1 Division of Neuroanatomy, Osaka University Graduate School of Medicine, Kobe
University, Kobe 650-0017, Japan
2 Department of Genome Sciences, Graduate School of Medicine, Kobe University,
Kobe 650-0017, Japan
3 CREST, Japan Science and Technology Corporation, Japan
4 Department of Physiology, Keio University School of Medicine, Tokyo 160-8582,
Japan
5 PRESTO, Japan Science and Technology Corporation, Japan
6 Division of Bioinformation, Department of Biosystems Science, Graduate School
of Science and Technology, Kobe University, Kobe 650-0017, Japan
7 Laboratory for Cell Fate Decision, Riken, Center for Developmental Biology,
Kobe 650-0047, Japan
* Author for correspondence (e-mail: sawa{at}cdb.riken.jp)
Accepted 10 February 2005
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SUMMARY |
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Key words: Mediator, Wnt, Asymmetric cell division, C. elegans
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Introduction |
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The Mediator complex was first identified in yeast as a complex associated
with RNA polymerase that can support activated transcription in vitro
(reviewed by Myers and Kornberg,
2000). A number of mammalian complexes related to yeast Mediator
have since been identified, the TRAP, DRIP, ARC and SMCC complexes, which have
nearly identical subunit compositions
(Malik and Roeder, 2000
).
These complexes can mediate the activities of various transcription factors,
such as Sp1, thyroid hormone receptor and p53, to activate or repress
transcription. The largest Mediator complexes contain about 20 subunits, but
they seem to be divided into functional and physical submodules. It has been
suggested that yeast Mediator can be divided into four modules: Srb4,
Gal11/Sin4, Med9/Med10 and Srb8-Srb11. For example, yeast mutants of the
Gal11/Sin4 module components (Gal11, Rgr1, Sin4, Med2 and Pgd1) exhibit
similar phenotypes (Jiang et al.,
1995
; Jiang and Stillman,
1995
), and the presence of Gal11, Sin4 and Pgd1 in the complex
depends on Rgr1 (Li et al.,
1995
). Under highly stringent conditions, the Srb8-Srb11 module is
isolated as a separate entity from the other components of Mediator
(Borggrefe et al., 2002
), and
this module has repressive functions in yeast
(Carlson, 1997
;
Chang et al., 2001
;
Holstege et al., 1998
). CDK8
and cyclin C, the human homologs of Srb10 and Srb11, respectively, also
repress activator-dependent transcription in vitro
(Akoulitchev et al., 2000
). In
addition, the human ARC-L complex, a large Mediator complex, is
transcriptionally inactive and contains CDK8 and Cyclin C, as well as MED12
and MED13 (homologs of Srb8 and Srb9, respectively)
(Taatjes et al., 2002
).
Therefore, Srb8/MED12, Srb9/MED13, Srb10/CDK8, and Srb11/Cyclin C associate
with each other physically and functionally in yeast and human cells. In
Drosophila, the MED12 and MED13 homologs are involved in the
development of the eye and wing (Janody et
al., 2003
; Treisman,
2001
). However, little is known about how these complexes are
regulated or contribute to animal development.
In C. elegans, the asymmetric division of certain blast cells,
including the T blast cell, is regulated by lin-17/frizzled and
lin-44/wnt (Herman et al.,
1995; Sawa et al.,
1996
). In lin-17 mutants, the asymmetry of the division
is disrupted, resulting in symmetric division
(Sternberg and Horvitz, 1988
).
In lin-44 mutants, the polarity of the division is reversed
(Herman and Horvitz, 1994
). It
has been proposed that the LIN-44 signal, which acts through the LIN-17
receptor, provides polarity to cells that undergo asymmetric division
(Sawa et al., 1996
). The Wnt
pathway, which controls the polarity of the T cell, shares some components
with the canonical Wnt pathway, such as a Tcf homolog POP-1
(Herman, 2001
). We have
previously shown that PSA-1 and PSA-4, components of the SWI/SNF complex, are
required for the asymmetric division of the T cell during mitosis, suggesting
that distinct cell fates are determined by alteration of the chromatin
structure (Sawa et al., 2000
).
Recently, it was reported that a putative transcription factor, TLP-1, is
expressed asymmetrically in the T-cell daughters, and this asymmetric
expression is regulated by the Wnt signaling pathway, suggesting that
tpl-1 is one of the target genes of the Wnt signal
(Zhao et al., 2002
). However,
it is not clear how the Wnt signal regulates the transcription of its target
genes.
We have identified mutations in the let-19 and dpy-22 genes that affect the asymmetric division of the T cell. The let-19 and dpy-22 mutations cause symmetrical expression of tlp-1 in the T-cell daughters. We cloned these genes and found that they encode homologs of MED13 and MED12, components of the transcriptional Mediator complex. LET-19 and DPY-22 also function in the fusion of the Pn.p cells, a process that is also regulated by the Wnt signaling pathway. These results indicate that LET-19 and DPY-22 encode components of the Mediator complex and regulate asymmetric cell division, as the complex does in yeast.
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Materials and methods |
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Cloning
pAY104 (a rescuing plasmid for let-19) contained both a 9.1 kb
PstI fragment of F07H5 (with a 0.4 kb sequence from the Lorist6
cosmid vector) and a 4.1 kb PstI fragment of F07H5 subcloned into the
pBSK vector. The let-19::GFP construct (pAY105) was made by inserting
a 0.1 kb PCR fragment (from the BstEII site to the C terminus of the
let-19 gene) and a GFP fragment from pPD95.79 (a gift from A. Fire)
into the BstEII site of the let-19 rescuing plasmid
(pAY104). To identify mutations, we sequenced the PCR products amplified from
let-19 and dpy-22 mutants using internal primers. The
mutations were confirmed by sequencing different PCR fragments. The
sur-2::HA construct (pAY106) consisted of a 10.4 kb
SacI-BanI fragment of F39B2, a 0.15 kb PCR fragment just
upstream of the stop codon and a HA fragment subcloned into the pT7Blue
vector. The expression of GFP::POP-1, tlp-1::GFP,
let-19::GFP and dpy-22::GFP was analyzed by confocal
microscopy (Zeiss LSM510), while that of mab-5::GFP was analyzed by
epifluorescence microscopy.
Preparation of nuclear extracts and co-immunoprecipitation analysis
HS490 [harboring SUR-2::HA in a sur-2(ku9) mutant background] and
HS518 [harboring SUR-2::HA and LET-19::GFP in a sur-2(ku9) mutant
background] strains were grown in liquid culture as described previously
(Stiernagle, 1999). To prepare
nuclear extracts, the animals were harvested and homogenized essentially as
described previously (Mains and McGhee,
1999
), except that the nuclear pellets were obtained from
sonicated homogenates of mixed-stage animals, including embryos, larvae and
adults, and the nuclear pellets were extracted with NEB350 [nuclear extraction
buffer: 20 mM HEPES (pH 7.6), 350 mM KCl, 2 mM EDTA, 25% glycerol, 0.5 mM DTT,
1 mM PMSF, 10 µM E-64, and 0.1% Nonidet P-40]. The nuclear extracts were
then co-immunoprecipitated with an anti-Flag antibody (M2, Sigma) or anti-GFP
antibody (3E6, Quantum biotechnologies) conjugated to protein A-Sepharose
beads (Amersham Pharmacia Biotech) overnight at 4°C. The
immunoprecipitates were washed four times with NEB270 (same as NEB350 except
containing 270 mM KCl), and eluted with Laemmli sample buffer. For detection
of LET-19::GFP and SUR-2::HA, samples were separated by SDS-PAGE (5%), and
transferred onto PDVF membranes (Immobilon P, Millipore) by electroblotting
for 180 minutes in 10 mM CAPS [3-(cyclohexylamino)-1-propanesulfonic acid; pH
11.0] transfer buffer containing 7.5% methanol. The membranes were
immunoblotted with anti-GFP (JL-8, CLONTECH) and anti-HA (12CA5, Boehringer
Mannheim), and bound antibodies were visualized with HRP-conjugated antibodies
against mouse IgGs (BioRad) using a chemiluminescence reagent (Western
Lightning, Perkin Elmer Life Sciences). To detect MED-6, an immunoblot
analysis was performed with anti-MED-6, as described previously
(Kwon et al., 1999
).
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Results |
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let-19 and dpy-22 are required for cell fusion regulated by the Wnt signaling pathway
To further investigate the roles of these genes in Wnt signaling, we
analyzed the phenotypes of the let-19 and dpy-22 mutants in
other developmental events regulated by the Wnt signaling pathway. Wnt
signaling is known to regulate cell fusion
(Eisenmann et al., 1998). The
ventral hypodermal cells, called Pn.p cells (P1.p through P11.p), can assume
alternative fates. In wild-type animals, the two anterior and three posterior
Pn.p cells fuse with the hypodermal syncytium (F fate), while the six central
cells (P3.p through P8.p) do not fuse and become precursor cells for the vulva
(VPCs). (The P3.p cell adopts the F fate in about 50% of animals.) In mutants
of the bar-1 gene, which encodes ß-catenin, cell fusion occurs
ectopically, producing fewer VPCs than in wild-type animals
(Eisenmann et al., 1998
).
BAR-1 maintains the expression of LIN-39/Hox, which inhibits cell fusion. In
lin-39 mutants, all the Pn.p cells fuse
(Clark et al., 1993
; Wang,
1993). We quantified the unfused ventral hypodermal cells in the
let-19 and dpy-22 mutants, using an adherens junction
marker, ajm-1::GFP (Koppen et
al., 2001
). We first found that the Pn.p cells in these mutant
animals sometimes underwent an extra division in the late L1 stage, producing
extra hypodermal cells. A similar phenotype was reported for lin-25
mutants (Tuck and Greenwald,
1995
). Despite the presence of these extra hypodermal cells in the
let-19 and dpy-22 animals, cell fusion occurred less
frequently than in wild-type animals (Table
3). Specifically, in five out of 16 let-19(mn19) animals
and in two of 26 dpy-22(os38) animals, neither P2.p nor P2.pp fused.
In addition, in four out of 26 dpy-22(os38) animals, P9.p (and in one
animal, P9.pa, P9.pp and P10.p) did not adopt the F fate. Furthermore, we
found that let-19 and dpy-22 mutations efficiently
suppressed the bar-1 mutant phenotype
(Table 3). Unfused P2.p or P9.p
cells were still observed in the let-19; bar-1 or bar-1
dpy-22 double mutants. By contrast, the let-19 mutations did not
suppress the lin-39 mutant phenotype. These results suggest that
let-19 and dpy-22 function to repress the
lin-39/Hox expression that is regulated by
bar-1/ß-catenin.
|
let-19 and dpy-22 encode components of the transcriptional mediator complex
let-19 was mapped to the right of rol-6 on chromosome II
(Sigurdson et al., 1984).
let-19 mutants were rescued by cosmid F07H5 and a subclone of F07H5
that contains the predicted gene K08F8.6
(Fig. 4A). The RNAi of this
gene was embryonically lethal, but escapers mimicked the Psa and extra Pn.p
phenotypes of let-19 (data not shown). We sequenced this gene in the
let-19 mutants and found mutations in all the alleles, confirming
that K08F8.6 was the let-19 gene. All the alleles had nonsense
mutations, indicating that they were strong loss-of-function mutants.
Consistent with this, all the alleles were fully recessive, and the Muv
phenotype of mn19 homozygotes was similar to that of
mn19/mnDf46, a deficiency in which the let-19 locus is
deleted (data not shown). let-19 encodes a protein of 2862 amino
acids that has been reported to be homologous to mammalian MED13, a component
of the Mediator complex (Ito et al.,
1999
).
|
We searched for homologs of other components of Mediator in the C.
elegans genome and found that a MED12 homolog mapped to the same region
of chromosome X as dpy-22. We found that dpy-22 was rescued
by cosmid F47A4 and a subclone of F47A4 that contains the MED12 homolog,
F47A4.2 (Fig. 4B). The RNAi of
this gene mimicked the Dpy Psa and the fertile phenotype of dpy-22
(data not shown). This gene was previously identified as the sop-1
gene (Zhang and Emmons, 2000).
sop-1 was identified from mutations that suppress the pal-1
mutant. In contrast to the dpy-22 mutants, which have a variety of
phenotypes, as described above, sop-1 mutants did not exhibit any
phenotypes by themselves. Most of the sop-1 mutants had nonsense
mutations near the C terminus that truncated the glutamine-rich domain of the
protein, except for bx103, which contained a splice-site mutation
(Zhang and Emmons, 2000
). We
identified the mutations in three dpy-22 mutants
(Fig. 4B). Among them,
os38, which had the strongest phenotype, contained a nonsense
mutation in the middle of the coding sequence, in addition to a missense
mutation near the N terminus, suggesting that it was a strong loss-of-function
mutant. sop-1 mutants are likely to be weak loss-of-function mutants
of the dpy-22 gene. dpy-22/sop-1 was shown to be expressed
ubiquitously during development (Zhang and
Emmons, 2000
).
sop-1 mutations can suppress pal-1 mutants for the
production of rays from the V6 cells in males. However, dpy-22(os38)
and let-19(mn19) males without the pal-1 mutation were
missing most of the rays [0 rays/sides of animals in let-19(mn19)
n=10 and 1.9 rays in average in dpy-22(os38) n=16]. (Both
T-derived and V6-derived rays appeared to be similarly affected in the
os38 animals.) We then analyzed the expression of the mab-5
gene, which acts downstream of pal-1 for ray production.
mab-5::GFP was often not expressed in the V6 cells in the
dpy-22(os38), let-19(mn19) or pal-1 mutants
(Table 4). Therefore, strong
loss-of-function mutants of dpy-22 have the opposite effects of weak
loss-of-function mutants (sop-1 class) on mab-5 expression
in the V6 cells. If both classes of mutations affect the transcription of
pal-1, let-19 and dpy-22 are likely to be involved in
pal-1 transcription through its intronic enhancer element, which
controls pal-1 expression (Zhang
and Emmons, 2000). By contrast, Zhang and Emmons suggested that
the sop-1-class of dpy-22 mutations activates pal-1
transcription through another element, only when the intronic element is
defective. Therefore, Mediator may regulate pal-1 expression through
two distinct promoter elements. It is also plausible that let-19 and
dpy-22 mutations directly disrupt the transcription of
mab-5, while sop-1-class mutations affect that of
pal-1.
|
let-19 and dpy-22 are expressed symmetrically in the T-cell daughters
To analyze the expression patterns of let-19 and dpy-22,
we made constructs in which the let-19 and dpy-22 genes were
fused in-frame to the GFP (green fluorescent protein) gene at the ends of
their coding sequences. Each construct rescued the let-19 or
dpy-22 phenotypes, respectively, indicating that the fusion proteins
were functional. Using these constructs, we found both let-19 and
dpy-22 to be expressed in most cells during embryogenesis and in many
if not all cells in developing larvae (data not shown). As shown in
Fig. 5, both genes were
expressed in the T cell and the T-cell daughters. GFP fluorescence was
observed in both of the daughter nuclei, indicating that there was no
asymmetry in the expression patterns of let-19 and dpy-22
during T-cell division.
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Discussion |
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Transcriptional repression of Wnt target genes by DPY-22 and LET-19
Two distinct Mediator complexes have been reported in mammals. The CRSP
complex is active for Sp1-dependent transcription, while the larger complex,
ARC-L, is transcriptionally inactive
(Taatjes et al., 2002).
Compared with CRSP, ARC-L has several additional components, including MED12
and MED13, which are homologs of DPY-22 and LET-19, respectively. In yeast,
Srb8/MED12 and Srb9/MED13 form a sub-complex and do not always participate in
the Mediator complex (Borggrefe et al.,
2002
; Myers and Kornberg,
2000
). Similarly, in C. elegans, LET-19/MED13 and
DPY-22/MED12 may be present only in the ARC-L-like but not in the CRSP-like
complex. Because the let-19 and dpy-22 mutations induce
symmetric cell division, similar to lin-17 mutants, activation of the
LIN-44/LIN-17 signaling pathway might convert the ARC-L-like complex to the
CRSP-like complex, by causing the release of a sub-complex containing LET-19
and DPY-22. Our data suggest that LET-19 and DPY-22 are involved in preventing
the expression of TLP-1 in the T.a cell, raising the possibility that the
LET-19-DPY-22 subcomplex directly inhibits the expression of tlp-1, a
candidate Wnt signal target in the T-cell division. In this case, the
ARC-L-like complex may inhibit the expression of tlp-1 in the T.a
cell, while the CRSP-like complex may activate transcription of tlp-1
in the T.p cell.
In addition to the tlp-1 expression, in the fusion of the Pn.p cells, our results indicate that LET-19 and DPY-22 function in transcriptional repression of the lin-39/HOX gene. In this case, the Wnt signal mediated by bar-1/ß-catenin may release LET-19 and DPY-22 from the Mediator complex, resulting in the induction of lin-39 expression. By contrast, in the absence of the Wnt signal, LET-19 and DPY-22 may participate in the Mediator to inhibit the expression of lin-39, resulting in cell fusion.
Despite defects in tlp-1 expression in the T.a cell, the neural fate of the T.p cell is abnormal in let-19 and dpy-22 mutants, rather than the hypodermal fate of the T.a cell being altered. This puzzling contradiction can be explained if let-19 and dpy-22 regulate the transcription of other genes required for neural fates in the T.p cell. Another possibility is that the expression of the tlp-1 gene in the T.a cell may affect the fate of the T.p cell, although interactions between the T.a and T.p cells have not been reported.
Functions of MED13 and MED12 in the Mediator complex
In yeast, the Srb8-11 subgroup forms a specific module, which is present in
holoenzyme preparations from cells growing exponentially in rich glucose
medium, but is absent in stationary-phase cells
(Holstege et al., 1998).
Genetic analyses indicate that the Srb8-11 module is involved in the negative
regulation of a small subset of genes
(Carlson, 1997
;
Holstege et al., 1998
). In
Drosophila, loss of either the skuld(skd)/MED13 or
kohtalo(kto)/MED12 gene has exactly the same effect. It was also
reported that the Skd and Kto proteins interact with each other
(Janody et al., 2003
;
Treisman, 2001
). In C.
elegans, we have shown here that mutations in either let-19 or
dpy-22 cause similar defects in T-cell division and fusion of the
Pn.p cells. They also share the Dpy and Muv phenotypes. A recent paper
reported that the male tail phenotype caused by the pal-1(e2091)
mutation was suppressed not only by dpy-22/sop-1 mutations, but also
by the reduced expression of let-19
(Wang et al., 2004
). These
observations strongly suggest that MED13 and MED12 function as a unit, which
is conserved evolutionally. A remaining question is, what are the roles of
Cdk8 and Cyclin C, the other components of the Srb8-11 submodule? Do Cdk8 and
Cyclin C also have a function similar to MED13 and MED12? Future studies of
these molecules will contribute to our understanding of the roles of the
Srb8-11 submodule in the Mediator complex.
In yeast, although disruption of Srb4/MED4 affects the transcription of
most genes (93% of 5361 genes examined), that of Srb10/CDK8 affects only a
small subset of them (3%) (Holstege et
al., 1998). In Drosophila, Skd/MED13 and Kto/MED12 are
specifically required for proper photoreceptor differentiation
(Treisman, 2001
), and Skd is
involved in the regulation of segment identity
(Boube et al., 2002
). In C.
elegans, disruption of LET-19 at the embryonic stage affects the
expression of a subset of developmentally regulated genes
(Wang et al., 2004
). We have
shown that let-19 and dpy-22 mutants have defects in
specific developmental events that are regulated by Wnt signaling. These
mutations affect the expression of the tlp-1 gene specifically in the
T-cell lineage and that of mab-5 in the V6 cell. These results
indicate that the Srb8-11 submodule acts on specific genes in specific
developmental contexts.
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ACKNOWLEDGMENTS |
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