towards areas of the nucleus
more amenable to transcription [31].
However, the question still remains as to whether
the nuclear lamina anchors specific chromosomes
within nuclei and whether this is relevant to the con-
trol of gene expression. We have assessed the posi-
tioning of specific chromosomes within cells that do
not appear to express A-type lamins and in human
studies we find little difference in the positioning of
four gene-poor chromosomes at the nuclear periphery
AB
Fig. 1. Solubility properties of lamins in human cultured cells.
(A) High salt ⁄ Triton X100 resistant fraction of SW13 cells (left lane)
and human dermal fibroblasts (right lane) separated on 20 cm long
10% polyacrylamaide gels [67]. Lamins are indicated by dots
(A, B1, B2 and C from top to bottom), vimentin by an arrowhead.
Note the very low amount of lamins compared to the cytoplasmic
intermediate filament protein vimentin. (B) Immunoblot of low salt-
soluble (lane 1), high salt-soluble and high salt ⁄ Triton X100 resistant
protein fractions of SW13 cells. Aliquot fractions were generated
according to a standard extraction protocol [67], separated by elec-
trophoresis on 10% polyacrylamide gels and either stained with

Coomassie Brilliant Blue (CBB) or blotted and immunostained
employing specific antibodies to lamin A (La A), lamin B1 (La B1),
lamin B2 (La B2) and LBR. The right panels of the immunoblots
are longer exposures of the corresponding left panels. Note that
lamin B1 is partially extracted into the low salt ⁄ Triton X100 fraction.
Fig. 2. Chromosome territories. A human nucleus with two individ-
ual chromosome territories revealed after painting with a whole
human chromosome painting probe by fluorescence in situ hybrid-
ization (green). The total amount of the DNA is delineated by the
fluorescent DNA stain DAPI (blue). Image from Ishita Mehta (Divi-
sion of Biosciences, Brunel University, London, UK). Bar ¼ 10 lm.
The nuclear lamina J. M. Bridger et al.
1356 FEBS Journal 274 (2007) 1354–1361 ª 2007 The Authors Journal compilation ª 2007 FEBS
in lymphoblastoid cell lines from patients with lam-
in A mutations [40]. One gene-poor chromosome
(chromosome 13), however, was found located away
from the nuclear periphery in two patient cell lines.
Interestingly, the lamin A mutation in these two cell
lines was within a DNA ⁄ chromatin binding domain
[35].
Further, we have found that in cells lacking A-type
lamins within the nuclear lamina, such as porcine pri-
mary ex vivo lymphocytes, there are fewer chromo-
somes located at the nuclear periphery. Thus, in
porcine lymphocytes many of the chromosomes that
are normally located abutting the nuclear lamina in
other cell types containing A-type lamins, are located
away from the nuclear edge (Foster H, Griffin D and
Bridger J, unpublished data). Taken together these two
pieces of data could imply that in disease cells and

nondisease cells of the haemopoietic lineage lacking
A-type lamins, a distinct alteration in chromosome
anchorage at the nuclear periphery may occur. The
role of the A-type lamin containing structures may not
be purely anchorage but there may be, in addition,
more subtle changes that are not elicited purely as
alternative chromosome location.
We have determined phases and stages in a cell’s life
where chromosome positioning is completely altered
from that of a young proliferating cell, namely
quiescence [30] and senescence ([30,41]; Bridger J,
unpublished data) or in differentiating precursor cells,
i.e., in spermatogenesis [15]. These drastic alterations
in chromosome positioning do coincide with changes
in lamin complement in spermatogenesis [42] and poss-
ible lamin interaction with chromatin in quiescence
[43]. It is interesting to note that territories of chromo-
some 18, normally positioned at the nuclear periphery,
are repositioned to the nuclear interior in cells induced
to enter quiescence by serum starvation, but do not
relocate to the nuclear periphery until after a mitosis
following restimulation of the cells by the addition of
serum [30]. Hence, chromosome 18 can probably
relocate in proliferating cells only because the interac-
tion with nuclear lamina components becomes possible
during the rebuilding of the nucleus at mitosis.
In primary fibroblast cell lines derived from patients
with laminopathies, i.e., mutations in lamin A, we have
also observed major changes in chromosome position-
ing, away from the nuclear periphery, however, these

cells appear to have A-type lamins as part of the nuc-
lear lamina [41]. These data assessing whole chromo-
some positioning support other studies in laminopathy
cell lines whereby chromatin is disorganized and
observed coming away from the nuclear periphery
[27,44–46]. Chromatin disorganization is also seen in
C. elegans worms that have their lamin expression
down-regulated [47].
Despite the small amount of evidence one may
hypothesize that nuclear lamin subtypes do play a role
in genome organization in the various cell cycle phases,
life cycle stages, cell lineage and differentiation states.
A functional interactive nuclear lamin
network
Early investigations described the lamina as a 15 nm
thick proteinaceous layer co-isolating with the nuclear
pore complexes [48]. Although electron microscopy of
thin-sectioned nuclei of cells and tissues indicated the
existence of a continuous layer of proteins apposed to
the inner membrane of the nuclear envelope, in the
vast majority of cells the nuclear lamina cannot be
resolved as such a distinct structure separating the
chromatin from the nuclear envelope. However, in
some special cell types of both invertebrate and verte-
brate origin, a lamina of 30–300 nm isolating the inner
nuclear membrane and chromatin can be visualized.
Most interestingly, in human synovial cells of patients
suffering from rheumatoid arthritis, a 50–70 nm thick
lamina containing lamin proteins can be observed [49].
Both B-type and A-type lamins can be found not

only at the nuclear periphery but also within nuclei
localized as internal foci [50–52]. Most attention has
focused on the A-type lamin foci. The function of
these internal lamin sites is not really determined but
they can also contain transcription factors [53] and
important proteins associated with cell proliferation
such as the retinoblastoma protein pRb [54]. In addi-
tion, these internal lamin structures contain lamina-
associated protein 2a (LAP2a), a protein with distinct
chromatin binding abilities [55]. Thus, there are sites
deep within nuclei that have putative chromatin ⁄ chro-
mosome binding and anchorage abilities. There are
even studies that display a networked filamentous
structure anatomising through nuclei, namely the nuc-
lear matrix, containing A-type lamins [56–58]. It has
been shown that even the internal lamin structures are
affected in cells that contain mutation in the LMNA
gene [59]. Whether internal lamins are only found in
particular foci or in a structured nuclear matrix is,
however, still debated. Nevertheless, both biochemical
and microscopic data indicate that lamins are present
throughout the nucleus. Without knowing their ultra-
structural state, one may consider that these lamin foci
are anchor points for the genome and that they could
be involved in the control of genome function. Such a
‘network’ comprised of lamins and chromatin could be
thought of as ‘intelligent scaffolding’ (Fig. 3). This net-
J. M. Bridger et al. The nuclear lamina
FEBS Journal 274 (2007) 1354–1361 ª 2007 The Authors Journal compilation ª 2007 FEBS 1357
work may furthermore be restructured dynamically

during different phases of the cell cycle and therefore
exhibit a different appearance in individual cells in
nonsynchronized cell cultures.
Outlook
The nuclear lamins are a very interesting group of
structural proteins that appear to have many functions.
Perhaps one of the most difficult to study functions is
the role within interphase genome organization and
their influence over genome function. It appears from
our studies that A-type lamins influence chromosome
position within interphase nuclei. How this happens and
what the consequences for genome function are remains
to be elucidated. It is also plausible that the A-type la-
mins are not purely anchorage sites for the genome but
perhaps they are involved in a signalling pathway that is
perturbed in diseased cells, falsely changing the cellular
status and eliciting a reorganization of the genome.
Indeed, signals received within the cytoplasm could be
translocated to the genome and translated by a linked
pathway of proteins from the cytoskeleton, across the
nuclear membrane to the nuclear lamin structures [60].
The existence of a structurally unified system consisting
of DNA, scaffold proteins and the surrounding cytoske-
leton has been proposed on the grounds of very interest-
ing data [61]. Moreover, it has been hypothesized for
many years that the cytoplasmic intermediate filament
system is determining and supporting the position of the
nucleus in the cell [62,63]. Now, the recent identification
of an interaction between the outer nuclear membrane
protein nesprin 3 and the intermediate filament-associ-

ated protein plectin provides direct support for such a
role [64]. M oreover, as cytoplasmic p roteins such as v imen-
tin and plectin are subject to multiple phosphorylation
reactions [65,66], a link between the structural and the
signalling state of the cytoskeleton with mechanisms
that control gene expression is open for investigation.
Acknowledgements
We wish to thank Peter Lichter for continuous interest
and support. JMB gratefully acknowledges support
from Sygen International PLC and Brunel University.
NF received a fellowship from the Schroedinger pro-
gramme (FWF, Austria). HH wants to acknowledge
funding from the European Union FP6 Life Science,
Genomics and Biotechnology for Health area (LSHM-
CT-2005018690) and the DKFZ-MOS program.
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