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First published online 20 August 2008
doi: 10.1242/dev.026443
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Research Report |
1 Institute of Medical Sciences, Cell and Developmental Biology Research
Programme, School of Medical Sciences, University of Aberdeen, Aberdeen AB25
2ZD, UK.
2 MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine,
University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS,
UK.
Author for correspondence (e-mail:
s.p.hoppler{at}abdn.ac.uk)
Accepted 29 July 2008
SUMMARY
Cardiogenesis is inhibited by canonical Wnt/β-catenin signalling and stimulated by non-canonical Wnt11/JNK signalling, but how these two signalling pathways crosstalk is currently unknown. Here, we show that Wnt/β-catenin signalling restricts cardiogenesis via inhibition of GATA gene expression, as experimentally reinstating GATA function overrides β-catenin-mediated inhibition and restores cardiogenesis. Furthermore, we show that GATA transcription factors in turn directly regulate Wnt11 gene expression, and that Wnt11 is required to a significant degree for mediating the cardiogenesis-promoting function of GATA transcription factors. These results demonstrate that GATA factors occupy a central position between canonical and non-canonical Wnt signalling in regulating heart muscle formation.
Key words: Cardiomyogenesis, GATA, Heart, Wnt, Xenopus
INTRODUCTION
The GATA family of transcription factors plays a pivotal role near the top
of the cascade of events that lead to heart muscle differentiation
(Brewer and Pizzey, 2006
;
Peterkin et al., 2005;
Peterkin et al., 2007).
Vertebrate GATA4, GATA5 and GATA6 are expressed in early cardiogenic tissue
(Molkentin, 2000;
Patient and McGhee, 2002), and
regulate cardiomyogenesis, in a partially redundant manner
(Holtzinger and Evans, 2007;
Kuo et al., 1997;
Molkentin et al., 1997;
Peterkin et al., 2007).
However, the precise roles and molecular targets of GATA transcription factors
in vertebrate heart formation are just beginning to be discovered.
Extracellular signals that regulate cardiogenesis have been primarily
identified by their ability to induce cardiac differentiation in non-cardiac
mesoderm. Among these are Wnt signals, such as Wnt11
(Pandur et al., 2002), but
also secreted Wnt antagonists, such as Dickkopf-1 and Crescent
(David et al., 2008;
Marvin et al., 2001;
Schneider and Mercola, 2001).
Wnt antagonists and Wnt signals were both found to promote heart development
because cardiogenesis requires both repression of canonical Wnt/β-catenin
signalling, which would otherwise inhibit cardiogenesis
(Marvin et al., 2001;
Schneider and Mercola, 2001),
and activation of non-canonical Wnt11/JNK signalling, which promotes
cardiogenesis (Eisenberg and Eisenberg,
1999; Pandur et al.,
2002; Terami et al.,
2004). These findings raise the important issue of how these two
Wnt signalling pathways interact to control cardiogenesis.
Because of their prominent roles in cardiogenesis, we investigated the relationship between GATA transcription factors and the two Wnt signalling pathways.
MATERIALS AND METHODS
Expression constructs and morpholino
GATA4GR and GATA6GR, activin (Afouda et
al., 2005) and Dickkopf-1
(Semenov et al., 2001) mRNA
expression constructs have been previously described. β-cateninGR is a
hormone-inducible β-catenin. Wnt11
(Pandur et al., 2002), GATA4
(Afouda et al., 2005) and GATA6
(Peterkin et al., 2003)
morpholinos have been previously characterised.
Embryos and explants culture
For animal cap assays, Xenopus embryos were injected at the
one-cell stage into the animal pole. Embryos were injected at the four-cell
stage into ventral blastomeres for the ventral marginal zone (VMZ) explant
experiments or into dorsal blastomeres for the dorsal marginal zone (DMZ)
explant experiments and the whole embryo analysis. mRNA and morpholino (MO)
were injected in sterile autoclaved water (10 nl). The total amount of MO
injected was 5 ng (Wnt11 MO), 10 ng (GATA6 MO) and 20 ng (GATA4 MO) per
embryo. Animal cap explants were dissected at stage 8 and cultured in
0.6xMMR as described previously
(Afouda et al., 2005).
Cycloheximide treatment was carried out as previously described
(Tada et al., 1997). DMZ or
VMZ explants were dissected at stage 10, when the prospective dorsal side is
clearly identifiable, and cultured in 0.6xMMR. Explants were cultured
until the appropriate control stage before processing for analysis of RNA
expression. Sets of experiments were repeated at least twice in order to
confirm results presented here. Cardiomyocyte differentiation of animal cap
and DMZ explants was analysed at phenotypical level at control stage 45 and
expressed as a percentage of rhythmically beating explants compared with
non-beating, but otherwise healthy, explants.
RNA expression analysis by RT-PCR
Total RNA extraction and the reverse transcription (RT) reaction were
performed as previously described (Afouda
et al., 2005). PCR reactions on cDNA were calibrated to be
strictly in the linear range (with a linearity control series for each figure)
and compared with ODC expression control. Primer sequences and PCR conditions
are available from the authors upon request.
RESULTS AND DISCUSSION
The cardiogenesis-specific functions of Wnt signalling and GATA
transcription factors are difficult to study in whole embryos because both Wnt
signalling and GATA transcription factors are also important regulators at
other developmental stages and in other embryonic tissues
(Afouda et al., 2005;
Liu et al., 2005;
Tada and Smith, 2000). We have
therefore adapted reliable Xenopus animal cap and cardiac mesoderm
explant assays (Ariizumi et al.,
2003; Latinkic et al.,
2003; Schneider and Mercola,
2001), which allow us to examine in isolation the regulatory
mechanisms by which Wnt/β-catenin and Wnt11/JNK signalling, and GATA
transcription factors, interact to regulate cardiogenesis.
|
). In
order to confirm that Wnt/β-catenin signalling can inhibit development of
cardiogenic mesoderm, we activated the pathway in a temporally controlled
manner by co-injecting β-cateninGR mRNA (hormone-inducible version of
β-catenin) and activating it with dexamethasone. Strikingly, the
activin-induced expression of GATA transcription factors and other cardiogenic
markers was abolished when β-cateninGR was activated at relatively early
stages, when cardiogenic mesoderm is being induced (stage 8), but also later
during subsequent heart development (stage 18)
(Fig. 1A).
Because of the observed inhibition of endogenous GATA expression by
β-catenin signalling and the prominent cardiogenesis-promoting role of
GATA factors (Latinkic et al.,
2003; Peterkin et al.,
2003; Peterkin et al.,
2007), we tested whether GATA genes are the relevant targets of
Wnt/β-catenin signalling in cardiogenesis. We reinstated GATA function
with hormone-inducible GATA proteins
(Afouda et al., 2005) that are
activated at the same time as co-injected β-cateninGR was causing reduced
expression of the endogenous GATA genes. The inhibition of cardiogenic marker
gene expression by β-cateninGR was indeed rescued by activating GATA4GR
and GATA6GR (Fig. 1A). This
result suggests a regulatory pathway in which Wnt/β-catenin signalling
restricts cardiogenesis by inhibiting GATA gene expression.
In order to substantiate our findings, we conducted similar experiments
using dorsal marginal zone (DMZ) explants
(Fig. 1B) and analysis in whole
embryos (Fig. 1C). DMZ explants
differentiate into heart tissue in the absence of added factors
(Foley and Mercola, 2005;
Schneider and Mercola, 2001).
Activation of β-cateninGR either at stage 10 or 18 strongly reduced the
expression of GATA genes and other heart development markers, yet their
expression was restored by reinstated GATA4 or GATA6 activity
(Fig. 1B). As expected, in the
whole embryo analysis the β-catenin-mediated reduction of cardiogenic
gene expression is only clearly detectable in the strictly heart
muscle-specific genes MLC2 and TnIc; nevertheless, their expression is
restored by activated GATA function (Fig.
1C, see Fig. S1 in the supplementary material). Our results
demonstrate that GATA transcription factors are sufficient to overcome the
negative regulation of cardiogenesis by Wnt/β-catenin signalling and
therefore suggest that GATA transcription factors act downstream of
Wnt/β-catenin signalling in cardiomyogenesis.
|
;
Peterkin et al., 2007). In
order to test whether GATA function is required for Wnt11 expression and
cardiomyogenesis, we used morpholinos to inhibit GATA4 and GATA6 expression.
We first used activin-injected animal caps as before to induce cardiogenic
marker gene expression (Fig.
2A) but also VMZ explants injected with Dkk-1 mRNA to induce
ectopic cardiogenesis (Fig. 2B)
(Foley and Mercola, 2005;
Marvin et al., 2001;
Schneider and Mercola, 2001)
and intact embryos (Fig. 2C).
In all three assays, we found that inhibition of either GATA4 or GATA6 alone
caused some reduction in gene expression of Wnt11 and other cardiogenic
markers, but a much stronger reduction when both were inhibited, confirming
that Wnt11 gene expression and heart development are dependent on normal GATA
function.
Nkx2-5 and Wnt11 are direct targets for GATA4 and GATA6
The pro-cardiogenic activity of GATA transcription factors in
overexpression experiments (Gove et al.,
1997; Latinkic et al.,
2003; Reiter et al.,
1999) is shared with Wnt11
(Eisenberg and Eisenberg, 1999;
Pandur et al., 2002;
Terami et al., 2004), which is
co-expressed with GATA factors during early cardiogenesis
(Ku and Melton, 1993) (see
Fig. S3 in the supplementary material). We therefore investigated whether
Wnt11 is a direct target of GATA transcription factors in cardiomyogenesis. We
activated GATAGR proteins with dexamethasone in the presence of protein
synthesis inhibitors that prevent indirect gene induction, and assayed for
Wnt11 and Nkx2-5 expression. Controls without dexamethasone showed no or low
Nkx2-5 gene expression. With dexamethasone, Nkx2-5 expression was induced
during early stages (Fig. 3A)
and at later stages (Fig. 3B),
even in the presence of cycloheximide, confirming Nkx2-5 as a direct target of
GATA regulation (Brewer et al.,
2005; Searcy et al.,
1998). Importantly, our experiments show for the first time that
Wnt11 gene expression is also directly regulated by GATA transcription factors
(Fig. 3A,B), as Wnt11 gene
expression was induced by dexamethasone-activated GATA4GR or GATA6GR, even
when protein synthesis was inhibited by cycloheximide, unlike the negative
control myosin heavy chain (MHC
).
|
). Furthermore, Wnt11 activation of a JNK-dependent pathway is
required for cardiogenesis in Xenopus, as well as in cell culture
models (Pandur et al., 2002).
As we had found that expression of Wnt11 requires GATA function and that it
was even among direct targets of regulation by GATA transcription factors, we
investigated the requirement for Wnt11 downstream of GATA function using a
Wnt11 morpholino (11MO) (Pandur et al.,
2002) together with GATAGR mRNAs.
We found that either GATA4GR or GATA6GR were able to initiate
cardiomyogenic gene expression (MLC2, TnIc) in animal cap explants
(Fig. 4A), but that only
GATA4GR was able to induce beating cardiomyocytes
(Fig. 4B,D). We had earlier
noticed subtle but consistent differences between GATA4GR and GATA6GR
activities (Fig. 1, see Fig. S2
in the supplementary material), indicating that GATA4GR is a slightly stronger
inducer of cardiogenic marker gene expression when activated at earlier
stages, whereas GATA6GR the relatively stronger inducer when activated later.
Our investigation does not address whether this is simply due to technical
differences between the GATA4GR and the GATA6GR constructs or whether it
reflects functional differences between the endogenous genes
(Nemer, 2008;
Peterkin et al., 2005;
Peterkin et al., 2007;
Xin et al., 2006;
Zhao et al., 2008), but we
think it is related to their differing abilities to induce beating
cardiomyocytes (Charron et al.,
2001; Latinkic et al.,
2003). Nevertheless, morpholino-mediated inhibition of Wnt11
caused clear reduction of cardiomyogenic gene expression
(Fig. 4A,C) and reduced
differentiation into beating cardiomyocytes
(Fig. 4D). These results show
that Wnt11 is required to a significant degree for mediating the
cardiogenesis-promoting activity of GATA factors.
To confirm that the need for Wnt11 function is not confined to artificially induced cardiogenesis, we tested whether Wnt11 function is also required for cardiomyogenic gene expression and cardiomyocyte differentiation in DMZ explants and in whole embryos. We found indeed that morpholino-mediated inhibition of Wnt11 causes reduced MLC2 and TnIc expression in DMZ explants and in whole embryos (Fig. 4E) and that it reduces the number of beating DMZ explants and embryos with a detectable heart beat (Fig. 4F). Our results therefore argue that Wnt11 is a key effector of cardiogenesis downstream of GATA transcription factors.
GATA factors link canonical and non-canonical Wnt signalling in cardiogenesis
Our results suggest a regulatory pathway controlling cardiomyogenesis
whereby GATA transcription factors link canonical and non-canonical Wnt
signalling. We have confirmed that Wnt/β-catenin signalling inhibits
cardiogenesis (Cohen et al.,
2008; Eisenberg and Eisenberg,
2006; Naito et al.,
2006; Tzahor,
2007; Ueno et al.,
2007), that GATA4/6 promote cardiomyogenesis
(Latinkic et al., 2003;
Peterkin et al., 2003;
Peterkin et al., 2007) and
that Wnt11 is required for cardiomyogenesis
(Pandur et al., 2002). We also
show for the first time that GATA4/6 can overrule Wnt/β-catenin-mediated
inhibition of cardiogenesis, that GATA4/6 directly induces Wnt11 expression
and that GATA4/6 promotes myocardial differentiation largely via Wnt11. These
findings establish a hierarchy of regulation with canonical Wnt/β-catenin
signalling restraining GATA gene expression, which otherwise induces
non-canonical Wnt11/JNK signalling to promote subsequent aspects of heart
muscle differentiation.
Our results do not necessarily argue for a strictly linear pathway. We find
that repression of GATA gene expression by activated Wnt/β-catenin
signalling is often not complete, which is likely to reflect additional
regulation of GATA gene expression, for example by Nkx transcription factors
(Molkentin et al., 2000) and
by Wnt11 (Pandur et al.,
2002), which may represent reinforcing regulatory loops operating
together with the regulatory hierarchical pathway we describe. Furthermore,
Wnt11 is not the only cardiogenesis-promoting factor induced by activated
GATA; Nkx2-5, a key regulator of heart development
(Brewer et al., 2005;
Cripps and Olson, 2002), is
also induced, which may suggest an alternative pathway downstream of GATA4/6.
Our results provide further evidence for this notion in the observed
incomplete abolition of cardiogenic gene expression and only reduced
differentiation into beating cardiomyocytes when Wnt11 is inhibited, which is
also consistent with the relatively mild heart phenotypes observed in the
zebrafish silberblick (wnt11) mutation
(Matsui et al., 2005) and the
mouse Wnt11 knockout (Majumdar et al.,
2003).
|
ACKNOWLEDGMENTS
We thank Professor Makoto Asashima (University of Tokyo) for primer sequences and PCR conditions, Dr Danielle Lavery for discussions, and Yvonne Turnbull for technical assistance. This work was funded by The Wellcome Trust (071101/Z/03/Z), British Heart Foundation (PG/07/043) and the Royal Society.
Footnotes
* Present address: Institute of Regenerative Medicine, A&M System Health
Science Center, 5701 Airport Road, Module C, Temple, Texas 76502, USA 
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