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First published online 24 October 2007
doi: 10.1242/dev.008367
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Review |
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
* Author for correspondence (e-mail: eric.olson{at}utsouthwestern.edu)
SUMMARY
The myocyte enhancer factor 2 (MEF2) transcription factor acts as a lynchpin in the transcriptional circuits that control cell differentiation and organogenesis. The spectrum of genes activated by MEF2 in different cell types depends on extracellular signaling and on co-factor interactions that modulate MEF2 activity. Recent studies have revealed MEF2 to form an intimate partnership with class IIa histone deacetylases, which together function as a point of convergence of multiple epigenetic regulatory mechanisms. We review the myriad roles of MEF2 in development and the mechanisms through which it couples developmental, physiological and pathological signals with programs of cell-specific transcription.
Introduction
The formation of specialized cell types and their integration into different tissues and organs during development requires the interpretation of extracellular signals by components of the transcriptional apparatus and through the subsequent activation of cascades of regulatory and structural genes by combinations of widely expressed and cell type-restricted transcription factors. The myocyte enhancer factor 2 (MEF2) transcription factor plays central roles in the transmission of extracellular signals to the genome and in the activation of the genetic programs that control cell differentiation, proliferation, morphogenesis, survival and apoptosis of a wide range of cell types.
Recent studies in mice and fruit flies have revealed upstream signaling systems that control MEF2 expression and activity, and downstream effector genes that mediate the actions of MEF2 throughout development, as well as in adult tissues. These studies point to MEF2 having a central role as a mediator of epigenetic regulatory mechanisms that involve changes in chromatin configurations and the modulation of microRNAs. Here we review the mechanisms that govern MEF2 activity and discuss commonalities in the functions of MEF2 as a regulator of differentiation of diverse cell types. The requirement of MEF2 for the differentiation of seemingly unrelated cell types from multiple lineages points to MEF2 being a key component of the regulatory codes that are required for metazoan development.
The MEF2 family
MEF2 proteins belong to the evolutionarily ancient MADS (MCM1, agamous,
deficiens, SRF) family of transcription factors
(Shore and Sharrocks, 1995
).
Saccharomyces cerevisiae, Drosophila and Caenorhabditis
elegans possess a single Mef2 gene, whereas vertebrates have
four - Mef2a, b, c and d. The N-termini of MEF2 factors
contain a highly conserved MADS-box and an immediately adjacent motif termed
the MEF2 domain (Fig. 1), which
together mediate dimerization, DNA binding, and co-factor interactions
(Black and Olson, 1998;
McKinsey et al., 2002a). The
C-terminal regions of MEF2 proteins, which function as transcriptional
activation domains, are subject to complex patterns of alternative splicing
(Martin et al., 1994) and are
divergent among family members (Fig.
1).
MEF2 proteins bind to the consensus DNA sequence YTA(A/T)4TAR as
homo- or heterodimers (Andres et al.,
1995; Fickett,
1996; Gossett et al.,
1989; Molkentin and Olson,
1996; Pollock and Treisman,
1991; Yu et al.,
1992). Although MEF2 is a transcriptional activator, it relies on
the recruitment of, and cooperation with, other transcription factors to drive
the expression of its target genes. In addition, complex transcriptional,
translational and post-translational mechanisms govern the functions of
MEF2.
Yeast MEF2, referred to as Rlm1, binds the same DNA sequence as the
vertebrate MEF2 proteins and functions as a downstream effector of the
mitogen-activated protein (MAP) kinase pathway
(Dodou and Treisman, 1997).
Rlm1 regulates a cadre of genes that encode proteins involved in cell wall
biosynthesis.
The four vertebrate Mef2 genes display distinct, but overlapping,
temporal and spatial expression patterns in embryonic and adult tissues, with
highest expression in striated muscles and brain
(Edmondson et al., 1994).
However, in vertebrates, MEF2 is also expressed in lymphocytes, neural crest,
smooth muscle, endothelium and bone (Arnold
et al., 2007; Edmondson et
al., 1994), and several reports claim that MEF2 proteins are
ubiquitous (Black et al., 1997;
Martin et al., 1993;
McDermott et al., 1993;
Pollock and Treisman, 1991;
Yu et al., 1992). The
expression of MEF2 proteins in many cell types, including in neurons,
chondrocytes and muscle (cardiac, skeletal, and smooth), occurs concomitantly
with the activation of their differentiation programs, and the balance between
the transcription-activating functions of MEF2 and the repressive functions of
class IIa histone deacetylases (HDACs) dictates the development of these
tissues (Fig. 2)
(Arnold et al., 2007;
Chang et al., 2004;
Chang et al., 2006;
Lu et al., 2000;
Verzi et al., 2007;
Youn and Liu, 2000).
In adult tissues, MEF2 proteins act as a nodal point for stress-response
and remodeling programs (for example, during cardiac hypertrophy and
fiber-type switching in cardiac and skeletal muscle, respectively)
(Potthoff et al., 2007b;
Zhang et al., 2002). MEF2
proteins have also been implicated in cell survival, apoptosis and
proliferation. In each of these settings, the spectrum of target genes
activated by MEF2 depends on the specific post-translational modifications
MEF2 undergoes and on its interaction with its co-factors.
Signaling to MEF2
MEF2 proteins serve as endpoints for multiple signaling pathways and
thereby confer signal-responsiveness to downstream target genes
(Fig. 2). MAP kinase signaling
pathways converge on MEF2 factors in organisms ranging from yeast to humans
(Dodou and Treisman, 1997;
Han et al., 1997;
Kato et al., 1997).
Phosphorylation of the transcription activation domain of MEF2 by MAP kinases
augments its transcriptional activity, and the MAP kinase ERK5 (also known as
BMK1 and MAPK7) serves as a MEF2 coactivator through its signal-dependent
direct association with the MEF2 MADS domain
(Yang et al., 1998).
|
|
;
de Ruijter et al., 2003;
McKinsey et al., 2001;
McKinsey et al., 2002a;
McKinsey et al., 2002b)
(Fig. 2), such as myogenin
(Cheng et al., 1993;
Edmondson et al., 1992;
Malik et al., 1995;
Yee and Rigby, 1993),
myoglobin (Bassel-Duby et al.,
1992) and matrix metalloproteinase 10 (Mmp10)
(Chang et al., 2006). Numerous
calcium-regulated protein kinases, including protein kinase D (PKD) and
calcium calmodulin-dependent protein kinases (CaMKs) phosphorylate class II
HDACs on a series of conserved serine residues. This phosphorylation promotes
the nuclear-to-cytoplasmic shuttling of these HDACs and the subsequent
activation of MEF2 (McKinsey and Olson,
2005; Zhang et al.,
2002). The regulated phosphorylation of class II HDACs thus
provides a mechanism for the modulation of MEF2 target genes in response to
physiological and pathological signaling. MEF2: a central regulator of Drosophila myogenesis
MEF2 was first identified as a regulator of muscle gene expression
(Gossett et al., 1989). The
central role of MEF2 in orchestrating muscle development has been delineated
most thoroughly in Drosophila. The single Mef2 gene in
Drosophila is expressed in early mesoderm and subsequently in
different muscle cell lineages, where it is required for myoblast
differentiation (Bour et al.,
1995; Lilly et al.,
1995; Ranganayakulu et al.,
1995) (Fig. 3). A
complex array of enhancers governs the transcription of Mef2 in
different cell types during Drosophila development. Mef2
expression within the early mesoderm (Fig.
3A) requires a mesodermal enhancer that is directly activated by
Twist (Cripps et al., 1998), a
bHLH transcription factor required for mesoderm formation
(Simpson, 1983). Twist and the
zinc-finger transcription factor Lame duck act through separate enhancers to
control Mef2 transcription in specific sets of somatic muscle cells
later in development (Fig. 3B)
(Duan et al., 2001). MAD and
Medea, downstream effectors of Decapentaplegic (DPP) signaling, also act
directly on an Mef2 enhancer to control its expression in the somatic
muscle lineage (Nguyen and Xu,
1998). In addition, Mef2 maintains its own transcription
late in the muscle differentiation pathway by activating a distal
Mef2-dependent autoregulatory enhancer
(Cripps et al., 2004).
Within the cardiac lineage (Fig.
3C), the homeodomain protein Tinman directs Mef2
transcription through a cardiac-specific enhancer that also contains essential
binding sites for GATA factors (Cripps and
Olson, 1998; Gajewski et al.,
1997). Intriguingly, a mutation of the GATA sites switches the
cell-type specificity of the enhancer from cardial to pericardial cells
(Gajewski et al., 1998).
In Mef2 mutant Drosophila embryos, somatic muscle founder
cells are appropriately specified, but there is a complete block in myoblast
fusion and in the expression of muscle differentiation markers
(Bour et al., 1995;
Lilly et al., 1995;
Prokop et al., 1996;
Ranganayakulu et al., 1995).
Similarly, cardiac cells within the dorsal vessel, which functions as a heart,
are patterned properly in Mef2 mutant embryos, but cardiac
contractile protein genes are not expressed.
Several approaches have been taken to identify MEF2 target genes in
Drosophila. The use of chromatin immunoprecipitation (ChIP), followed
by microarray analysis (ChIP on chip) on a tiling array that covers 
50%
of the Drosophila genome, identified more than 200 direct target
genes of MEF2 and over 650 regions of the genome that are bound by MEF2,
highlighting the central role of MEF2 in the transcriptional hierarchy for
myogenesis (Sandmann et al.,
2006). Similar findings were made by an independent study that
combined ChIP with spotted DNA microarrays that contain in-silico predicted
cis-regulatory module targets (the so-called ChEST strategy)
(Junion et al., 2005).
MEF2 exhibits three temporal patterns of enhancer binding during
Drosophila muscle development. Although MEF2 is present at high
levels early in development, it does not bind the enhancers of muscle
differentiation genes until later in development, indicating the existence of
mechanisms that govern target gene recognition by MEF2
(Sandmann et al., 2006).
Twist, the central bHLH protein partner for MEF2 in the somatic muscle lineage
in Drosophila (Cripps and Olson,
1998), binds with MEF2 to enhancers that are activated early in
the mesodermal and myogenic lineages
(Sandmann et al., 2007).
|
). This
type of function of MEF2 in the early stages of myogenesis coincides with the
early, Twist-dependent phase of MEF2 expression and its regulation of genes in
the early mesoderm (Taylor,
2000; Ruiz-Gomez et al.,
2002).
Unexpectedly, MEF2 also regulates the enhancers of muscle identity genes,
suggesting that it contributes to the robustness of myogenesis
(Sandmann et al., 2006). At
later stages of myogenesis, MEF2 regulates genes that are involved in muscle
attachment, neuromuscular junction (NMJ) formation, ion transport, channel
activity, metabolism and contractility
(Sandmann et al., 2007)
(Fig. 3B). These studies
suggest that MEF2 regulates most, if not all, muscle genes, not just those
encoding `late' structural proteins of differentiated muscle, and thereby acts
as a central regulator of myogenesis.
The ectopic expression of MEF2 in the epidermis of Drosophila
results in the activation of skeletal muscle genes, such as Tropomyosin
1 (Tm1), whereas ectopic expression of MEF2 in the nervous
system does not activate these genes (Lin,
M. H. et al., 1997), suggesting that the epidermis expresses a
co-factor that cooperates with MEF2 to activate the muscle gene program. In
this regard, a novel PAR-domain bZIP transcription factor, PDP1, which is
expressed in cell types that are susceptible to MEF2-dependent muscle gene
activation, has been shown to cooperate with MEF2 to activate muscle gene
expression (Lin, S. C. et al.,
1997).
In contrast to Drosophila, which contains a single Mef2
gene, elucidation of the functions of mammalian Mef2 genes has been
comparably more difficult owing to the existence of four related genes that
have overlapping expression patterns. In vertebrates, loss-of-function
mutations frequently reveal only a subset of MEF2 functions in tissues in
which the genes do not function redundantly. By generating conditional alleles
of the different Mef2 genes, we are now beginning to ascertain the
importance of specific MEF2 proteins in various tissues through their
combinatorial deletion (Arnold et al.,
2007). Alternatively, the overexpression of chimeric MEF2 fusion
proteins, such as the super-active MEF2-VP16 or super-repressive
MEF2-engrailed, has been used to elucidate MEF2 function in different tissues
while bypassing functional redundancy
(Arnold et al., 2007;
Karamboulas et al., 2006;
Potthoff et al., 2007b).
MEF2 control of vertebrate skeletal muscle differentiation
Vertebrate skeletal muscle differentiation is regulated by the cooperative
interactions of myogenic transcription factors with MEF2, and by signaling
pathways that regulate MEF2 activity (Fig.
4). MEF2 factors alone do not possess myogenic activity but, in
combination with bHLH transcription factors, drive and amplify the myogenic
differentiation program (Molkentin et al.,
1995; Wang et al.,
2001). MEF2 also interacts with additional transcription factors
that are required for proper muscle development. For example, the
mastermind-like protein 1, MAML1, was recently shown to interact with MEF2C
and to mediate crosstalk between Notch signaling and MEF2 in the regulation of
myogenic differentiation (Shen et al.,
2006). MEF2 has also been implicated in regulating skeletal
myocyte survival through a CREB-dependent pathway
(Berdeaux et al., 2007).
In addition to regulating numerous muscle structural genes, vertebrate MEF2
proteins regulate the expression of myogenic bHLH genes, such as myogenin, as
well as other genes that encode transcription factors, thereby providing a
positive feed-forward loop that perpetuates and amplifies the decision to
differentiate (Cheng et al.,
1993; Edmondson et al.,
1992; Molkentin and Olson,
1996; Tapscott,
2005; Yee and Rigby,
1993). MEF2C has also been shown to positively regulate its own
expression during mouse embryogenesis
(Wang et al., 2001),
consistent with the autoregulatory activity of Drosophila MEF2
(Cripps et al., 2004).
Moreover, MEF2C activates the expression of the class IIa HDAC, HDAC9, thereby
creating a negative-feedback loop that modulates and restrains MEF2 from
excessive activity (Haberland et al.,
2007) (Fig. 4).
This type of negative-feedback loop also confers signal responsiveness to
MEF2-dependent gene programs through the regulated phosphorylation of class
IIa HDACs.
|
;
Zhao et al., 2005), that
post-transcriptionally repress gene expression by binding the 3'
untranslated regions of mRNA targets and disrupting mRNA translation and
stability (He and Hannon,
2004). Recently, several microRNAs were identified that affect
skeletal muscle differentiation and proliferation
(Boutz et al., 2007;
Chen et al., 2006;
Kim et al., 2006;
Rao et al., 2006).
Interestingly, miR-1 has been shown to target class II HDACs (such as HDAC4)
(Chen et al., 2006) to
establish a positive feed-forward mechanism for MEF2 activation and skeletal
muscle differentiation (Fig.
4). This form of regulation, which enhances MEF2 activity, would
oppose the direct activation of HDAC9 expression by MEF2, which represses MEF2
activity, illustrating the multifaceted mechanisms that exist to modulate
MEF2. Presumably, these different regulatory loops are differentially
controlled during various stages of skeletal muscle development and postnatal
muscle remodeling.
Despite extensive studies of MEF2 in skeletal muscle in vitro, relatively
little is known about the roles of MEF2 proteins in vertebrate skeletal muscle
in vivo. During mouse embryogenesis, Mef2c is the first Mef2
gene to be expressed in the somite myotome (E9.0), with Mef2a
and Mef2d expressed about a day later
(Edmondson et al., 1994).
Global deletion of Mef2a or Mef2d has little or no effect on
skeletal muscle development (Potthoff et
al., 2007a; Potthoff et al.,
2007b). Since Mef2c-null mice die around E9.5
(Lin, Q. et al., 1997), its
role in skeletal muscle was not examined until recently. Skeletal muscle
deficient in Mef2c differentiates and forms myofibers during
embryogenesis (Potthoff et al.,
2007a; Potthoff et al.,
2007b). However, on a C57BL/6 mixed genetic background, myofibers
from mice with a skeletal muscle-specific deletion of Mef2c rapidly
deteriorate after birth owing to the occurrence of disorganized sarcomeres and
to the loss of integrity of the sarcomere M-line
(Potthoff et al., 2007a).
Interestingly, similar results have been observed in zebrafish following the
combined knockdown of mef2c and mef2d
(Hinits and Hughes, 2007).
Notably, the muscle-specific overexpression of a super-active MEF2 protein in
mice does not drive premature skeletal muscle differentiation
(Potthoff et al., 2007b),
consistent with previous in vitro studies that have demonstrated that MEF2 is
not sufficient to drive skeletal muscle differentiation
(Molkentin et al., 1995).
These results reveal a key role for MEF2 proteins in the maintenance of
sarcomere integrity and in the postnatal maturation of skeletal muscle.
Control of vertebrate heart development by MEF2
MEF2 regulates the expression of numerous cardiac structural and
contractile proteins. Cardiac-specific overexpression of the repressive
MEF2C-engrailed fusion protein under the control of the Nkx2-5
enhancer (E7.5) is sufficient to inhibit cardiomyocyte differentiation in
vitro and in vivo. Moreover, the overexpression of MEF2C-engrailed
downregulates the expression of GATA and NKX proteins in cardiomyocytes
(Karamboulas et al., 2006),
confirming the role of MEF2 as a regulator of the other core cardiac
transcription factors that are required for cardiomyocyte differentiation.
Notably, cardiomyocyte development can still occur despite the loss of
individual vertebrate MEF2 proteins. In the mouse and chick, MEF2C is the
first MEF2 factor to be expressed, appearing initially in mesodermal
precursors that give rise to the heart
(Edmondson et al., 1994).
Shortly thereafter, the other Mef2 transcripts are expressed.
Mef2c-null mice die around E9.5 from cardiac looping defects
(Lin, Q. et al., 1997), and
Mef2a-null mice exhibit perinatal lethality from an array of
cardiovascular defects (Naya et al.,
2002). By contrast, Mef2d-null mice appear normal
(Arnold et al., 2007). Although
Mef2c-null mice exhibit early embryonic lethality, cardiomyocytes are
still able to differentiate prior to the looping defects that occur
(Lin, Q. et al., 1997).
Interestingly, mice with a cardiac-specific deletion of Mef2c, which
occurs at around E9.5 (
MyHC-cre), are viable
(Vong et al., 2005), which
demonstrates that Mef2c is dispensable in the heart after cardiac
looping, probably owing to it being compensated for by other MEF2 factors.
|
|
) (Fig. 5). In
Mef2c mutant embryos, derivatives of the anterior heart field fail to
form (Lin, Q. et al., 1997).
Activation of Mef2c transcription in the anterior heart field is
controlled by at least two separate enhancers: one that is activated directly
by the forkhead DNA-binding transcription factor FOXH1, together with NKX2-5,
which also confers TGF-ß responsiveness to Mef2c
(von Both et al., 2004); and
a second enhancer that serves as a direct target of GATA4 and the
LIM-homeodomain transcription factor ISL1, which is itself required for the
formation of the anterior heart field
(Dodou et al., 2004;
Cai et al., 2003). Expression
of the transcriptional repressor and putative histone methyltransferase BOP
(also known as SMYD1) in the anterior heart field is controlled by the direct
activation of an upstream enhancer by MEF2C
(Phan et al., 2005), and the
cardiac defects seen in Bop mutant embryos partially phenocopy those
of Mef2c mutants, suggesting that Bop is an essential
downstream mediator of the actions of MEF2C in the anterior heart field
(Gottlieb et al., 2002). The
bHLH transcription factor HAND2 appears to be a key target of BOP regulation,
although the mechanistic basis for this regulation has not been resolved. Control of neural crest development by MEF2
Neural crest cells are multipotent, migratory cells that originate between
the dorsal neural tube and epidermis of the embryo
(Knecht and Bronner-Fraser,
2002; Trainor,
2005). In response to specific signaling cues, neural crest cells
undergo an epithelial-to-mesenchymal transition, and then migrate to different
parts of the embryo to give rise to a variety of cell types, including
neurons, skeletal and smooth muscle, chondrocytes, osteocytes, melanocytes,
hormone-producing cells, and many more
(Knecht and Bronner-Fraser,
2002). Loss of Mef2c in neural crest cells results in
craniofacial defects and neonatal lethality caused by an upper airway
obstruction (Verzi et al.,
2007); in zebrafish, loss of mef2ca produces similar
craniofacial defects (Miller et al.,
2007). MEF2C directly activates the expression of the homeodomain
transcription factors DLX5 and DLX6, two transcription factors that are
necessary for craniofacial development, and MEF2C acts synergistically with
these factors to direct craniofacial development
(Miller et al., 2007;
Verzi et al., 2007)
(Fig. 6).
The peptide hormone endothelin controls a diverse array of developmental
processes, including neural crest migration and differentiation during
craniofacial development (Clouthier et
al., 1998; Kurihara et al.,
1994). DLX6 and the transcription factor HAND2 are important
regulators of branchial arch development and require endothelin signaling for
their expression (Charitè et al.,
2001; Clouthier et al.,
2000; Thomas et al.,
1998). Interestingly, aspects of endothelin signaling in zebrafish
require Mef2, including activation of the endothelin target genes hand2,
dlx5 and dlx6 (Miller et
al., 2007) (Fig.
6). Therefore, MEF2 plays a crucial role in neural crest
development by activating the expression of endothelin signaling-dependent
transcription factors that are required for proper development.
Control of bone development by MEF2
During embryonic development, bones develop through intramembranous or
endochondral ossification. Endochondral ossification involves a cartilaginous
intermediate, whereas intramembranous ossification occurs through the direct
conversion of mesenchymal tissue into bone
(Hall and Miyake, 1995).
During endochondral ossification, mesenchymal precursor cells become committed
to cartilage cells, forming a template for future bone. These committed
mesenchymal cells differentiate into chondrocytes, proliferate rapidly to form
a template for osteoblasts (committed bone precursor cells), secrete a
cartilage-specific extracellular matrix, and then stop dividing and undergo
hypertrophy (Bruder and Caplan,
1989). Signaling coordinated by Indian hedgehog (IHH) and
parathyroid hormone-related peptide (PTHrP; also known as PTHLH) regulates the
hypertrophy of chondrocytes, which is necessary for bone vascularization,
osteoblast differentiation and endochondral ossification. IHH produced by
prehypertrophic chondrocytes induces the expression of PTHrP, which regulates
the rate at which chondrocytes undergo hypertrophy
(Karaplis et al., 1994;
Lanske et al., 1996;
St-Jacques et al., 1999;
Vortkamp et al., 1996;
Weir et al., 1996).
|
) (Fig. 7A).
Interestingly, this function of MEF2 is tightly regulated by the opposing
function of HDAC4 (Arnold et al.,
2007; Vega et al.,
2004). Genetic deletion of Hdac4
(Vega et al., 2004) or the
chondrocyte-specific overexpression of a constitutively activated form of
MEF2C - the MEF2C-VP16 fusion protein - in mice is sufficient to drive
premature bone formation (Arnold et al.,
2007) (Fig. 7A).
Conversely, the genetic deletion of Mef2c, or the overexpression of a
MEF2-engrailed repressor in mouse chondrocytes, prevents chondrocyte
hypertrophy and endochondral ossification
(Arnold et al., 2007)
(Fig. 7A). MEF2 functions, at
least in part, by directly activating collagen 10a1 (Col10a1)
expression, a specific marker of chondrocyte hypertrophy, and Runx2,
a transcription factor necessary for chondrocyte hypertrophy
(Arnold et al., 2007)
(Fig. 7B). Undoubtedly,
however, there are additional downstream targets and upstream regulators of
MEF2 in developing chondrocytes that remain to be defined. Control of vascular integrity by MEF2
The development of the vasculature occurs through two stages, termed
vasculogenesis and angiogenesis. Vasculogenesis is the de novo formation of
blood vessels from mesodermal progenitor cells, and angiogenesis is the
expansion of a capillary plexus by the formation of additional branches from
pre-existing vessels (Patan,
2000). MEF2 proteins are expressed in developing endothelial and
smooth muscle cells (Lin et al.,
1998) and are required for vascular development and for the
maintenance of vascular integrity. Mef2c expression in the developing
endothelium is controlled by a conserved endothelial-specific enhancer that
binds ETS-family factors and drives expression as early as E8.5 in all
endothelial cells of the mouse embryo and yolk sac
(De Val et al., 2004).
Endothelial cells are specified and differentiated in Mef2c-null
mice, but they are unable to organize properly
(Lin et al., 1998).
MEF2 proteins have been implicated in maintaining vascular integrity by
promoting endothelial cell survival
(Hayashi et al., 2004;
Olson, 2004)
(Fig. 8). The MAP kinase ERK5
is necessary for endothelial cell survival and proliferation; its conditional
deletion from endothelial cells in mice results in vascular death and
embryonic lethality (at E9.5-10.5) due to apoptosis and a failure of
endothelial cells to proliferate (Hayashi
et al., 2004). The introduction of MEF2C-VP16 into ERK5-deficient
endothelial cells is sufficient to partially protect the cells from apoptosis,
whereas the removal of ERK5 from endothelial cells eliminates the
serum-stimulated activation of MEF2 in these cells
(Hayashi et al., 2004).
Recently, we demonstrated an unexpected role for MEF2-HDAC signaling in the
maintenance of vascular integrity (Fig.
8). HDAC7 is expressed specifically in endothelial cells during
development, and global deletion of Hdac7 results in embryonic
lethality due to blood vessel rupture caused by defects in cell-cell adhesion,
a phenotype that is recapitulated by the endothelial-specific deletion of
Hdac7 (Chang et al.,
2006). Knockdown of HDAC7 in human endothelial cells in vitro
results in a similar loss in cell adhesion, accompanied by upregulation of
MMP10, a secreted endoproteinase that degrades the extracellular matrix, and
downregulation of its inhibitor, tissue inhibitor of metalloproteinase 1
(TIMP1). MEF2 proteins directly activate the expression of MMP10, and HDAC7 is
sufficient to repress this activation
(Chang et al., 2006).
Abnormalities in growth and integrity of the vascular endothelium lead to a
variety of cardiovascular disorders (for example, atherosclerosis and
aneuryisms). During development, MEF2 may be involved in angiogenesis by
promoting cell survival (Hayashi et al.,
2004) and vascular remodeling
(Chang et al., 2006). In
response to stress signals (for example, oxidative or fluid shear stress),
MEF2 activation may actually promote vascular remodeling at the site of
injury. In this regard, ERK5 has been demonstrated to be atheroprotective, as
it displays increased activation in response to fluid shear stress and
oxidative stress (Pi et al.,
2004). Therefore, if MEF2 becomes activated at local sites of
injury, which results in blood vessel remodeling, then removal of MEF2
repression by deletion of Hdac7 might explain the global vascular
rupture that is seen in Hdac7-null embryos.
|
). This
function of MEF2 occurs, at least partly, through myocardin, a serum response
factor (SRF) and MEF2 transcriptional coactivator that is necessary for smooth
muscle differentiation (Wang et al.,
2004; Wang et al.,
2003). We recently showed that MEF2 recruits a specific isoform of
myocardin, which together with MEF2 coactivates the myocardin gene through a
positive-feedback loop (Creemers et al.,
2006). Interestingly, MEF2 is upregulated in activated smooth
muscle cells (Firulli et al.,
1996), which suggests that MEF2 functions in the smooth muscle
stress response after injury or in pathological states (e.g.
artherosclerosis). Control of neuronal differentiation and survival by MEF2
MEF2 proteins are highly enriched in neurons and exhibit distinct patterns
of expression in different regions of the brain, with highest levels being
present in the cerebellum, cerebral cortex and hippocampus
(Ikeshima et al., 1995;
Leifer et al., 1993;
Lin et al., 1996;
Lyons et al., 1995). MEF2
protects neurons from apoptotic death (Mao
et al., 1999; Mao and
Wiedmann, 1999; Okamoto et
al., 2000), which contrasts with its pro-apoptotic function in
thymocytes (Woronicz et al.,
1995). The ability of MEF2 to regulate neuronal-specific
transcriptional programs may occur through DNA-binding site selection. MEF2
that is expressed in neurons shows optimal DNA-binding constraints for
specific nucleotide sequences that flank the MEF2 site, and this is not
observed with MEF2 factors from other cell types
(Andres et al., 1995).
Recently it was shown that MEF2 proteins regulate dendrite morphogenesis,
differentiation of post-synaptic structures
(Shalizi et al., 2006) and
excitatory synapse number (Flavell et al.,
2006). Sumoylation of MEF2A promotes the post-synaptic
differentiation of neurons by repressing the expression of the NUR77
transcription factor (Shalizi et al.,
2006), a negative regulator of dendritic differentiation
(Scheschonka et al., 2007). In
addition, dephosphorylation of MEF2 by calcineurin regulates the expression of
activity-regulated cytoskeletal-associated protein (Arc) and synaptic
RAS GTPase-activating protein (synGAP; also known as
Syngap1) (Flavell et al.,
2006). ARC and synGAP play important roles in synaptic disassembly
by promoting the internalization of glutamate receptors
(Flavell et al., 2006) and by
inhibiting Ras-MAP signaling (Vazquez et
al., 2004), respectively. In response to activity-dependent
calcium signaling, calcineurin dephosphorylates MEF2 at Ser408, signaling a
switch from the sumoylation to the acetylation of its residue Lys403. This
change restricts the numbers of synapses that form
(Flavell et al., 2006) and
inhibits dendritic claw differentiation
(Shalizi et al., 2006) through
the activation of the orphan nuclear receptor Nur77 and of
Arc and synGAP.
Thus, specific signaling events modulate gene expression by post-translationally modifying MEF2 to control synapse development and plasticity. The functions of individual MEF2 proteins and their roles in synaptic differentiation and disassembly in vivo have yet to be examined. Based on recent literature, however, MEF2 appears to play a role in synaptic plasticity, suggesting an important role for these proteins in learning and memory.
Control of T-cell development by MEF2
The development and activation of thymocytes (T-cells) is a highly
regulated process that requires multiple signaling cascades to direct changes
in gene expression that alter T-cell state or fate. Calcium signaling pathways
play important roles in T-cell selection during development and in T-cell
receptor (TCR)-induced apoptosis
(Woronicz et al., 1995).
NUR77 is a crucial mediator of TCR-induced apoptosis, and TCR-induced
expression of NUR77 is mediated through two MEF2 sites in the Nur77
promoter (Youn et al., 1999).
In unstimulated T-cells, MEF2 is associated with transcriptional
co-repressors, such as HDAC7 and Cabin1, which inhibit Nur77
expression (Dequiedt et al.,
2003; Youn and Liu,
2000; Youn et al.,
1999).
Following TCR activation, HDAC7 becomes dissociated from MEF2 through
nucleocytoplasmic shuttling. Phosphorylation of HDAC7 by PKD1 recruits 14-3-3
and translocates HDAC7 to the cytoplasm, allowing the activation of MEF2
(Parra et al., 2005).
Conversely, HDAC7 is dephosphorylated by protein phosphatase 1ß
(PP1ß; also known as PPP1CB) and myosin phosphatase targeting subunit 1
(MYPT1; also known as PPP1R12A), which are components of the myosin
phosphatase complex that promote HDAC7 nuclear localization and repression of
NUR77 expression (Parra et al.,
2007). Therefore, regulation of MEF2 activity by association with
transcriptional repressors is highly regulated in T-cells, and demonstrates
the importance of MEF2-HDAC signaling in T-cell development, differentiation
and thymocyte selection (Kasler and
Verdin, 2007).
Conclusion
MEF2 is an ancient mediator of signal-dependent transcription and cell differentiation, and predates most of the transcription factors with which it cooperates to control metazoan development. In virtually every cell type in which its functions have been investigated, MEF2 has been found to serve as a central component of differentiation and development through its ability to potentiate the activities of other regulators, and we speculate that MEF2 will be found to regulate the differentiation of additional cell types, in which its functions have yet to be investigated. In addition to its central role in tissue-specific gene expression and differentiation, MEF2, through its responsiveness to upstream signaling pathways and through its association with other signal-dependent activators and repressors, such as class II HDACs, also serves as a key intermediary in the transmission of extracellular signals to the genome. This function brings signal-dependence to its downstream programs of gene expression. How MEF2 engages its myriad partner proteins in different cell types to activate different and often opposing programs of gene expression, and why such a diversity of cell types and gene programs evolved with a reliance on MEF2, are interesting questions for the future.
Understanding the mechanism of action of MEF2 has provided not only a window into the logic of development, but has also revealed basic mechanisms of numerous diseases. Armed with these insights, it should be possible to modulate complex developmental and disease phenotypes through the manipulation of MEF2 activity.
ACKNOWLEDGMENTS
We thank Jennifer Brown for assistance with manuscript preparation and Alisha Tizenor for graphic design.
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