1 McLaughlin Research Institute, 1520 23rd Street South, Great Falls, MT 59405,
USA
2 INSERM 129, ICGM, F-75014 Paris, France
* Author for correspondence (e-mail: pxu{at}po.mri.montana.edu)
Accepted 4 April 2003
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SUMMARY |
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Key words: Six1, Kidney development, Eya1, Pax2, Six2, Sall1, Metanephric mesenchyme, Apoptosis, Gdnf, Mouse
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INTRODUCTION |
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It has been shown that without the metanephric mesenchyme, neither the
collecting system nor the nephrons can form
(Ashley and Mostofi, 1960).
Thus, the formation of a functional metanephric mesenchyme is required for
normal renal development. Gene inactivation and in situ hybridization
experiments have recently implicated several transcription factors in a role
in mediating the formation of the metanephric mesenchyme. The Foxc1
gene, which encodes a winged helix protein, has been shown to play a role in
positioning the mesenchyme, because in Foxc1-/- mice, the
metanephric mesenchymes form unusually far anteriorly, which causes the ureter
to grow too anteriorly or to form more than one ureter
(Kume et al., 2000
). The
homeobox gene Lim1 is expressed in the intermediate mesoderm from its
inception and has been shown to be required for all kidneys
(Tsang et al., 2000
). The
paired box gene Pax2 is expressed in the intermediate mesoderm from
E8.5 and in the metanephric mesenchyme, Wolffian duct and ureteric bud at
E10.5 (Torres et al., 1995
).
Pax2-/- mice fail to form any kidneys and there is no
ureteric bud, although the metanephric mesenchyme can be observed
morphologically (Torres et al.,
1995
; Brophy et al.,
2001
). Recent studies have shown that the absence of Pax2
causes Gdnf expression to be lost from the metanephric mesenchyme,
and Pax2 regulates Gdnf transcription in vitro
(Brophy et al., 2001
). The eyes
absent 1 (Eya1) gene, which encodes a transcriptional coactivator, is
only expressed in the metanephric mesenchyme and Eya1-/-
mice show renal agenesis and their posterior intermediate mesoderm fails to
produce Gdnf (Xu et al., 1999
;
Buller et al., 2001
).
Sall1, which encodes a zinc finger protein, is also expressed in the
metanephric mesenchyme and Sall1-/- mice show the failure
of tubule formation because of the incomplete ureteric bud outgrowth
(Nishinakamura et al., 2001
).
The transcription factor Wt1 is first expressed in the metanephric mesenchyme
before induction, and in Wt1-knockout mice the ureteric bud fails to
grow out of the Wolffian duct and the metanephric mesenchyme subsequently
apoptoses, leading to a complete failure of kidney development
(Kreidberg et al., 1993
).
However, how these regulatory genes function and whether they interact during
early metanephric induction is unclear. In addition, the molecular pathway
controlling the formation of metanephric mesenchyme is not established.
The glial-derived neurotrophic factor (Gdnf) has been identified as a
mesenchyme-derived signal that acts on the receptor tyrosine kinase (Ret) and
Gfr1 coreceptor which are distributed in the ureteric epithelium and
induces it to produce a ureteric bud which invades the metanephric mesenchyme
(Sainio et al., 1997
;
Saarma and Sariola, 1999
).
Indeed, the null mutants of Gdnf, c-Ret and
Gfr
1 show similar perturbation of ureteric bud
outgrowth (Schuchardt et al.,
1994
; Moore et al.,
1996
; Pichel et al.,
1996
; Sanchez et al.,
1996
; Cacalano et al.,
1998
). Despite the importance of Gdnf and its receptors c-Ret and
Gfr
1 as inductive signals in early kidney morphogenesis, exactly how
this signal transduction pathway regulates the development of the ureteric bud
and the mechanisms controlling the expression of Gdnf in the
mesenchyme are not well understood.
The Six1 gene is homologous to Drosophila sine oculis
(so) gene, an early regulator for Drosophila eye formation
(Cheyette et al., 1994;
Serikaku and O'Tousa, 1994
).
In Drosophila, so functions synergistically with the fly
Pax6 gene eyeless (ey), eyes absent
(eya) and dachshund (dac) to regulate the eye
morphogenesis (reviewed by Treisman,
1999
). The mammalian Six gene family consists of six members
(Six1-6) which share two highly conserved domains, a homeodomain (HD)
and a specific Six-domain (SD) crucial for protein-protein interaction
(Kawakami et al., 1996
;
Chen et al., 1997
;
Pignoni et al., 1997
). Besides
the eye, the Six genes are widely coexpressed with Pax, Eya and Dach (the
mammalian Dachshund) genes in many tissues during mammalian
organogenesis, suggesting possible interaction between their gene products and
the existence of a conserved Pax-Eya-Six regulatory
hierarchy (Oliver et al.,
1995a
; Oliver et al.,
1995b
; Xu et al.,
1997a
; Xu et al.,
1997b
; Xu et al.,
1999
; Xu et al.,
2002
). In early mammalian kidney development, Six2 is
expressed in the metanephric mesenchyme before and after induction of kidney
organogenesis and its expression in the metanephric mesenchyme is
Eya1-dependent (Xu et al.,
1999
).
Similarly, we have recently found that Six1 is also expressed in the metanephric mesenchyme before and after induction. However, the function of Six genes during kidney development has not been established.
We have recently generated Six1 null mutant mice and the mice die
at birth because of malformations in several organs
(Xu et al., 2002;
Laclef et al., 2003
). We have
now examined the role of Six1 during early kidney development.
Six1 is expressed in the uninduced and induced metanephric mesenchyme
and Six1-/- embryos lack kidneys because of a failure of
metanephric induction. Our analyses show that the epistatic relationship
between Pax, Eya and Six in the metanephric mesenchyme during early kidney
development is distinct from a genetic pathway elucidated in the
Drosophila eye imaginal disc. Furthermore, our results show that
Six1 is also required for the expression of Six2 and
Sall1 in the metanephric mesenchyme. These analyses indicate that
Pax2, Eya1, Six1, Six2 and Sall1 function in a molecular and
genetic pathway during early kidney development, suggesting a role for
Six1 in the establishment of the inductive capacity of the
metanephric mesenchyme.
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MATERIALS AND METHODS |
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Genotyping of mice and embryos was performed as described
(Torres et al., 1995;
Xu et al., 1999
;
Xu et al., 2002
).
Phenotype analyses and in situ hybridization
Embryos for histology and in situ hybridization were dissected out in PBS
and fixed with 4% paraformaldehyde at 4°C overnight. Embryonic membranes
were saved in DNA isolation buffer for genotyping. Histology was performed as
described (Xu et al., 1999).
To visualize Six1lacZ expression, mutant embryos were
stained with X-gal and sectioned as described
(Xu et al., 2002
).
For in situ hybridization, we used four wild type or mutant embryos at each
stage for each probe as described (Xu et
al., 1997a).
TUNEL analysis
We performed TUNEL assay for detecting apoptotic cell death using the
ApopTag detection kit (Intergen). We used six wild type or mutant embryos for
this assay.
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RESULTS |
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|
|
Six1 is required for the expression of Pax2 and
Six2 in the metanephric mesenchyme
To determine the molecular defects in early kidney development of
Six1-/- animals, we first examined whether the expression
of the Pax and Eya gene families depends upon Six1. Studies in
Drosophila indicate that eya is epistatic to so and
both genes reside within the same genetic and molecular pathway downstream of
the Pax6 gene ey (Halder
et al., 1998). In the kidney, Pax2, Eya1 and
Six1 expression overlaps in the metanephric mesenchyme and all three
mutants lack kidney formation (Torres et
al., 1995
; Xu et al.,
1999
). To determine whether the Drosophila
Pax-Eya-Six regulatory hierarchy is conserved during
mammalian kidney development, we analyzed whether the expression of
Pax2 or Eya1 is Six1-independent. The paired box
gene Pax2 is normally expressed in the intermediate mesoderm before
the formation of metanephric mesenchyme, in uninduced and induced metanephric
mesenchyme, Wolffian duct and ureteric epithelium
(Torres et al., 1995
;
Brophy et al., 2001
). In
Six1-/- embryos, no significant difference of
Pax2 expression in the intermediate mesoderm, Wolffian duct and
ureteric epithelium was observed at E9.0-10.5
(Fig. 3A-D). However,
Pax2 expression was absent from Six1-/-
metanephric mesenchyme at E10.5 (arrows,
Fig. 3D). Eya1 is
normally expressed in the metanephric mesenchyme before and after induction
(Xu et al., 1999
). In
Six1-/- embryos at E10.5, the expression of Eya1
in the metanephric mesenchyme was observed at normal levels
(Fig. 3E,F). Because recent
studies demonstrated that Pax2 expression in the uninduced mesenchyme
is independent of induction by the ureteric bud
(Brophy et al., 2001
), these
results indicate that Six1 is required for the expression of
Pax2, but not Eya1 in the metanephric mesenchyme before
induction.
|
Six1 is also required for the expression of Sall1
in the metanephric mesenchyme
We next analyzed the expression of several other well-characterized
molecular markers in metanephric mesenchyme at E10.5 and 11.5. Bmp4,
a member of the Tgfß superfamily of secreted signals, is
expressed in the mesenchymal cells surrounding the Wolffian duct and ureteric
stalk (Fig. 4A) and has been
implicated in regulating ureteric bud growth and branching
(Miyazaki et al., 2000;
Raatikainen-Ahokas et al.,
2000
). Bmp4+/- mutant mice show kidney defects
that are caused by the misregulated development of the ureteric bud
(Miyazaki et al., 2000
). Bmp4
protein has also been shown to regulate genes that are expressed by both the
ureteric bud and the mesenchyme, including Gdnf in organ culture
(Miyazaki et al., 2000
;
Raatikainen-Ahokas et al.,
2000
). No significant difference of Bmp4 expression was
observed between wild type and Six1-/- mesenchyme at E10.5
(Fig. 4A,B), indicating that
Six1 is not required for the expression of Bmp4 during early
kidney development. Bmp7, another member of the Tgfß
superfamily, has been proposed to function as a survival signal that prevents
mesenchymal cells from undergoing apoptosis during kidney development (Dudley
et al., 1999; Reddi, 2000
;
Al-Awqati and Oliver, 2002
).
Bmp7 is normally expressed in the metanephric mesenchyme and ureteric
epithelium and its expression level was unaffected in both structures in
Six1-/- embryos at E10.5
(Fig. 4C,D). However, its
expression domain in Six1-/- metanephric mesenchyme is
reduced in size (Fig. 4D).
Wt1 is expressed in the metanephric mesenchyme and its absence leads
to failure of mesenchymal induction
(Kreidberg et al., 1993
). In
E10.5 Six1-/- embryos, although the expression level of
Wt1 in the mesenchyme is normal, its expression domain became smaller
than that in wild-type embryos (Fig.
4E,F). Sall1, which encodes a zinc finger protein, is
expressed in the kidney mesenchyme (Fig.
4G) and its inactivation in mice leads to incomplete ureteric bud
growth and failure of tubule formation
(Nishinakamura et al., 2001
),
similar to that seen in Six1-/- animals. Interestingly,
Sall1 expression in Six1-/- metanephric
mesenchyme was reduced to background level at E10.5-11.5 (arrows,
Fig. 4H), indicating that
Sall1 expression in the mesenchyme is Six1-dependent.
|
Our results also show that both Pax2 and Bmp7 expression
in the ureteric epithelium was unaffected in Six1-/-
embryos (Fig. 3C,D and
Fig. 4C,D). To determine
whether the failure of kidney development in Six1-/- mice
is also caused by a defect in the ureteric epithelium, we next examined
several other epithelial factors that are known to be important for early
kidney formation, including c-Ret, Gfr1 and Lim1. Our results show that
the expression of these markers in the ureteric bud epithelium was also
unaffected in the absence of Six1 (data not shown).
Eya1, Six1 and Sall1 expression in the
metanephric mesenchyme is Pax2 -independent
To further clarify the genetic relationship between Pax, Eya, Six and
Sall1 in the metanephric mesenchyme during early kidney development,
we next examined the expression of Sall1, Eya1 and Six1 in
Pax2-/- embryos. Pax2 mutant mice do not have a
ureteric bud, however the metanephric mesenchyme can be observed
morphologically (Torres et al.,
1995; Brophy et al.,
2001
). As shown in Fig.
5, the expression levels of all three genes in the metanephric
mesenchyme were unaffected in Pax2-/- embryos at E10.5.
This result is consistent with previous observation that Six2
expression was also unaffected in Pax2-/- mesenchyme at
E10.5 (Torres et al., 1995
).
In addition, similar to the expression of Six2 in
Eya1-/- embryos at E10.5
(Xu et al., 1999
),
Six1 expression was also reduced to background level in
Eya1-/- mesenchyme at E10.5
(Fig. 5G,H). These results
together with previous observations further indicate that Eya1, Six1
and Six2 function upstream of Pax2 in the metanephric
mesenchyme during early kidney development. Therefore, the genetic
relationship between these genes in the metanephric mesenchyme before
induction differs from that observed in Drosophila eye imaginal
disc.
|
|
|
Six1-/- metanephric mesenchyme is incompetent for
tubulogenesis in organ culture
To further demonstrate that kidney development is arrested at the initial
step in Six1-/- embryos, kidney rudiments were isolated
from Six1-/- embryos at E11.0 and cultured in vitro. Five
days after culture, all wild type or heterozygous rudiments developed into a
fully branched kidney structure showing strong Pax2 expression
(n=5 and n=10, respectively;
Fig. 7A). In contrast,
Six1-/- kidney rudiments formed no kidneys (n=6,
Fig. 7B). We next examined
whether Six1 mutant mesenchyme could respond to inductive signals by
culturing E11.0 Six1-/- mesenchyme with wild type or
heterozygous spinal cord. Five days after culture, 100% (11/11) of the
Six1+/- mesenchymal cultures exhibited characteristic
tubules showing Pax2 mRNA expression
(Fig. 7C). In contrast, none of
the Six1-/- mesenchymes (0/6) exhibited any sign of tubule
formation (Fig. 7D). The
Six1-/- mesenchyme left in the cultures showed no
expression of Pax2 (arrow, Fig.
7D). Pax2 mRNA expression was detected in the spinal
cord, which was used as a heterologous inducer. Thus, Six1 mutant
mesenchyme was unresponsive to inductive signals.
|
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DISCUSSION |
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The formation of mammalian kidney involves three distinct processes: first,
establishment of the metanephric mesenchyme from posterior intermediate
mesoderm; second, outgrowth and branching of the ureteric bud; and third,
transformation and differentiation of the metanephric mesenchyme to renal
epithelial cells. Our data indicate that in the absence of Six1,
kidney development was arrested at the second step of these three processes.
Although the ureteric bud is present in Six1-/- embryos,
it fails to invade the mesenchyme completely and the mesenchymal cells undergo
abnormal apoptosis from E11.5. Subsequent branching morphogenesis of the
ureteric bud and tubule differentiation in the mesenchyme do not occur. It is
known that Gdnf and its receptors, c-Ret and Gfr1, are essential for
normal growth and branching morphogenesis of the ureteric bud during kidney
development. Indeed, Gdnf can function as a chemoattractant for Ret-expressing
epithelial cells and stimulate branching morphogenesis of the ureteric bud
(Vega et al., 1996
;
Tang et al., 1998
). Consistent
with the observation that the ureteric bud has formed in
Six1-/- animals, we have detected Gdnf expression
in Six1-/- metanephric mesenchyme. This result
demonstrates that the initial expression of Gdnf at mRNA level does
not require Six1. Although we were unable to directly determine
whether GDNF protein is produced by Six1-/- metanephric
mesenchyme, our results demonstrate that whatever amount is made in
Six1-/- embryos, is insufficient to ensure invasion of the
ureteric bud into the metanephric mesenchyme. This evidence also suggests that
some other factors that are under the control of a Six1-regulatory
pathway may be important for fully supporting ureteric bud invasion of the
metanephric mesenchyme. They could be, for example, cell atrix components that
mediate interaction between the epithelium and mesenchyme. Further expression
studies in Six1 mutant embryos are required to test this
hypothesis.
In the mammalian kidney, Pax2, Eya1, Six1 and Six2
expression overlaps in the metanephric mesenchyme and the null mutants of
Pax2, Eya1 and Six1 lack kidney formation
(Torres et al., 1995;
Xu et al., 1999
). Because
Pax2 expression in the intermediate mesoderm was unaffected in
Eya1-/- embryos at E9.5 and Six2 expression was
lost in Eya1-/- metanephric mesenchyme at E10.5, we
previously suggested that the Drosophila
Pax-Eya-Six regulatory hierarchy has been conserved in
mammalian kidney development (Xu et al.,
1999
). Although we previously did not detect Pax2
expression in Eya1-/- metanephric mesenchyme at E10.5, we
concluded that it was because of deficient ureteric bud outgrowth and failure
of metanephric induction. This interpretation was based on previous analyses
in Danforths' Short tail (Sd) mutants suggesting that
Pax2 expression in the metanephric mesenchyme requires inductive
interaction between the mesenchyme and the ureteric bud
(Phelps and Dressler, 1993
).
However, recent expression studies in Ret mutants have demonstrated
that Pax2 is expressed in the metanephric mesenchyme before induction
and its expression in the mesenchyme is independent of ureteric bud outgrowth
(Brophy et al., 2001
). Here we
show that during mouse kidney development, Pax2 expression in the
metanephric mesenchyme before induction is Eya1- and
Six1-dependent. Consistent with our observation, it has been
previously shown that Six2 expression is also preserved in
Pax2-/- mesenchyme
(Torres et al., 1995
). In
contrast, we have found that Six1 expression in the mesenchyme was
lost in Eya1-/- embryos, similar to that of Six2
(Xu et al., 1999
).
Interestingly, we have found that Six2 expression in the metanephric
mesenchyme is also Six1-dependent. Therefore, our results together
with previous observations suggest that there is an
Eya1-Six-Pax2 regulatory hierarchy controlling early
mammalian kidney development, distinct from the Pax-Eya-Six
regulatory pathway elucidated in Drosophila eye imaginal disc.
Detailed examination of kidneys in Pax2/Six1 or
Eya1/Six1/Pax2 compound knockouts will enhance our understanding of
the possible molecular and genetic interactions between these transcription
factors during early mammalian kidney morphogenesis.
Pax2 has recently been proposed to be a direct positive regulator
of Gdnf, because Pax2-/- embryos do not express
Gdnf in the uninduced mesenchyme and Pax2 regulates the
expression of Gdnf in vitro
(Brophy et al., 2001). However,
our result shows that Pax2 is not required for the expression of
Gdnf in the metanephric mesenchyme. We propose two hypotheses to
explain these observations. First, because Pax2 expression in the
intermediate mesoderm was unaffected in Six1-/- embryos,
we hypothesize that Pax2 expression in the posterior intermediate
mesoderm is required for the initiation of Gdnf expression during the
specification of metanephric mesenchyme. Once Gdnf is turned on in
the mesenchyme, Pax2 expression in the mesenchyme may not be required
for the maintenance of Gdnf expression as metanephric development
proceeds. This could explain why Gdnf expression was absent in
Pax2-/- embryos. Consistent with this hypothesis,
Gdnf expression was also observed in Wt1-/-
metanephric mesenchymes which do not express Pax2 protein, although
Pax2 mRNA expression was observed in Wt1-/-
metanephric mesenchyme (Kreidberg et al.,
1993
; Donovan et al.,
1999
). Second, because Pax2 is expressed normally in the
Wolffian duct and ureteric bud in Six1-/- embryos, it is
possible that the expression of Pax2 in the Wolffian duct and ureteric bud
epithelium is required for the maintenance of Gdnf expression in the
mesenchyme. This could also explain the reduction of Gdnf expression
observed in Pax2-/- metanephric mesenchyme. In support of
this hypothesis, a greatly reduced level of Gdnf mRNA in the
metanephric mesenchyme at E11.5 has also been seen in mice defective for
Emx2, a homeobox gene expressed primarily in the ureteric bud, whose
disruption inhibits ureteric bud growth and branching
(Miyamoto et al., 1997
).
Interestingly, Pax2 expression was also significantly reduced in
Emx2-/- ureteric bud at E11.5, whereas its expression in
Emx2-/- metanephric mesenchyme was apparently normal at
this stage (Miyamoto et al.,
1997
).
Our results also show that Sall1 functions downstream of Six1. Sall1 is a mammalian homolog of the Drosophila region-specific homeotic gene spalt (sal). Inactivation of murine Sall1 results in renal agenesis or severe dysgenesis because of incomplete ureteric bud outgrowth and the failure of tubule formation, similar to that seen in Six1-/- embryos. It has been shown previously that Gdnf, Eya1, Pax2 and Wt1 are expressed in Sall1-/- metanephric mesenchyme at E10.5, indicating that Sall1 may function downstream of or independent from these genes. Because our results show that Sall1 expression is also unaffected in E10.5 Pax2-/- metanephric mesenchyme, it is possible that Sall1 and Pax2 function in parallel during early kidney development. Heterozygous mutations in the human SALL1 lead to Townes-Brocks syndrome, which shows phenotypic overlap with Branchio-Oto-Renal (BOR) syndrome, a deficiency for the human EYA1 gene. Interestingly, Sall1 expression was also undetectable in Eya1-/- mesenchyme (data not shown). Therefore, it is probable that Eya1, Six1, Six2, Pax2 and Sall1 function in a genetic and molecular pathway in the metanephric mesenchyme during early kidney morphogenesis.
Wt1 is also expressed in the metanephric mesenchyme and its
absence leads to failure of ureteric bud outgrowth and apoptosis of the
mesenchyme. Our results show that Six1 is not required for the
expression of Wt1. It has been shown previously that Six2 is
expressed in Wt1-/- metanephric mesenchyme
(Donovan et al., 1999) and
Wt1 is expressed in Eya1-/- mesenchyme
(Xu et al., 1999
). Thus, it is
possible that Wt1 functions in a pathway independent from
Eya1 and Six genes for metanephric development. It is also possible
that Wt1 functions in parallel or synergistically with Eya1
and Six genes for metanephric development.
Finally, it should be noted that during late embryonic mouse kidney
development, Six1 expression was only observed in collecting tubules,
but not in renal epithelia which are derived from metanephric mesenchyme.
Although it is generally accepted that metanephric mesenchyme is committed to
differentiating into nephrons whereas the ureteric bud is restricted to
forming the renal collecting system, several in vitro cell fate studies
demonstrated that metanephric mesenchyme differentiates into portions of the
renal collecting system, in addition to nephron epithelia
(Koseki et al., 1991;
Herzlinger et al., 1992
;
Qiao et al., 1995
). The
observation of Six1 expression in a subpopulation of collecting
tubule epithelial cells during kidney development is consistent with this
finding. Therefore, it is possible that the Six1-expressing
metanephric mesenchymal cells at E11.5 are pluripotent renal epithelial stem
cells and a subpopulation of those cells are recruited into collecting tubule
epithelia during renal collecting system morphogenesis. Our results indicate
that in addition to its early function in the initiation of mammalian kidney
development, Six1 may also play a role in the morphogenesis of the
renal collecting system.
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ACKNOWLEDGMENTS |
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