2000-Review_Nuclear_lamins_-_Structural_proteins_with_fundamental_functions

Prévia do material em texto

Revie tein
Y arel,*
*Departm sity of
Ce Medici
ised fo
The
nuclea
is com
brane p
ated p
other, w
scaffol
most o
interac
is requ
tin org
tion, a
nuclea
cause g
of the
chrom
were r
the rol
and ap
lamina
Academic
Key W
replica
phy; LA
LBR.
A de
partme
The nu
cytopla
membranes, a perinuclear space, nuclear pore com-
plexes (NPCs), and a nuclear lamina (Fig. 1). The
outer nuclear membrane is continuous with the
endop
riboso
space
on. T
ore co
ansp
eview
ner m
roma
Grow
The
ave a
uclea
g var
(LAP
995; F
artin
an1 (
r (LB
990),
in et a
999) (
imos
ndoub
rotein
lves.
hey a
omolo
l pr
itosis
mins
eutra
luble
mins
isoelectric points, and during mitosis tend to remain
associated with membranes (Gerace and Burke,
1 To
563306
2 Pre
nia at S
Journal of Structural Biology 129, 313–323 (2000)
doi:10.1006/jsbi.2000.4216, available online at http://www.idealibrary.com on
lasmic reticulum (ER) and is covered with
mes; the outer membrane and the perinuclear
function in protein translation and modifica-
1988). Vertebrate genomes contain two type B lamin
genes, termed B1 and B2, and one type A lamin gene.
These three genes encode at least seven different
polypeptides: lamins A, AD10, C1, and C2, which are
splicing variants of the lamin A gene, and lamins
B1–3. Lamin B3 is a splice variant of the lamin B2
gene. Lamins B3 and C2 are specific to germ cells
(Furukawa and Hotta, 1993; Furukawa et al., 1994),
whom correspondence should be addressed. Fax: 1972-2-
6. E-mail: gru@vms.huji.ac.il.
s
a
w: Nuclear Lamins—Structural Pro
osef Gruenbaum,*,1 Katherine L. Wilson,† Amnon H
ent of Genetics, The Institute of Life Sciences, The Hebrew Univer
ll Biology and Anatomy, The Johns Hopkins University School of
Received November 1, 1999, and in rev
nuclear lamina is located between the inner
r membrane and the peripheral chromatin. It
posed of both peripheral and integral mem-
roteins, including lamins and lamina-associ-
roteins. Lamins can interact with one an-
ith lamina-associated proteins, with nuclear
d proteins, and with chromatin. Likewise,
f the lamina-associated proteins are likely to
t directly with chromatin. The nuclear lamina
ired for proper cell cycle regulation, chroma-
anization, DNA replication, cell differentia-
nd apoptosis. Mutations in proteins of the
r lamina can disrupt these activities and
enetic diseases. The structure and assembly
nuclear lamina proteins and their roles in
atin organization and cell cycle regulation
ecently reviewed. In this review, we discuss
es of the nuclear lamina in DNA replication
optosis and analyze how mutations in nuclear
proteins might cause genetic diseases. r 2000
Press
ords: nuclear envelope; nuclear lamina; DNA
tion; apoptosis; chromatin; muscular dystro-
P1; LAP2; emerin; otefin; YA; UNC-84; Man1;
INTRODUCTION
fining feature of eukaryotic cells is the com-
ntalization of chromosomes inside the nucleus.
clear envelope separates the nucleus from the
sm. It is composed of outer and inner nuclear
ti
p
tr
(r
in
ch
A
h
n
in
2
1
M
M
to
1
L
1
(S
u
p
se
T
h
ca
m
la
n
so
la
where
ent address: Department of Biology, University of Califor-
n Diego, La Jolla, CA 92093.
313
s with Fundamental Functions
,2 Michal Goldberg,* and Merav Cohen*
Jerusalem, Jerusalem, 91904, Israel; and †Department of
ne, 725 N. Wolfe Street, Baltimore, Maryland 21205
rm December 30, 1999
he two membranes are joined at the nuclear
mplexes, which are sites for macromolecular
ort between the nucleus and the cytoplasm
ed in Stoffler et al., 1999). Underlying the
embrane and associated with the peripheral
tin is the fibrous nuclear lamina.
ing Number of Nuclear Envelope Proteins
inner nuclear membrane and nuclear lamina
unique protein composition that includes the
r lamins (Gerace et al., 1978), different splic-
iants of lamina-associated polypeptides 1 and
1 and LAP2) (Berger et al., 1996; Harris et al.,
oisner and Gerace, 1993; Gant et al., 1999;
et al., 1995), emerin (Bione et al., 1994),
Paulin Levasseur et al., 1996), lamin B recep-
R) (Worman et al., 1988), otefin (Padan et al.,
nurim (Rolls et al., 1999), young arrest (YA;
l., 1991), and possibly UNC-84 (Malone et al.,
Fig. 1), as well as LBR kinase, p34, and p18
et al., 1996). Other nuclear envelope proteins
tedly remain to be discovered. The major
s of the nuclear lamina are the lamins them-
Lamins are type V intermediate filaments.
re classified as type A or type B, according to
gy in sequence, expression pattern, biochemi-
operties, and their cellular localization in
(reviewed in Stuurman et al., 1998). Type A
are expressed in differentiated cells, have
l isoelectric points, and become completely
in the cytoplasm during mitosis. Type B
are expressed in every cell, have acidic
they probably play a role in chromatin reorga-
1047-8477/00 $35.00
Copyright r 2000 by Academic Press
All rights of reproduction in any form reserved.
nizatio
Drosop
type B
1988),
and Sa
the com
elegans
LAP
UNC-8
LAP2,
gous d
which
domain
three
domain
are ho
protein
Spann
third L
FIG. 1
complex
N-termin
ONM, a
topology
314 REVIEW: GRUENBAUM ET AL.
n during meiosis (Alsheimer et al., 1999). The
hila genome contains two lamin genes: one
lamin, termed lamin Dm0 (Gruenbaum et al.,
and one type A lamin, termed lamin C (Bossie
nders, 1993). There is only one lamin gene in
pletely sequenced genome of Caenorhabditis
, which is a type B lamin (Riemer et al., 1993).
1, LAP2, emerin, MAN1, LBR, nurim, and
4 are all nuclear integral membrane proteins.
emerin, and Man1 share a 43-residue homolo-
omain, located at or near their N-termini,
is termed the LAP2–emerin–MAN1 (LEM)
(Lin et al., 2000). In C. elegans there are
open reading frames that contain a LEM
. Two of these LEM domain proteins, which
mologous to MAN1 and emerin, are integral
s of the nuclear envelope (Lee, Gruenbaum,
, and Wilson, manuscript in preparation). The
EM protein has not yet been tested. Otefin
h
re
le
g
a
re
a
b
in
w
is
p
g
b
p
of
d
co
. Schematic view of the nuclear envelope. ONM, outer nuclear
; LAP, lamina-associated polypeptide; YA, young arrest. Man1
al domains share homology with the N-terminal chromatin-bind
s its topology in the nuclear envelope is unknown. It is also not
of emerin, MAN1, and nurim with respect to the inner nuclear me
weakly conserved LEM domain, and is cur-
the known Drosophila cDNA with the highest
homology to human Man1.
is a lamin B-binding protein that is homolo-
the ER-localized sterol C14 reductases SR1
2 (Holmer et al., 1998). LBR has sterol C14
ase activity when expressed in yeast (Silve et
8). Nurim consists of five putative transmem-
domains that mediate its targeting to the
uclear membrane, where it interacts tightly
e nuclear scaffold (Rolls et al., 1999). UNC-84
ewly identified C. elegans nuclear envelope
. The C-terminal region of UNC-84 is homolo-
the Schizosaccharomyces pombe spindle pole
rotein Sad1 and to two predicted mammalian
s (Malone et al., 1999). The exact localization
-84 within the nuclear envelope has not been
ined. Young arrest (YA) is a maternally en-
protein that is required in Drosophila for the
rane; INM, inner nuclear membrane; NPC, nuclear pore
merin probably interact with chromatin because their
ain of LAP2. UNC-84 is placed in both the INM and the
et whether it forms dimers (Raff, 1999). In addition, the
e is hypothesized from their primary sequence.
as a
ntly
vel of
LBR
ous to
nd SR
duct
l., 199
rane
ner n
ith th
a n
rotein
ous to
ody p
rotein
UNC
eterm
ded
memb
and e
ing dom
clear y
mbran
transition from meiosis to mitosis (Liu et al., 1995).
YA is a peripheral membrane protein that associates
with bothlamin Dm0 and chromatin (Goldberg et al.,
1998; Lopez and Wolfner, 1997).
One
each co
multip
betwee
examp
emerin
Goldbe
Likewi
barrier
DNA-b
Craigie
observ
1997).
and p3
1996).
mediat
electro
envelo
ing of
(Lenz-B
Nuclea
Man
During
of the
throug
1997;
essenti
the chr
actions
ins and
BAF, a
interac
tive pa
in org
periph
HP1 a
from m
lamina
both fo
tion an
UNC-8
elegans
and ho
facilita
quired
et al.,
fusion
membr
functio
membr
interesting to learn the exact localization of UNC-84
within the nuclear envelope. Nuclear lamina pro-
teins show specific patterns of expression during
development and differentiation, so it is not surpris-
g tha
ecific
al.,
inally
rly s
popto
LAMI
EQU
Stud
AP2b
plica
perim
ssemb
roma
985;
in th
o m
ith th
resen
g the
id not
PCs
sulti
plica
l., 19
ere a
ficien
min
store
plica
re sev
uclea
mina
roma
on fo
ight
affold
l., 19
mins
plica
oir e
lly ex
Addi
ssemb
lam
ence t
rowth
315REVIEW: NUCLEAR LAMINS
major theme that has emerged is the idea that
mponent of the nuclear lamina interacts with
le partners, forming a network of attachments
n the nuclear membrane and chromatin. For
le, lamins can interact with LAP1, LAP2,
, Man1, LBR, otefin, and YA (reviewed in
rg et al., 1999; Gotzmann and Foisner, 1999).
se, LAP2 and emerin each can interact with
to autointegration factor (BAF), a small
inding protein (Furukawa, 1999; Lee and
, 1998; Lee, Craigie, and Wilson, unpublished
ations), and LBR interacts with HP1 (Ye et al.,
Two relatively uncharacterized proteins, p18
4, are associated with LBR (Simos et al.,
Lamins also interact with NPC proteins and
e the positioning of the NPCs, as shown by
n microscopy of detergent-extracted nuclear
pes (Pante and Aebi, 1997) and by the cluster-
NPCs in cells with a mutated lamin gene
ohme et al., 1997).
r Envelope-Dependent Functions
y nuclear activities require the nuclear lamina.
mitosis, proper disassembly and reassembly
nuclear lamina are required to progress
h the cell cycle (reviewed in Gant and Wilson,
McKeon, 1991). The nuclear lamina has an
al role in nuclear organization by anchoring
omatin to the nuclear envelope. Specific inter-
have now been demonstrated between lam-
histones, between LEM domain proteins and
s well as between LBR and HP1. Thus,
tions between these proteins and their respec-
rtners in the lamina are likely to be involved
anizing silenced chromatin at the nuclear
ery (Wilson, 2000). The histones, BAF, and
re also located throughout the nucleus away
embrane-anchored proteins. The nuclear
is required for DNA replication (see below),
r making the chromatin competent for replica-
d for the elongation step of DNA replication.
4 is required for nuclear migration in C.
. Based on its nuclear envelope localization
mology to Sad1, it was proposed that UNC-84
tes a nuclear–centrosomal interaction re-
for nuclear migration and anchorage (Malone
1999). Thus, even though an UNC-84–GFP
protein appears to colocalize with inner nuclear
ane proteins by light microscopy, its proposed
n would require it to be an outer nuclear
ane protein (Malone et al., 1999). It will be
in
sp
et
F
ea
a
R
L
re
ex
a
ch
1
ta
tw
w
p
in
d
N
re
re
a
w
ef
la
re
re
a
n
la
ch
ti
m
sc
a
la
re
(M
a
a
on
d
g
t mutations in these proteins cause tissue-
phenotypes (Bonne et al., 1999; Lenz-Bohme
1997; Liu et al., 1995; Manilal et al., 1996).
, the breakdown of the nuclear lamina is an
tep in apoptosis that is required for the proper
tic pathway in the nucleus (Rao et al., 1996).
NS AND LAMINA-ASSOCIATED PROTEINS ARE
IRED FOR BOTH NUCLEAR GROWTH AND DNA
REPLICATION
ies in vitro and in vivo show that lamins and
are involved in both nuclear growth and DNA
tion. The most informative studies involved
ents in which interphase-like nuclei were
led from Xenopus egg extracts and sperm
tin (Hutchison et al., 1989; Lohka and Maller,
Newport, 1987). The assembly extracts con-
ree type B lamins (Lourim et al., 1996). The
inor lamin forms, B1 and B2, are associated
e membranes. The major lamin form, B3, is
t mostly in a soluble cytoplasmic pool. Remov-
cytoplasmic pool of lamin B3 from the extract
inhibit the assembly of nuclear membrane or
around the sperm chromatin. However, the
ng nuclei were small, fragile, and unable to
te their DNA (Jenkins et al., 1993; Newport et
90). Although the lamin B3-depleted nuclei
bout half the size of control nuclei, they
tly imported nuclear proteins. Addition of
B3 to the lamin B3-depleted extract partially
d the phenotype; nuclei expanded and DNA
tion commenced (Goldberg et al., 1995). There
eral explanations for the effect of lamins on
r growth and DNA replication. (A) The nuclear
might be required to spatially organize the
tin as a prerequisite to forming active replica-
ci (Hutchison et al., 1994). (B) The lamina
be required to assemble an internal nuclear
, to which replication foci attach (Hozak et
95). (C) The most direct model proposes that
and lamin-associated proteins are present in
tion foci and are required for DNA replication
t al., 1995). These possibilities are not mutu-
clusive.
tion of mutant forms of lamins to Xenopus
ly extracts caused dominant negative effects
in assembly and provided more direct evi-
hat the nuclear lamina is involved in nuclear
and DNA replication. When a headless form
of Xenopus lamin B1 fused to GST was incubated in
the assembly extracts, prior to the addition of sperm
chromatin, it formed heterodimers with lamin B3.
The re
nuclea
as prev
larly, w
residue
Xenopu
membr
1997).
interac
in intr
nuclei
fragile
very in
of Xeno
The
replica
cating
and ac
mainte
tion. T
indirec
Xenopu
localiza
nuclea
ters an
the lim
and di
These
scaffold
necess
NLS s
binds c
al., 199
Whe
dues 29
G1 pha
into S
strongl
the lam
inhibit
sugges
functio
that co
and th
1–408)
1999).
growth
tion oc
in the
ments
in both
these t
Internal Lamins and DNA Replication
It is now clear that, in addition to localizing at the
nuclear periphery, lamins are present in the nuclear
terio
oldm
994; S
min
der s
tran
ntibo
lls th
ntain
on o
uclea
serv
DNA
irect i
NA r
hich
as ad
pann
quire
ch a
lam
rotein
lexes,
, wer
ould
idesp
mins
min
HE R
Apop
enetic
evelo
e acti
ecific
idd,
ceivi
orph
topla
ge of
om th
enta
mes,
The
f sub
spas
on a
uclea
me co
oth t
popto
onse
nd K
316 REVIEW: GRUENBAUM ET AL.
sulting nuclei were small, did not contain a
r lamina, and could not replicate their DNA,
iously seen in lamin B3-depleted nuclei. Simi-
hen a human lamin A that lacks its first 33
s was expressed in BHK cells or added to
s assembly extracts, there was no effect on
ane formation or nuclear import (Spann et al.,
However, in both assays, the headless lamin A
ted with endogenous type B lamins, resulting
anuclear aggregation of A and B lamins. The
assembled in this Xenopus extract were small,
, and unable to replicate their DNA (or did so
efficiently), as in the case of the headless form
pus lamin B1.
mutant form of lamin B1 had no effect on DNA
tion when added after nuclear assembly, indi-
that once active replication foci were formed
tivated, lamin B3 was not necessary for their
nance or for the progression of DNA replica-
his finding suggests that lamin B3 plays an
t role in DNA replication (Ellis et al., 1997). A
s lamin B1–GST fusion that lacked its nuclear
tion signal (NLS) had a milder effect on
r size, but nuclei still formed replication cen-
d initiated DNA replication, consistent with
ited ability of the NLS mutant to enter nuclei
srupt endogenous lamins (Ellis et al., 1997).
experiments suggest that chromatin or lamin-
organization (rather thannuclear growth) is
ary for DNA replication. Interestingly, the
ignal is located in the region of lamins that
hromatin (Goldberg et al., 1999; Taniura et
5).
n the lamin-binding domain of LAP2b (resi-
8–373) was injected into HeLa nuclei in early
se, it prevented nuclear growth and entrance
phase (Yang et al., 1997a). These effects
y resemble those seen in nuclei assembled in
in B3-depleted Xenopus extracts. Dominant
ion by the lamin-binding domain of LAP2b
ts that LAP2 is coimplicated in the replication
ns of the nuclear lamina. A protein construct
ntained both the chromatin-binding region
e lamin-binding region of LAP2b (residues
also inhibited nuclear growth (Gant et al.,
Intriguingly, at lower concentrations, nuclear
was still largely inhibited but DNA replica-
curred on average two- to fivefold better than
control assembled nuclei. The latter experi-
revealed that the nuclear lamina is involved
nuclear growth and DNA replication and that
wo activities can be uncoupled.
in
G
1
la
or
in
a
ce
co
ti
n
ob
in
d
D
w
w
(S
re
su
of
p
p
a
w
w
la
la
T
g
d
b
sp
K
re
m
cy
a
fr
m
so
o
ca
ti
n
ti
B
a
sp
a
r (Bridger et al., 1993; Broers et al., 1999;
an et al., 1992; Hozak et al., 1995; Moir et al.,
pann et al., 1997). During interphase, most
molecules are either assembled into higher
tructures (Broers et al., 1999) or present in
uclear foci (Moir et al., 1994). Using specific
dies to lamin B, it was shown in mammalian
at during G1 phase and early S phase, foci
ing lamin B colocalize with sites of incorpora-
f bromodeoxyuridine and proliferating cell
r antigen (PCNA) (Moir et al., 1994). These
ations predict a direct involvement of lamin B
replication. Further evidence for the possible
nvolvement of lamins in the elongation step of
eplication comes from the experiments in
human lamin A lacking the first 33 residues
ded to Xenopus assembly extracts (see above)
et al., 1997). In these experiments, proteins
d for the elongation step of DNA replication,
s PCNA and RFC, colocalized with aggregates
ins A and B (Spann et al., 1997). In contrast,
s that are required to form initiation com-
such as MCM3, ORC2, and DNA polymerase
e distributed normally (Spann et al., 1997). It
be useful to ask whether these effects are
read. For example, do PCNA and mutant
coaggregate in mammalian cells and does
B3 localize to replication foci in Xenopus?
OLE OF THE NUCLEAR LAMINA IN APOPTOSIS
tosis (programmed cell death) is a defined
process that is required for the normal
pment and homeostasis of tissues and can also
vated in response to cancer, virus infection,
drugs, or stress (reviewed in Hetts, 1998;
1998; Lincz, 1998; Thompson, 1998). Upon
ng the apoptotic signals, cells undergo specific
ological changes in both their nuclei and their
sm. Nuclear changes include proteolytic cleav-
the nuclear lamina, detachment of chromatin
e nuclear envelope, clustering of NPCs, frag-
tion of chromatin by nucleases into oligonucleo-
and chromatin condensation.
execution phase of apoptosis involves a family
strate-specific cysteine proteases named
es. The proteins targeted by caspase degrada-
nd the kinetics of degradation of different
r envelope proteins reveal the nature and
urse of nuclear destruction during apoptosis.
ype A and type B lamins are degraded in
sis in many different cell types and in re-
to many different apoptotic stimuli (Anjum
har, 1997; Antoku et al., 1997; Fraser et al.,
1997; Kaufmann, 1989; Kawahara et al., 1998; Kluck
et al., 1997; Lazebnik et al., 1993; Neamati et al.,
1995; Oberhammer et al., 1994; Orth et al., 1996; Rao
et al.,
Pommi
1996a,
Weave
integra
ing LA
and po
Goulet
NUP15
1999).
residue
the a-h
et al.,
cleavin
Lam
which
chroma
hamme
al., 19
degrad
tion in
HeLa
(Shimi
before
Goulet
fragme
lope (B
whethe
death.
tion d
human
campto
which
being
(Shimi
duced t
no cha
(Weave
The
apopto
detach
change
import
expres
lamin B
Cells t
alone o
onset o
in thes
oligonu
tion of
degrad
tion. T
ever, suggests that lamin proteolysis may facilitate
the activation of nucleases responsible for DNA
fragmentation.After the 12- to 16-h delay, the nuclear
velo
roma
he te
e for
ao et
nclea
omain
min A
e nu
One
sis d
iewed
al.,
ngle
min
ieme
AP2/e
ain (
nd LE
egan
uclea
MUT
GE
Eme
rst de
mery
e on
ary b
nd w
MIM
rst ob
redom
g an
ndon
perie
uscle
ie fro
eath)
een
ythm
bnorm
ng P
eatin
g da
s sho
pe I fi
EDM
ant.
nked
l., 19
herea
317REVIEW: NUCLEAR LAMINS
1996; Shimizu et al., 1998; Shimizu and
er, 1997; Smith et al., 1992; Takahashi et al.,
b; Ucker et al., 1992; Voelkel et al., 1995;
r et al., 1996; Zhivotovsky et al., 1997). Nuclear
l membrane proteins are also targeted, includ-
P2b (but not emerin) (Buendia et al., 1999)
ssibly LBR (Buendia et al., 1999; Duband-
et al., 1998), as well as nuclear pore protein
3 (but not p62 or gp210) (Buendia et al.,
These nuclear proteins are cleaved at specific
s by specific caspases. Lamins are cleaved in
elical rod domain, probably by caspase 6 (Rao
1996). Caspase 3 is probably responsible for
g LAP2 and Nup153 (Buendia et al., 1999).
ins are early targets for caspase degradation,
begins before detectable DNA cleavage or
tin condensation (Lazebnik et al., 1993; Ober-
r et al., 1994; Rao et al., 1996; Takahashi et
96b; Weaver et al., 1996). For example, the
ation of lamin B1 precedes DNA fragmenta-
apoptotic thymocytes (Neamati et al., 1995),
cells (Mandal et al., 1996), and HL60 cells
zu et al., 1998). Lamins are also degraded
LBR and LAP2 (Buendia et al., 1999; Duband-
et al., 1998). Cleaved lamin and LAP2b
nts remain associated with the nuclear enve-
uendia et al., 1999), but it is not known
r these fragments play any further role in
The role of phosphorylation in lamin degrada-
uring apoptosis is not clear. Treatment of
cells with the DNA topoisomerase I inhibitor
thecin produced an apoptotic response in
lamin B was phosphorylated by PKCa before
degraded and prior to DNA fragmentation
zu et al., 1998). In contrast, thymocytes in-
o undergo apoptosis with dexamethasone had
nge in the levels of lamin B phosphorylation
r et al., 1996).
cleavage of lamins, LAP2, and LBR during
sis may be required to allow chromatin to
from the nuclear lamina. It may also allow
s in nuclear envelope shape and rigidity. The
ance of lamins in apoptosis was shown by
sing uncleavable mutant forms of lamin A or
in BRK tissue culture cells (Rao et al., 1996).
hat expressed uncleavable lamins A or B,
r together, showed a 12- to 16-h delay in the
f apoptosis. Although caspases were activated
e cells, the chromatin failed to condense and
cleosomal cleavage was delayed. The activa-
caspases in these cells confirms that lamin
ation occurs downstream of caspase activa-
he delay in oligonucleosomal cleavage, how-
en
ch
T
th
(R
u
d
la
th
to
v
et
si
la
(R
L
m
a
el
n
fi
E
th
v
a
(O
fi
p
le
te
ex
m
d
d
tw
rh
a
lo
cr
in
ie
ty
n
li
a
w
pe began to change its structure, but the
tin remained attached to the nuclear lamina.
rminal nuclear events of apoptosis, including
mation of apoptotic bodies, were not affected
al., 1996). It would be interesting to express
vable mutant forms of LAP2 and other LEM
proteins alone, or together with uncleavable
, to ask whether the apoptotic destruction of
cleus can be further delayed.
of the best-defined systems for studying apop-
uring normal development is C. elegans (re-
in Hengartner and Horvitz, 1994; Metzstein
1998). The genome of C. elegans contains a
caspase gene (ced-3) (Xue et al., 1996), a single
gene (lbx-1; previously termed CeLam-1)
r et al., 1993), and three genes from the
merin/Man1 family, containing a LEM do-
Linet al., 2000). Studying the roles of lamins
M domain proteins during apoptosis in C.
s will yield important information about
r lamina function in apoptosis.
ATIONS IN THE EMERIN AND THE LAMIN A/C
NES CAUSE EMERY-DREIFUSS MUSCULAR
DYSTROPHY
ry–Dreifuss muscular dystrophy (EDMD) was
scribed in 1955 (Dreifuss and Hogan, 1961;
and Dreifuss, 1955) and is characterized by
set of muscle weakness. EDMD symptoms
etween individuals with different mutations
ithin families carrying the same mutation
310300). In most EDMD cases, the disease is
served in the teens with muscle shortening,
inantly in the proximal muscles of the lower
d upper arm, and shortening of the Achilles
, pes cavus, and elbow. Patients can also
nce weakness of the scapulohumeroperoneal
and limited neck flexion. Most affected people
m severe ventricular dysrythmias (sudden
. In most cases, heart problems emerge be-
the ages of 20 and 40 and include atrial
disturbance, A–V conduction defects, and
al EKG (slow rate, small or absent P waves,
R intervals, and abnormal rhythms). Serum
e kinase levels are slightly elevated, indicat-
mage to muscle cells. Muscle pathology stud-
w variable muscle fiber size and atrophy of
bers.
D can be either X-linked or autosomal domi-
Mutations in the emerin gene cause the X-
form of EDMD (Manilal et al., 1996; Nagano et
96; reviewed in Morris and Manilal, 1999),
s mutations in the lamin A/C gene cause the
autosomal-dominant form (Bonne et al., 1999).
Emerin mutations associated with the disease in-
volve a complete loss or mislocalization of the emerin
protein
gene ca
gene co
emerin
muscle
to the
Emerin
to inte
quired
1999).
part o
protect
et al.,
amoun
might
to the n
tin str
affect g
an add
that a
the ER
that E
loss of
an exc
The ER
that is
or by t
putativ
specula
The
els are
ments.
EDMD
subtly.
held m
dict tha
would
type. A
selectiv
no lam
types (
lamin A
cells a
phenot
Disting
require
tated b
and for
Model
Dyst
Muta
membr
candidates for other forms of muscular dystrophy.
This view is based on the EDMD phenotype associ-
ated with mutations in lamin A and emerin and is
ppor
gion
996)
59000
Mou
for E
A m
/C ge
athol
e mo
ulliv
ok lik
thei
hese
cludi
e m
uscle
uman
e lam
ouse
/C ac
gous
uscle
In la
om t
velo
AP2b
lls th
uclea
milar
utati
l., 19
eficie
lized
sent
nd th
uclea
indin
taini
al., 1
The
min
uired
l., 199
m0 g
uses
ohme
is w
ent,
ave i
ises
uscle
318 REVIEW: GRUENBAUM ET AL.
. In contrast, loss of one copy of the lamin A
uses disease even when there is still a good
py remaining. It is not clear why mutations in
and lamin A genes specifically affect adult
cells. Several molecular mechanisms leading
onset of EDMD have been suggested: (A)
or lamin A–emerin complexes are proposed
ract with specific transcription factors re-
to maintain muscle integrity (O¨stlund et al.,
(B) Emerin and lamins A/C are proposed to be
f a nucleocytoplasmic skeleton that helps
muscle cells from mechanical stress (Tsuchiya
1999). (C) Emerin deficiency or reduced
ts of lamin A/C in nuclei that lack lamin B1
partially disrupt heterochromatin attachment
uclear envelope, or destabilize heterochroma-
ucture at the nuclear envelope, and thereby
ene expression (Wilson, 2000). (D) We propose
itional model, which is based on the findings
small fraction of emerin is always present in
(O¨stlund et al., 1999; Yang et al., 1997b) and
DMD patients experience either a complete
emerin from both the nucleus and the ER or
ess of ER-localized emerin (Ellis et al., 1998).
-localized emerin might have a positive role
disrupted in mutant cells, either by too much
oo little emerin in the ER. The nature of this
e ER-localized function for emerin remains
tive.
above models are general, and improved mod-
likely to emerge soon from further experi-
None of the current models can explain why
affects muscle cells so selectively and so
This shortcoming also applies to the widely
echanical stress model, which seems to pre-
t all contracting skeletal and cardiac muscles
be affected equally, unlike the EDMD pheno-
t present, the only good clue to the muscle
ity of EDMD is that muscle cells have little or
in B1, which is a major lamin in most other cell
Broers et al., 1997). Thus, the reduction of
/C may be particularly significant in muscle
nd may potentially explain why the EDMD
ype is muscle-specific (Manilal et al., 1999).
uishing between these different models will
a great deal more work and would be facili-
y knowing the null phenotype for each lamin
other key nuclear envelope proteins.
Systems for ‘‘Nuclear Envelope’’ Muscular
rophies
tions in genes encoding lamins and nuclear
ane proteins are now widely considered as
su
re
1
1
A
A
p
th
(S
lo
in
T
in
th
m
h
th
m
A
zy
m
fr
en
L
ce
N
si
m
a
d
ca
es
a
n
B
re
et
la
q
a
D
ca
B
th
m
h
ra
m
ted by the mapping of lamin B1 to the same
of chromosome 5 (5q23.3–q31.1; Wydner et al.,
as limb-girdle muscular dystrophy (OMIM
; Morris and Manilal, 1999).
se Knockout in Lamin A Gene as a Model
DMD
ouse knockout in the emerin or in the lamin
nes would provide a model for studying the
ogical mechanism for EDMD. A knockout in
use lamin A/C gene was recently obtained
an et al., 1999). At birth, the homozygous mice
e wildtype mice. However, they are retarded
r growth and die at the age of 4–8 weeks.
mice develop a cardiac and skeletal myopathy,
ng dystrophy in the perivertebral muscles,
uscles surrounding the femur, and heart
s, similar to human EDMD. However, unlike
EDMD, the levels of serum creatine kinase in
in A-deficient mice are normal. It seems that
muscle cells are less sensitive to loss of lamin
tivity than those of human, since mice hetero-
for the lamin A deletion have no apparent
phenotype.
min A-deficient mice and cell lines derived
hese mice, the distribution of other nuclear
pe proteins is affected. Type B lamins and
remain in the nuclear envelope, but in many
ey are missing from one pole of the nucleus.
r pore complexes are occasionally clustered,
to Drosophila flies that carry a homozygous
on in the lamin Dm0 gene (see below) (Harel et
98; Lenz-Bohme et al., 1997). In lamin A-
nt mouse cell lines, emerin is strikingly mislo-
to the ER. This suggests that lamins A/C are
ial to maintain emerin in the nuclear envelope
at in their absence, emerin is free to leave the
r envelope and to diffuse back to the ER.
g to intranuclear structures is essential for
ng several nuclear envelope proteins (O¨stlund
999; Soullam and Worman, 1993).
lamin Dm0 gene, which is the only type B
in Drosophila, is an essential gene and re-
for normal embryonic development (Harel et
8). A weak mutation in the Drosophila lamin
ene (,20% of normal lamin Dm0 expression)
specific phenotypes in adult flies (Lenz-
et al., 1997). Flies that are homozygous for
eak mutation are retarded in their develop-
have reduced viability, are mostly sterile, and
mpaired locomotion. The latter phenotype
the possibility that lamins are required for
activity in flies, as well as humans. However,
it has not been determined whether the mutation
affects muscle cells or nerve cells. Further studies of
these flies and future analysis of the Drosophila type
A lami
1993) m
patholo
Mutati
Dun
Dun
(FPLD
degene
resista
Hegele
kindre
human
knocko
muscle
(Sulliv
these m
phy dis
LAMI
Prot
volved
Patien
ies aga
1990b;
al., 198
et al., 1
(Wesie
nuclea
1990c;
1991; N
al., 19
(Paulin
al., 199
Hill et
Lassou
1997;
Reeves
al., 199
al., 198
The
physio
diagno
the mo
tibodie
lamins
are fou
of auto
mune l
tibodie
or can
These
et al., 1983), systemic lupus erythematosus (Brito et
al., 1994; Guilly et al.,1987; Lassoued et al., 1988b;
Reeves et al., 1987; Senecal et al., 1999), autoim-
une
988b;
al.,
iliary
erska
l., 199
990),
nd ot
990c;
994).
ens in
onst
The
s and
irecte
mong
odies
ost a
omain
sus p
tire
eum
ain o
omain
The
le th
ctivit
eing i
fun
uclea
nticip
rogre
ecaus
velo
ue to
isease
nks b
embr
plori
mina
e pat
We th
cience
ble Tr
ateful
r critic
lsheim
(1999)
sperm
319REVIEW: NUCLEAR LAMINS
n gene (termed lamin C, Bossie and Sanders,
ay lead to a better understanding of muscle
gy in EDMD.
ons in the Lamin A/C Gene Can Also Cause
nigan-type Familial Partial Lipodystrophy
nigan-type familial partial lipodystrophy
) is characterized by progressive adipocyte
ration, often associated with profound insulin
nce and diabetes. A recent report (Cao and
, 2000) mapped this disease in Canadian
ds to a R482Q missense mutation in the
lamin A/C gene. Interestingly, mice with a
ut in the lamin A/C gene, in addition to the
phenotypes, also suffer from loss of fat cells
an et al., 1999), which would probably make
ice good models for studying this lipodystro-
ease.
NS AND LAMINA-ASSOCIATED PROTEINS ARE
TARGETS FOR AUTOIMMUNE DISEASES
eins of the nuclear membrane are also in-
in a wide range of autoimmune diseases.
ts have been identified who make autoantibod-
inst the NPC proteins gp210 (Courvalin et al.,
Courvalin and Worman, 1997; Lassoued et
8a; Nickowitz and Worman, 1993; Nickowitz
994; Wesierska Gadek et al., 1996a) and p62
rska Gadek et al., 1996b), as well as inner
r membrane proteins LBR (Courvalin et al.,
Courvalin and Worman, 1997; Lassoued et al.,
ickowitz et al., 1994), LAP1, (Konstantinov et
95), LAP2 (Konstantinov et al., 1995), Man1
Levasseur et al., 1996), and lamins (Brito et
4; Courvalin et al., 1990a; Guilly et al., 1987;
al., 1996; Konstantinov et al., 1995, 1996;
ed et al., 1988b, 1989, 1990; Malka et al.,
McKeon et al., 1983; Philipp et al., 1995;
and Ali, 1989; Reeves et al., 1987; Senecal et
9; Senecal and Raymond, 1992; Wesierska et
8, 1989, 1990).
autoantibodies may play a role in the patho-
logy of autoimmune diseases and can serve as
stic tools. However, very little is known about
lecular basis of the formation of these autoan-
s. Autoantibodies against different human
(lamin A, lamin C, lamin B1, and lamin B2)
nd in a subset of patients with a diverse group
immune diseases and particularly in autoim-
iver diseases (Hill et al., 1996). These autoan-
s can be either specific for each type of lamin
recognize epitopes common to all lamins.
diseases include linear scleroderma (McKeon
m
1
et
b
si
a
1
a
1
1
g
(K
ti
d
a
b
m
d
to
en
rh
m
d
el
a
b
of
n
a
p
b
en
d
d
li
m
ex
la
th
S
ta
gr
fo
A
hepatitis (Brito et al., 1994; Lassoued et al.,
Malka et al., 1997; Philipp et al., 1995; Reeves
1987; Wesierska et al., 1988, 1990), primary
cirrhosis (Courvalin and Worman, 1997; We-
et al., 1988), rheumatoid arthritis (Brito et
4; Konstantinov et al., 1996; Lassoued et al.,
polymayalgia rhheumatica (Brito et al., 1994),
her autoimmune diseases (Courvalin et al.,
Lassoued et al., 1990, 1991; Nickowitz et al.,
Interestingly, the frequency of LAP2 autoanti-
rheumatic disease is similar to that of lamins
antinov et al., 1995).
lamin B2 autoantibodies in rheumatoid arthri-
systemic lupus erythematosus patients were
d against the rod domain, which is conserved
all intermediate filament proteins. Autoanti-
from rheumatoid arthritis patients were al-
lways specific for coil 2 of the lamin B2 rod
, whereas those of systemic lupus erythema-
atients recognized epitopes located along the
rod domain. In contrast, some polymayalgia
atica sera specifically detected the NLS do-
f lamin B2, which is present in the lamin tail
(Brito et al., 1994).
SUMMARY
nucleus is a complicated and dynamic organ-
at is responsible for a stunning variety of
ies. The large number of models currently
nvoked to explain EDMD mirrors the variety
ctions, both known and suspected, for the
r lamins and lamin-associated proteins. We
ate that the next few years will see significant
ss in our understanding of the nuclear lamina,
e of the increasing rate of discovery of new
pe proteins, the enhanced interest in this area
the emergence of envelope-based human
s, and the emerging molecular and functional
etween the lamins, chromatin, and nuclear
ane proteins. We also anticipate progress in
ng the dark side of the nucleus—how the
participates, either actively or passively, in
hway of nuclear destruction during apoptosis.
ank the Israel–U.S.A. Binational Fund (BSF), the Israel
Foundation (BRF) (to Y.G.), and the W. W. Smith Chari-
ust (to K.L.W.) for their support of this research. We are
to Sheona Drummond, Dale Shumaker, and Kenny Lee
ally reading the manuscript.
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	INTRODUCTION 
	FIG. 1. 
	LAMINS AND LAMINA-ASSOCIATED PROTEINS ARE REQUIRED FOR BOTH NUCLEAR GROWTH AND DNA REPLICATION 
	THE ROLE OF THE NUCLEAR LAMINA IN APOPTOSIS 
	MUTATIONS IN THE EMERIN AND THE LAMIN A/C GENES CAUSE EMERY-DREIFUSS MUSCULAR DYSTROPHY 
	LAMINS AND LAMINA-ASSOCIATED PROTEINS ARE TARGETS FOR AUTOIMMUNE DISEASES 
	SUMMARY 
	REFERENCES