Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
* Author for correspondence (e-mail: tevans{at}aecom.yu.edu)
Accepted 12 July 2005
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SUMMARY |
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Key words: Organogenesis, Heart, Liver, Pancreas, Zebrafish
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Introduction |
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However, recent progress has been made by taking advantage of tetraploid
embryo complementation assays, whereby wild-type cells rescue the requirement
for Gata4 in extra-embryonic endoderm, with mutant cells constituting the
embryo proper (Watt et al.,
2004). These experiments revealed essential functions for Gata4 in
heart tube morphogenesis (probably related specifically to pro-epicardial
development). Gata6 is a closely related gene that is also required for
extra-embryonic endoderm development
(Koutsourakis et al., 1999
;
Morrisey et al., 1998
), and
similar rescue experiments revealed a required role for Gata6 in liver
development subsequent to hepatic specification
(Zhao et al., 2005
). Because
Gata4 and Gata6 are expressed in overlapping patterns in both heart and gut
tissues, it raises the question of whether they might play redundant roles in
some aspects of heart or liver development. The murine Gata4 `embryo-specific'
mutant embryos still die too early to evaluate a role in gut-derived organ
development. In the case of Gata6 mutants, the heart appears to be unaffected.
It was suggested that Gata4 might play a redundant role for hepatic
specification, but unlike Gata6 might not be required for subsequent organ
growth (Zhao et al.,
2005
).
Here, we describe a loss-of-function analysis for Gata4 in the zebrafish. A primary advantage of this model is that, unlike mouse, fish embryos are not dependent upon support from a primitive (visceral) extra-embryonic tissue. Furthermore, the mutant zebrafish survive beyond the cardiomyopathy, as embryos do not require a functional heart for several days, including during the time for normal gut development. Using the morpholino approach, it is possible to block the expression of both Gata4 and Gata6 in order to reveal potential functional redundancies. We show that, in zebrafish, Gata4 is essential for the generation of endoderm-derived organs, including the intestine, liver, pancreas and swim bladder. In addition, our results show that there is a functional redundancy between Gata4 and Gata6 at an early stage of liver development.
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Materials and methods |
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Morpholino design and microinjections
A Pac clone containing the gata4 gene was isolated and used to
define the 5'UTR and intron/exon structure
(Heicklen-Klein and Evans,
2004). Two morpholino oligomers were designed against the
gata4 sequences (Gene Tools, LLC). MO
(5-TCCAGGTGAGCGATTATTGCTCC-3') is complementary to the 5'UTR of
the mature gata4 transcript (a translation blocker), whereas MO1
(5'-TGGACGCAGACTGAGAGAAAGAGAG-3') was designed to bind to
sequences at the boundary between intron 1 and exon 2 of the gata4
pre-mRNA (a splicing blocker). Blast searches predicted that the morpholinos
should be specific for Gata4. Morpholinos were injected into fertilized eggs
in various doses to establish an optimal dose. Embryos presented a consistent
phenotype with injections of between 5 and 20 ng MO. All the experiments shown
(except for Fig. 2C) used 10 ng
MO per injection. MO1 caused early embryonic death at high doses, but
generated an identical phenotype to that generated by MO when using less than
1 ng, and a typical dose used was 0.3 ng per injection. The morpholino
designed to target Gata6 was previously described and characterized with
respect to specificity (Peterkin et al.,
2003
). This morpholino targets the `long form' of Gata6, and the
sequence is present therefore in the RNA derived from the gata6:GFP
transgene.
Whole-mount in situ hybridization
Whole-mount in situ hybridization was performed essentially as described
(Alexander et al., 1998).
Briefly, embryos were treated with 0.003% phenylthiourea (PTU) to prevent
pigmentation. After fixation, embryos older than 24 hours were treated with 10
µg/ml proteinase K. Hybridization was performed at 70°C, in 50%
formamide buffer with digoxigenin-labeled RNA anti-sense probes. The probes
used for in situ hybridization were prepared and used as described: Gata4/5/6
(Heicklen-Klein and Evans,
2004
), Nkx2.5 (Alexander et
al., 1998
), Cmlc2 and Amhc
(Yelon et al., 1999
). The
probe for transferrin RNA was derived from the RT-PCR product described
below.
Histology
Embryos at 5 days post-fertilization (dpf) were fixed in paraformaldehyde,
processed under standard conditions and embedded in paraffin wax. Cross
sections at 5 µm were cut with a cryostat, mounted onto slides, and
subjected to Hematoxylin and Eosin staining. Sections were observed with
brightfield inverted light, and photographed at 20x magnification.
RT-PCR
RNA was isolated from staged embryos using Trizol Reagent, and purified and
used for reverse transcriptase (RT) reactions as described previously
(Jiang et al., 1998).
Conditions for semi-quantitative RT-PCR were established empirically by
testing cycle number and ensuring that a 2-fold increase of input RNA led to
an approximately 2-fold increase in product. 20 µl RT reactions contained
either 1 or 2 µg of RNA for one hour at 37°C. PCR reactions used 2
µl of an RT sample in 50 µl. PCR primers are described in
Table 1.
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Results |
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As shown in Fig. 1, transgenic gata4:GFP embryos that had been injected at the one-cell stage with the Gata4-specific MO fail to express GFP in the heart or notochord. GFP expression is fully blocked until at least 5 dpf. The analysis indicates that the ATG-targeted morpholino effectively interacts with the gata4 UTR sequence to inhibit translation. In addition, 100% of the MO-injected embryos develop a consistent and penetrant phenotype by 2-3 dpf (Fig. 1B), although they continue to survive until approximately 6-8 dpf, thereby allowing us to investigate thoroughly the embryonic functions of Gata4. Injection of control morpholinos caused no abnormal phenotypes (data not shown).
Gata4 is required for development of the heart, gut, pancreas, liver and swim bladder
In contrast to Gata5/faust mutants [and Gata6 morphants
(Peterkin et al., 2003)], the
Gata4 morphant embryos never display a bifid phenotype. However, by 2-3 dpf,
every injected embryo is distinguished by a kink in the tail, regression of
the yolk stalk extension, and a non-looping but beating heart tube within an
edemic cavity (Fig. 2A,B).
Development is slightly delayed and the embryos are approximately 25% smaller
than controls. To demonstrate that these phenotypes are specific to the loss
of Gata4, we designed a distinct morpholino (MO1), to target the splice site
at the junction of the first intron and the second exon, upstream of the
region encoding the zinc fingers. Injection of embryos with MO1 consistently
generates a phenotype that is indistinguishable in all respects from that
caused by the ATG-targeted MO (Fig.
2C, and data not shown).
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Molecular markers were analyzed to evaluate the stage of heart development affected by the loss of Gata4. The expression of Nkx2.5, an early marker for cardiogenic progenitors, is normal at 19.5 hours post-fertilization (hpf), indicating that the initial stages of cardiogenesis are intact, including formation of the cardiac cone and the subsequent extension of the heart tube (Fig. 3A,B). Chamber specification is also normal, as Amhc (an atrial marker) and Cmlc2 (an atrial and ventricular marker) are both expressed in the MO-injected embryos (Fig. 3C-F). By evaluating GFP expression in tie2:GFP transgenic fish injected with the Gata4 MO, we find that endocardium forms in the morphant embryos, including the establishment of cardiac cushions (see Fig. S2 in the supplementary material). However, the marker analysis reveals that between 2 and 3 dpf the shape of the heart tube becomes disturbed relative to that in control embryos. This late defect was also confirmed by watching morphogenetic changes in the heart tube of transgenic embryos that express GFP in cardiomyocytes (data not shown). Specifically, the more caudal presumptive atrial portion of the tube fails to make the appropriate rostral-anterior jogging movement, or to expand in size relative to the presumptive ventricular region. Therefore, at this stage the heart tube remains straight and uniformly thin, and by 4 dpf forms a distended heart string.
Organogenesis from the primordial gut tube requires Gata4
Similarly, we characterized the progression of endoderm development in
morphant embryos compared with controls. Early markers specific to endoderm,
including Sox17 and Foxa2, are expressed equivalently in control and morphant
embryos at 28 or 48 hpf (Fig.
4A), indicating that endoderm specification is normal in embryos
depleted for Gata4. However, at 4 dpf, expression of organ-specific markers
for differentiated intestine (I-fabp), liver (transferrin) or pancreas
(elastaseB) are either absent or significantly reduced in the morphant embryos
(Fig. 4B). The reproducible low
levels of transferrin led us to consider whether some limited tissue had in
fact differentiated in the morphant embryos. Therefore, control and morphant
embryos were analyzed for transferrin expression by in situ hybridization at
2, 3, 4 and 5 dpf. As shown in representative samples
(Fig. 4D,F,H,J), we
consistently find a small patch of transferrin-positive cells in morphant
embryos at the position of the liver bud by 2 dpf. However, this patch fails
to expand at subsequent stages, when compared with the control embryos. This
result suggests that, in embryos deficient for Gata4, the liver bud is
specified from the gut tube at the appropriate time and place, and that
specified hepatocytes can differentiate, but that the bud fails to grow and
expand in size, thus compromising organogenesis.
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At the highest morpholino concentration (5 ng), the embryos blocked for Gata6 expression undergo a developmental arrest starting around the 14-somite stage, which precludes analysis of gut development. However, embryos injected with a slightly lower amount (2.5 ng) of the Gata6 morpholino continue to develop beyond the heart tube defect stage. These embryos (because they continue embryonic development) presumably still express low levels of Gata6, although it is likely to be very low, as GFP expression from the gata6:GFP transgene is not evident. These embryos are markedly shorter than control embryos and display the same heart tube defects described above. When analyzed at 3 dpf, transferrin expression is variable, but it is always reduced when compared with control embryos, and in many cases it strongly resembles that of the Gata4 morphants (Fig. 7). Typically, transferrin expression marks a small liver bud, similar to that seen in the Gata4 morphants, except that it is sometimes misplaced to the right side, or else shows a more diffuse staining pattern in the region of the intestinal rod. Therefore, zebrafish Gata6, similar to mouse Gata6 and to zebrafish Gata4, is required for liver development. Using these same conditions, we next tested the effect of reducing both Gata4 and Gata6 by co-injection of morpholinos specific to each gene. In this case the results are very clear, in that there is a complete failure in the development of transferrin-positive liver buds (Fig. 7D). To determine whether this block to liver development is caused by an early endoderm defect, embryos injected with morpholinos targeting Gata4, Gata6, or both genes, were isolated at early stages and examined for the expression of early endoderm markers by semi-quantitative RT-PCR. At the shield stage, the Gata4, Gata6 and double morphants all express normal levels of the endoderm markers FoxA2 and Sox17, when compared with controls. Therefore, the complete block to liver development caused by the injection of both morpholinos cannot be explained by an early failure in endoderm specification.
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Discussion |
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Gata4/Gata5/Gata6 regulates organogenesis from the gut tube
An advantage of the zebrafish model is that embryos can survive a
cardiomyopathy, which facilitates the analysis of other phenotypes
(Heicklen-Klein et al., 2005).
In addition to the heart, we find that Gata4 is required for formation of the
intestine, liver, pancreas and swim bladder. Gata4/Gata5/Gata6 gene expression
has been previously associated with endoderm-derived organs, and mouse
knockout models showed specific functions for Gata4 in the foregut
(Kuo et al., 1997
;
Molkentin et al., 1997
) and
gastric (Jacobsen et al.,
2002
) epithelium, and for Gata6 in the visceral endoderm
(Morrisey et al., 1998
) and
lung epithelium (Yang et al.,
2002
). The zebrafish gata5 gene is also essential for gut
morphogenesis and liver development, based on the analysis of the
faust mutant (Reiter et al.,
1999
; Reiter et al.,
2001
), and depletion of Gata6 in Xenopus or zebrafish
endoderm appears to disrupt normal intestinal morphogenesis
(Peterkin et al., 2003
).
Therefore, all three of these Gata genes have essential non-redundant
functions in regulating organogenesis or differentiation of the gut. However,
it is not entirely clear which functions are conserved, and whether certain
functions are masked by redundancy, as the experiments have used various model
systems.
We find that, in zebrafish, Gata4 is required for both liver and pancreas
development. Gata4 was shown previously to be involved in the establishment of
albumin gene expression in murine liver progenitor cells
(Bossard and Zaret, 1998;
Cirillo et al., 2002
;
Zaret, 1999
), and to be
capable of trans-activating the expression of the glucagon gene
(Ritz-Laser et al., 2005
). The
defects seen in the Gata4 morphant embryos do not appear to be related to
specification or differentiation. Initial morphogenetic movements occur,
including intestinal tube looping to the left, and initial liver and
pancreatic budding. However, failure of intestinal bulb, liver and pancreas
growth is evident by 3-4 dpf, supported by the decreased levels of
differentiation markers. Previous work by Stainier and colleagues demonstrated
that vascularization is not required for liver development
(Field et al., 2003
). This, in
addition to the apparently normal trunk vasculature, indicates that the
phenotype is not secondary to a vasculature defect. It is interesting that the
endocrine pancreas initiates budding, as the specific defect in exocrine
pancrease development is consistent with the observation that, in the mouse,
Gata4 is expressed in the murine exocrine (but not endocrine) pancreas
(Ketola et al., 2004
).
Most recently, a requirement for Gata6 in liver development was documented
in the mouse, by analyzing embryos rescued for the requirement of Gata6 in
extra-embryonic endoderm by tetraploid embryo complementation
(Zhao et al., 2005). These
mutant embryos fail in liver bud expansion, although hepatic specification is
intact and the cells of the ventral hepatic endoderm are capable of
differentiation, based on RT-PCR analysis for liver-specific markers. This
phenotype is essentially identical to that of zebrafish embryos blocked for
expression of Gata4. We cannot definitively rule out that the small
transferrin-positive liver buds arise in the Gata4 morphant embryos as a
result of leakage of the block, because the embryos are not genetically null.
However, this seems unlikely, because when analyzed for transferrin expression
by in situ hybrdization, every morphant embryo develops the same sized small
bud, over a range of morpholino concentrations that appear to block completely
Gata4:GFP expression. Zhao et al. suggest that the mouse Gata6 phenotype might
result from a functional redundancy of Gata4 and Gata6 at the earlier stage of
hepatic specification. Our data supports this hypothesis, as injection of
morpholinos that inhibit the expression of both Gata4 and Gata6 completely
eliminates the liver bud and blocks liver-specific gene expression.
Furthermore, we show that the function of Gata6 in liver bud growth appears to
be conserved with mouse, and that both Gata4 and Gata6 have secondary
non-redundant functions for liver bud growth. Such a role for Gata4 in the
mouse was considered unlikely (Zhao et
al., 2005
), as Gata4 expression levels are reduced in hepatoblasts
at this stage; however, our results suggest that this should be functionally
investigated in the mouse.
Gata factors and early endoderm development
Early endoderm development appears to be normal in both the Gata4 and Gata6
morphants, based on the expression of early markers that are not specific to
defined organ systems. A recent study by Patient and colleagues
(Afouda et al., 2005) supports
a more general role for Gata4/Gata5/Gata6 genes in the specification of early
endoderm, in response to TGFß signaling during germ layer patterning. The
specific defects that we describe here were not noted by Afouda et al., when
using a morpholino to target Xenopus Gata4. It is difficult to
compare the experiments, as the Xenopus genome encodes two distinct
Gata4 alleles (Jiang and Evans,
1996
), which are difficult to target with a single MO (A.H. and
T.E., unpublished). Therefore, Xenopus Gata4 might have been only
partially targeted, or Xenopus may be better compensated, with
respect to organogenesis, by Gata5 and/or Gata6 than zebrafish. We show that
depletion of both Gata4 and Gata6 is not sufficient to eliminate the
expression of early endoderm markers. Although our analysis was limited to a
few genes, these have been considered to be reliable markers of endoderm
specification. Unlike the Gata4 or Gata6 morphants, loss of Gata5 in the
faust embryo is sufficient to show a significant loss of early
endoderm (Reiter et al.,
2001
). Therefore, if Gata4 and/or Gata6 do regulate endoderm
specification, Gata5 is likely to compensate for their loss.
However, our analysis shows that Gata4 and Gata6 have distinct essential
functions in both heart and gut development. The cardiac phenotype for each
morphant is unique, and the double morphant indicates a lack of functional
redundancy and an earlier morphogenetic function for Gata6 than for Gata4. At
the highest doses of Gata6 morpholino, presumed to be the most similar to a
null allele, there is a developmental arrest that precludes analysis of the
gut endoderm, although it does not block the expression of the early endoderm
markers. At slightly lower doses, the embryos continue to grow and, although
the liver fails to develop, the phenotype is similar but not identical to that
of the Gata4 morphant. Much like the heart phenotype, it is variable and the
transferrin-expressing cells are often misplaced from the normal site of liver
budding. This is in contrast to the Gata4 morphant. However, depletion of both
genes demonstrates a functional redundancy with respect to the earliest stages
of liver budding and differentiation. In summary, there are likely to be
overlapping (redundant) functions for Gata4/Gata5/Gata6 during endoderm
specification, and both redundant and non-overlapping (non-redundant)
functions with respect to specific organ systems at later stages. There is
also an essential and redundant role for Gata factors during mesendoderm
specification in C. elegans
(Maduro et al., 2001;
Maduro and Rothman, 2002
;
Zhu et al., 1997
). The fact
that Gata4 functions in diverse organ systems, including the heart, liver and
pancreas, may be related to the common embryonic origins of heart and gut
tubes from mesendoderm. With respect to the early Gata factor network, we find
that, in zebrafish, Gata4 is not required for maintaining the expression of
its own gene, or that of Gata5 or Gata6, but that it negatively regulates both
itself and Gata5.
Novel functions for Gata4 revealed by the fish model
The swim bladder also fails to develop in the Gata4 morphant embryo, and
although this could be caused by a number of direct or indirect mechanisms
(McCune and Carlson, 2004), in
this case it is probably related to a general failure of endoderm-derived
organogenesis. In addition to its roles in heart and gut organogenesis, our
experiments reveal functions for Gata4 in tail mesoderm and hematopoiesis.
Gata4 morphant embryos develop with a kink at a specific position of the
caudal tail. Although the significance of this is not known, we note that
Gata4 is expressed in the posterior tail bud mesoderm by the 10-somite stage
(Griffin et al., 2000
;
Heicklen-Klein and Evans,
2004
). The failure in blood development occurs around 3-4 days of
development, coinciding with the anticipated contribution of the definitive
`adult' stage of hematopoiesis, which replaces the transient `embryonic' or
yolk sac population (Davidson and Zon,
2004
). This might not have been noticed in the Gata4
knockout mouse model, as the mutant embryos die before the emergence of the
definitive lineage. Because Gata4 is not known to be expressed in
hematopoietic cells, it seems likely that the defect in definitive
erythropoiesis is secondary to the lack of an appropriate inductive signal. An
excellent candidate source is the liver, which fails to develop at this stage
in the morphant embryos, and is a possible source of erythropoietin. Indeed,
Gata4 regulates the expression of the Epo gene in mouse hepatocytes
(Dame et al., 2004
). The
availability of a zebrafish loss-of-function model for Gata4 will facilitate
further investigation of these issues, and should stimulate additional efforts
to determine conserved functions in other model systems, including
mammals.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/132/17/4005/DC1
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