1 Johannes-Müller-Institut für Physiologie, Medizinische Fakultät
(Charité), Humboldt-Universität Berlin, Germany
2 University of Nice, INSERM U470, 06108 Nice, France
* Author for correspondence (e-mail: schedl{at}unice.fr)
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Summary |
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Key words: Splice-specific functions, Glomerulosclerosis, Knockout mouse models, Frasier syndrome, Denys-Drash syndrome, Sex determination
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Introduction |
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The complexity of WT1 action during development is also reflected on the
molecular level. Post-transcriptional modifications of the Wt1
pre-mRNA lead to the production of up to 24 different isoforms, which seem to
serve distinct but also overlapping cellular and developmental functions.
Here, we examine the roles of these various isoforms and highlight recent
advances in our understanding of WT1 function in development, focusing
particularly on gonad formation and sex determination. We also draw attention
to open questions, which should be addressed in future experiments. Owing to
space limitations, we do not discuss WT1 function in cancer, and interested
readers are referred to other more specialized reviews (e.g.
Loeb and Sukumar, 2002;
Scharnhorst et al., 2001
).
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WT1 and embryonic development: an update |
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Given the variety of organs WT1 seems to be required for, is there a common theme in the action of WT1 during development? We still don't know the answer to this question. What is striking, however, is that many organs, including the gonads, kidneys, spleen and the retina, show a dramatic increase in apoptotic activity in Wt1-/- knockout mice. Whether this is due to a lack of repression of apoptotic genes, lack of activation of anti-apoptotic genes or is simply a reaction of the organ to abnormal cellular differentiation remains to be elucidated.
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Additional roles for WT1 in adult life |
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What are the consequences of these studies for human patients? The finding
that heterozygous knockout mice develop renal failure suggests that a similar
process may occur in patients who have heterozygous mutations in WT1.
This has been demonstrated in a large cohort study of patients with Wilms'
tumours (Breslow et al., 2000).
The risk for development of renal failure 20 years after initial diagnosis is
significantly higher in WAGR patients missing one WT1 allele (38%),
than in patients with unilateral Wilms' tumour without WT1 germ line
mutations (1%). Hence, patients who have deletions or mutations should be
carefully monitored throughout life. The availability of a mouse model may
also allow us to investigate the molecular mechanisms occurring during
WT1-dependent mesangial sclerosis and develop therapies for it.
Although expression in kidneys is maintained throughout life, the situation
in the heart is somewhat different. During development, WT1 is expressed in
the subepicardial layer of this organ, but then gets switched off and is
absent in adult heart. Hypoxia and ischemia, however, seem to stimulate WT1
expression in the heart with de novo expression in smooth muscle and
endothelial cells of the coronary arteries after myocardial infarction and
after normobaric hypoxia (Wagner et al.,
2002a). WT1 co-localizes with cell proliferation markers and
vascular endothelial growth factor (VEGF) in ischemic and hypoxic hearts.
Since proliferation of vascular endothelial and smooth muscle cells is a
critical step in the formation of collaterals from pre-existing coronary
vessels, WT1 might have a role in the proliferation of coronary vascular cells
and thereby in the neovascularization process in the heart. This idea is
supported by a study by Natoli et al., which describes a disturbed capillary
development in the kidney when WT1 levels are reduced
(Natoli et al., 2002a
). The
molecular signals underlying the activation of WT1 expression during hypoxia
and ischemia in the heart remain to be determined.
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Multifunctionality through protein variety |
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RNA editing has been observed in human, rat and mouse WT1 RNA. The
proportion of edited RNA observed, however, varied in different studies, and
the relevance of this RNA modification remains to be seen. Similarly, we know
very little about isoforms produced from alternative translation start sites,
which generate proteins with longer or shorter N termini
(Bruening and Pelletier, 1996;
Scharnhorst et al., 1999
). The
amount of these variants seems, however, relatively small compared with that
produced from the major ATG in all tissues analysed so far. Moreover, the
effect of the different N termini on the transcriptional activation/repression
activity of WT1 is not dramatic, and it remains to be seen whether these
isoforms fulfil an important function in vivo or just represent evolutionary
remnants.
Much more data are available on the function of the alternatively spliced
isoforms and, given the importance of WT1 in development and disease, they
merit a closer examination. There are two alternatively spliced exons in WT1:
exon 5 and exon 9. Exon 5, which is mammal specific, encodes 17 amino acids
that are included or omitted between the Pro/Glu-rich N-terminus and the Zn
finger domain. Exon 9 possesses two alternative splice donor sites. Usage of
donor site 1 results in omission, and that of donor site 2 in inclusion, of a
KTS sequence between the third and fourth zinc finger. Consequently, isoforms
lacking the KTS sequence are often referred to as WT1(-KTS), whereas those
containing this are called WT1(+KTS). The ratio between WT1(+KTS) and
WT1(-KTS) proteins is nearly constant in all cell types, whereas the ratio of
exon 5 splice variants differs between cell types, species and developmental
stages (Pritchard Jones and Renshaw,
1997). Interestingly, mutations interfering with the ratio of
WT1(+KTS) and WT1(-KTS) proteins lead to Frasier syndrome in humans,
indicating the importance of the ratio of these variants (see below).
Biochemical and genetic analysis has given some insights into the functions
of the alternatively spliced protein variants. Exon 5 contains a
protein-protein interaction domain, which permits association with prostate
apoptosis response factor 4 (Par4)
(Richard et al., 2001). On a
cellular level, this interaction seems to be important, because only exon 5
containing isoforms of WT1 can overcome a UV-induced apoptotic signal, when
transfected into HEK293 cells. The ratio between WT1 variants containing and
lacking exon 5 seems to vary, which further suggests a modulating role of this
alternative exon. The presence of exon 5 only in mammals, upregulation in the
uterine embryonic implantation site (Zhou
et al., 1993
), and expression in the adult mammary glands
(Silberstein et al., 1997
)
suggested this isoform has a role in mammal-specific functions (i.e. embryonic
implantation and lactation). Furthermore, the presence/absence of exon 5 might
modify the function of the WT1 protein when additional mutations exist. Natoli
et al. expressed various variants of WT1 in the developing nephron
ectopically, by using the nephrin promoter
(Natoli et al., 2002a
). In
mice expressing a Wt1 cDNA with a deletion of the third and fourth
zinc finger, no influence on mouse renal development and function could be
detected when the construct contained exon 5. However, when exon 5 was also
missing, the mice showed poor postnatal survival, and glomerular abnormalities
with a reduced number of glomerular capillaries that were dilated. In these
animals, expression of platelet endothelial cell adhesion molecule 1 (PECAM-1)
is greatly reduced on glomerular endothelial cells, suggesting a role of WT1
in vasculogenesis during kidney development. Surprisingly, exon 5 function
during normal development seems to be much more obscure: Natoli et al. found
out that mice carrying a deletion of exon 5 have no developmental defects and
are fertile (Natoli et al.,
2002b
). Unfortunately, their study did not include mutations that
interfere with the production of WT1 +exon 5 variants only, which may have
given additional clues to the function of this alternative splicing event. At
the moment, we can only conclude that exon 5 does not seem to represent a
major modifier of WT1 function. More subtle defects might be discovered in
long-term studies of genetically modified mice or its function might become
apparent only in a diseased state.
Much more studied, but in many ways even more mysterious, are the WT1 (KTS)
splice variants produced by alternative splicing of exon 9. A myriad of
studies have demonstrated that WT1 (-KTS) variants act as transcriptional
regulators that have activating and repressing capabilities depending on
promoter, cell type and cell cycle stage. WT1 (+KTS) products, however, show a
distinct nuclear staining (Larsson et al.,
1995; Englert et al.,
1995
) and co-purify and interact with splicing machinery
(Davies et al., 1998
). The
distinct nuclear localization of WT1 (+KTS) variants was recently confirmed in
vivo in mice producing only one of the alternatively spliced products
(Hammes et al., 2001
). Since
WT1(+KTS) also seems to have a much higher affinity for RNA than DNA
(Caricasole et al., 1996
;
Laity et al., 2000
), this
variant might play a role in RNA processing. Indeed, WT1(+KTS) isoforms
co-purify with the active component of splicing extracts
(Ladomery et al., 1999
), and
WTAP, a protein that interacts with WT1, has a homologue in
Drosophila that functions in splicing during sex determination
(Hastie, 2001
;
Ortega et al., 2003
).
Unfortunately, apart from this circumstantial evidence, we do not have any
direct proof for a role of WT1 in splicing.
Recent work has described specific in vivo functions of the different WT1
splice variants in embryonic development. Hammes et al. generated mouse
strains that specifically lack the WT1(-KTS) or WT1(+KTS) splice variant
(Hammes et al., 2001).
Homozygous mice of both strains survive until birth, indicating that these
different splice variants are functionally redundant in cardiac development.
Postnatally, the phenotypes differ: more severe defects are found in mice
lacking the WT1(-KTS) variant. These animals display hypoplastic kidneys and
streak gonads with an increased number of apoptotic cells in the gonads during
embryonic development, indicating that the WT1(-KTS) variant is required for
the survival of embryonic kidneys and gonads. Homozygous animals lacking the
WT1(+KTS) variant also die soon after birth, owing to renal failure, but the
phenotype seems to be caused by a lack of podocyte differentiation. In
addition, gonads develop as ovaries in both XX and XY animals owing to reduced
expression levels of Sry, a gene essential for the initiation of male
development (see below). Heterozygous animals develop normally but,
interestingly, mice that have reduced levels of WT1(+KTS) variants die after
several months owing to renal insufficiency caused by focal segmental
glomerular sclerosis combined with diffuse mesangial sclerosis. Hammes et al.
have thus proposed that the WT1(+KTS) isoforms are more important for
maintenance of podocyte function (Hammes
et al., 2001
). The mice lacking the WT1(+KTS) variants represent a
good model for the human Frasier syndrome, which is characterised by reduced
levels of the WT1(+KTS) variants due to mutations in the splice donor site of
WT1 exon 9, the development of renal insufficiency with focal and
segmental glomerulosclerosis and male-to-female sex reversal
(Barbaux et al., 1997
;
Klamt et al., 1998
). Further
analysis of this mouse model may help us to understand the molecular processes
leading to the development of the human syndrome.
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WT1 and sex determination: at the heart of a complex network |
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In the mouse, gonads form at E9.5 through proliferation of the coelomic epithelium overlying the mesonephros. At E10.5, this primordium is bi-potential and can differentiate along the male or the female pathway, depending on the presence or absence of the sex-determining gene Sry. Expression of Sry leads to the activation of a molecular cascade involving the action of genes such as Sox9 and MIS, and the differentiation of cells into the components of a testis, including Sertoli, Leydig and myotubular cells. In contrast, absence of Sry expression results in the differentiation of the gonads into ovaries.
WT1 is already expressed within the undifferentiated gonad, and its
importance there has been demonstrated in Wt1-/- mice, in
which the gonads undergo apoptosis. Since the gonads and adrenal cortex share
a common primordium (Hatano et al.,
1996) it is perhaps unsurprising that adrenal glands are also
affected in these mice (Moore et al.,
1999
). This phenotype is reminiscent of that found in homozygous
Sf1-knockout animals, which also lack gonads and adrenals owing to
massive apoptosis in the adreno-genital primordium
(Luo et al., 1994
). Moreover,
expression of Sf1 and expression of WT1 in the gonad begin at roughly the same
time and might be dependent. Indeed, Wilhelm and Englert recently demonstrated
that WT1, and more specifically its DNA binding form WT1(-KTS), can activate
the Sf1 promoter in vitro and in vivo
(Wilhelm and Englert, 2002
).
The apoptotic phenotype in Wt1-knockout mice might therefore be
caused by a lack of Sf1 expression. Alternatively, WT1 might activate an
Sf1-independent pathway required for adrenogenital survival. This could
include the anti-apoptotic factor Bcl-2, which might be directly activated by
WT1 (Mayo et al., 1999
).
A second role for WT1 during gonad formation occurs at the level of sex
determination. We have seen that expression of Sry is important for the
activation of the male differentiation pathway. In vitro experiments suggested
that WT1 is responsible for transcriptional activation of Sry. As
expected, only the DNA binding variant of WT1(-KTS) can transactivate this
gene; WT1(+KTS) isoforms showed no effect in co-transfection assays
(Hossain and Saunders, 2001).
Interestingly, our own analysis in vivo paints a somewhat different picture.
Mouse mutants lacking WT1(-KTS) products still show some expression of the
downstream gene Sox9 at E12.5, albeit the expression is restricted to
a relatively small number of cells (Hammes
et al., 2001
). Hence, the male sex determination pathway in this
strain seems to be active. In contrast, gonads in mice lacking WT1(+KTS)
variants completely lack Sox9 expression, as well as that of its putative
downstream target the Müllerian-inhibiting substance (MIS), also known as
AMH. The lack of activation of male-specific genes could be traced back to a
significant reduction of Sry expression to
25% of wild-type levels, which
is known to be insufficient to induce testis formation in mice. Consequently,
gonads in mice lacking WT1(+KTS) products develop along the female pathway. At
the moment it is not clear how WT1(+KTS) proteins act on Sry. Further
analysis should shed light on this important question.
Other potential targets during gonad formation include Wnt-4
(Sim et al., 2002),
Dax1 (Kim et al.,
1999
) and MIS, all of which seem to be activated by
WT1(-KTS) variants. The best studied is certainly the regulation of
MIS, and in vitro experiments suggested that WT1(-KTS) transactivates
its promoter through direct interaction with Sf1 protein
(Nachtigal et al., 1998
). This
transactivation of the MIS promoter, but also of the Dax1
promoter, seems to be further increased through interaction of WT1 with the
LIM-only co-activator FHL2 (Du et al.,
2002
). Dax1, a gene that can interfere with male sexual
development in mouse and man was proposed to be a repressor of the
MIS promoter that could displace WT1 from its complex with Sf1. By
using site-specific mutagenesis in ES cells, Arango et al. demonstrated that
the Sox-binding site in the MIS promoter region is absolutely
required for activation of this gene, whereas the Sf1/WT1 binding site acts
only as a quantitative regulator (Arango et
al., 1999
). MIS expression is
30% of wild-type levels when it
is detected. A schematic representation of these interactions is shown in
Fig. 2.
|
Finally, the continuous expression of WT1 in Sertoli cells in testes and granulosa cells in ovaries throughout life might mean that it has an additional role in the maintenance of cellular functions in these cell types. Analysis of this role will have to wait for the generation of conditional WT1-knockout mice.
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Conclusions |
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Acknowledgments |
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