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First published online 21 June 2006
doi: 10.1242/dev.02457
1 Division of Integrative Cell Biology, Institute of Molecular Embryology and
Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
2 Division of Stem Cell Regulation, The Institute of Medical Science, The
University of Tokyo, Tokyo 108-8639, Japan.
3 Graduate School of Sciences, The University of Tokyo, Tokyo 113-8654,
Japan.
4 Research Center for Advanced Science and Technology, The University of Tokyo,
Tokyo 153-8904, Japan.
5 Laboratory of Gene Expression and Regulation, The Institute of Medical
Science, The University of Tokyo, Tokyo 108-8639, Japan.
6 PRESTO, JST, Saitama 332-0012, Japan.
Author for correspondence (e-mail:
ryuichi{at}kaiju.medic.kumamoto-u.ac.jp)
Accepted 24 May 2006
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Sall4, spalt, Embryonic stem cells, Okihiro syndrome, Townes-Brocks syndrome, Organogenesis, Mouse
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Matsuda et al.,
1999; Ying et al.,
2003). LIF induces phosphorylation and nuclear localization of
STAT3, a transcription factor essential for the LIF-dependent pathway for
self-renewal. BMP4 induces phosphorylation and nuclear localization of Smad1,
and the subsequent upregulation of Id helix-loop-helix proteins that block
neural differentiation and maintain the pluripotency of ES cells in the
presence of the LIF signal. Intrinsic factors include Oct3/4, Nanog
and Eras. Oct3/4 and Nanog are expressed at high levels in
ES cells and have been shown to be essential for maintaining pluripotency in
ES cells (Chambers et al.,
2003; Mitsui et al.,
2003; Nichols et al.,
1998). Eras and Utf1 are also expressed
abundantly in ES cells, and they play crucial roles in the proliferation of
stem cells (Takahashi et al.,
2003; Nishimoto et al.,
2005).
The spalt (sal) gene was first isolated from
Drosophila and it encodes a protein characterized by multiple double
zinc-finger motifs of the C2H2 type. sal acts as a region-specific
homeotic gene, and is required for the specification of the head and tail
regions during early development (Jurgens,
1988; Kuhnlein et al.,
1994). During the later stages of development, sal
regulates pattern formation and cell fate decisions in the wing disc
(de Celis et al., 1996;
Nellen et al., 1996), trachea
(Kuhnlein and Schuh, 1996) and
sensory organ development (de Celis et al.,
1999). sal is expressed at the anteroposterior boundary
of the wing imaginal discs, and its expression is controlled by the
dpp (decapentaplegic) gene (de
Celis et al., 1996; Nellen et
al., 1996).
Humans and mice each have four known Sal-related genes (known as
SALL1-SALL4 in humans and Sall1-Sall4 in mice). Mutations in
SALL1 on chromosome 16q12.1 have been associated with Townes-Brocks
syndrome, an autosomal dominant disease characterized by dysplastic ears, a
preaxial polydactyly, imperforate anus and, less commonly, kidney and heart
anomalies (Kohlhase et al.,
1998). Mice deficient in Sall1 show kidney agenesis or
severe dysgenesis, but other phenotypes observed in the human disease are not
apparent (Nishinakamura et al.,
2001). This discrepancy could be explained by the formation of
truncated SALL1 proteins as a result of mutations in SALL1, as
comparison with Sall1-null mice showed that mutant mice producing a
truncated Sall1 protein exhibited more severe defects, including renal
agenesis, exencephaly, as well as limb and anal deformities
(Kiefer et al., 2003). It has
been reported that Sall1 also functions as a transcriptional repressor by
localizing in the heterochromatin and interacting with components of chromatin
remodeling complexes such as histone deacetylase (HDAC)1, HDAC2,
retinoblastoma-associated protein 46/48 (RbAp46/48), metastasis-associated
protein (MTA)1 and MTA2 (Kiefer et al.,
2002).
It is still unclear if SALL2 is associated with human disease;
however, it has been reported that Sall2 functions as a tumor suppressor
(Li et al., 2001;
Li et al., 2004).
Sall2-deficient mice show no apparent phenotype, and mice lacking
both Sall1 and Sall2 show kidney phenotypes comparable with
those of Sall1 knockout mice
(Sato et al., 2003). Although
no diseases are thus far directly linked to SALL3, this gene is
located in a region that is commonly deleted in cases of 18q deletion syndrome
(Kohlhase et al., 1999).
Individuals with this deletion exhibit hearing loss, cardiac problems, mental
retardation, midfacial hypoplasia, delayed growth and limb abnormalities
(Strathdee et al., 1997).
Sall3-null mice die on the first postnatal day and deficiencies in
the cranial nerves and abnormalities in the oral structures are present
(Parrish et al., 2004).
Mutations in SALL4 cause an autosomal dominant disorder known as
Okihiro syndrome, which is characterized by limb deformity, eye movement
deficits and, less commonly, anorectal, ear, heart and kidney anomalies
(Al-Baradie et al., 2002;
Kohlhase et al., 2002).
To investigate the roles of Sall family genes and their functional redundancy in organogenesis, we generated Sall4-deficient mice. In this study, we report that the mouse Sall4 gene was found to be unexpectedly essential for early embryogenesis, and for the proliferation of ES cells. We further reveal the importance of the heterodimerization of Sall4 and Sall1 in vivo, which could explain the underlying genetic mechanisms involved in Townes-Brocks syndrome that is caused by truncations of SALL1.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
Five out of 114 G418-resistant E14.1 ES clones were correctly targeted and two
were used to generate germline chimeras that were bred with C57BL/6J females.
E14.1 ES cells were maintained on mitomycin C-treated primary embryonic
fibroblasts in the presence of LIF (103 U/ml) and serum in all the
procedures and experiments described in this paper. The primer sequences used
for genotyping were as follows: 5'-GAGGACTCCATACCGGTGAA-3',
5'-GTGCCCAGCTTCTTCAAGTC-3' and
5'-CCTCTTCGCTATTACGCCAG-3' (the length of the amplified segment
was 272 bp in the wild-type allele and 379 bp in the mutated allele). As the
Sall4-deficient mice (Sall4-del) lacked proper lacZ
expression, we also generated mice using the
Sall4-IRES-ß-geo vector described below.
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Generation of a Sall4 floxed allele
The Sall4-flox vector was constructed by incorporating the
5' HindIII-HindIII 3.5 kb fragment, the
HindIII-ApaLI 4.7 kb fragment and the 3'
ApaLI-EcoRV 6.0 kb fragment into a vector that contained
pGK-Neo flanked by Frt and loxP sequences and pMC1DTA (see Fig. S1 in the
supplementary material). LoxP sequences were placed so that exon 2 and 3 were
excised upon Cre treatment, resulting in disruption of all zinc-finger motifs.
Five out of 170 clones were correctly targeted (flox/+) and one of them was
further transfected with the Sall4-IRES-Hyg vector.
Both resulting clones, flox/- and +/-, proliferated normally. Neor
placed in intron 2 did not affect Sall4 expression as shown in
Fig. 3C. These ES cells were
infected with adenovirus expressing Cre under the CAG promoter (AxCANCre
provided by RIKEN Bioresource Center)
(Niwa et al., 1991;
Kim et al., 2002) at a m.o.i
(multiplicity of infection) of 50. After incubation for 1 hour, cells were
diluted and plated onto 6-well plates coated with mitomycin C-treated
embryonic fibroblasts.
Histology and blastocyst culture
Histological examination was performed as described earlier
(Nishinakamura et al., 2001).
In situ hybridization was performed using the AmpMap Kit and an automated
Discovery System (Ventana) according to the manufacturer's protocols.
Blastocyst culture and immunosurgery were also performed as described earlier
(Nichols et al., 1998). cDNA
was synthesized using SuperScript III CellsDirect cDNA Synthesis System
(Invitrogen). Primer sequences used for RT-PCR are available upon request.
5-Bromo-2'-deoxyuridine (BrdU) labeling and detection kit I (Roche) was
used to examine proliferation of the blastocysts upon 30 minutes of BrdU
incorporation.
Chimera formation
Two independent Sall4-deficient clones were transfected with
pCAG-GFP-IRES-puro and selected on
puromycin-resistant embryonic fibroblasts
(Tucker et al., 1997). Cells
retaining ubiquitous green fluorescent protein (GFP) expression from each
Sall4-deficient clone were injected into blastocysts, and consistent
results were obtained. Frozen sections of the chimeras were stained by an
anti-GFP antibody (Molecular Probes) and detected using ImmunoPure metal
enhanced DAB substrate kit (Pierce).
Proliferation and rescue analysis of ES cells
For the proliferation assay, 1x104 cells were plated per
well in 24-well plates in triplicate on mitomycin C-treated primary embryonic
fibroblasts in media containing LIF and serum, and passaged at the same
density every 4 days for 16 days to determine the cumulative cell number. A
BrdU Flow Kit (BD Biosciences) was used for cell cycle analysis of ES cells
after 2 hour incorporation of BrdU. For rescue analysis, the Sall4
expression vector (Sall4 in
pCAG-IRES-puro) or GFP expression vector
(negative control) was introduced into Sall4-deficient cells by
electroporation. Multiple clones were selected on puromycin-resistant
embryonic fibroblasts and expanded.
siRNA transfection
The siRNA duplexes were designed to target the coding region of mouse
Sall4 cDNA at nucleotide 2761-2785 and synthesized by Invitrogen.
Sall4-siRNA or control siRNA containing the same GC content was transfected
into D3 embryonic stem cells using Lipofectamine2000 (Invitrogen) according to
the manufacturer's instruction, except for the maintenance of D3 cells, which
were cultured on gelatin-coated plates in the presence of LIF. D3 cells at a
density of 1x104 cells per well in 24-well plates were
transfected in triplicate with 25 pmol siRNA, and counted every day. The
negative control siRNA showed no growth or morphological impairment compared
with the mock-transfected or the non-transfected cells.
Immunocytochemistry and confocal microscopy
The anti-Sall1 monoclonal antibody
(Sato et al., 2004) and an
anti-Sall4 polyclonal antibody raised against polypeptide (MAKHQFPHFLEENKI)
corresponding to amino acids 1050-1064 were used. A monoclonal anti-Sall4
antibody was generated using Sall4 cDNA encoding amino acids 95-216.
The following additional antibodies were used for staining blastocysts and ES
cells: monoclonal anti-Oct3/4 (Santa Cruz), rabbit antisera against Oct3/4
(Niwa et al., 2005) and
monoclonal anti-Cdx2 (BioGenex). GFP-fused Sall4 and Sall1
zinc-finger mutants in which the cysteine residues were replaced by glycine
were produced using PCR. NIH 3T3 cells were plated onto six-well plates at a
density of 1x105 cells per well 1 day prior to transfection.
The cells were transfected with 3 µg of the plasmids using FuGENE 6 (Roche)
and cultured for 48 hours prior to analysis by confocal microscopy.
Construction of Sall1-GFP and
Sall11-435-DsRed, immunoprecipitation,
immunocytochemistry and confocal microscopy were performed as described
previously (Sato et al.,
2004).
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RESULTS |
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Next, heterozygous cells were generated containing a floxed allele of Sall4 by homologous recombination (see Fig. S1 in the supplementary material). When the Sall4-IRES-Hyg vector was introduced into this clone, both alleles were targeted with a similar frequency (wild-type allele, 10/23; floxed allele, 11/23), resulting in two types of cells: flox/- and +/- (Fig. 3C). As shown by western blot, Neor in intron 2 of the floxed allele did not affect Sall4 expression, and there was no difference in proliferation between the two types of cells. Upon infection with adenovirus expressing Cre, flox/- cells became almost Sall4-null by day 3, while +/- cells served as a negative control, as determined by western blot (Fig. 3C). Indeed, when cells were subsequently replated and single clones were picked, 44 out of 47 clones were Sall4 null, and all these Sall4-null clones grew significantly slower than the clones retaining Sall4 despite being treated identically (Fig. 3D), but could be cultured for a prolonged period of time (more than 1 month). None of the clones from the other groups (flox/- without Cre, +/- with or without Cre) showed impaired proliferation, and re-expression of Sall4 cDNA under a ubiquitous promoter in Sall4-null cells restored proliferation (data not shown), confirming that this phenotype was Sall4 dependent. Cell cycle analysis revealed that Sall4-null cells showed a decreased S-phase and increased G1-phase compared with heterozygous cells (Fig. 3E). These data suggest that Sall4 absence in ES cells leads to inefficient G1/S transition, which may possibly explain the phenotypes observed in blastocyst culture and embryos in vivo.
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Sall4 haploinsufficiency results in anorectal and heart anomalies and exencephaly
Genotyping from heterozygous crosses showed that nearly half the
Sall4 heterozygous mice died in utero
(Table 1). Out of 86 born
heterozygous mice, 13 were runt and died or were eaten by their mothers within
3 weeks (Table 3). Eight more
died within the next 3 weeks and six of these mice had significantly dilated
bowels and apparent anal stenosis (Fig.
4A, open arrowhead). The number of enteric ganglia in these
heterozygotes was not affected (data not shown); hence, gastrointestinal
dilation is likely to be a secondary effect of anal dysplasia. When examined
at E17.5-18.5, ventricular septum defects were also observed in some of the
heterozygotes (Fig. 4B and
Table 4). These phenotypes
partially mimic the Okihiro syndrome caused by SALL4 mutations in
humans, and, thus, anorectal and heart anomalies could be caused by
SALL4 haploinsufficiency. Other phenotypes observed in Okihiro
syndrome were not detected in Sall4-heterozygous mice. All the
heterozygotes that survived beyond 3 weeks (n=73) had normal
appearing extremities and closer examination of newborns did not show any
anomalies in digit, metacarpus or metatarsus formation (n=6)
(Fig. 4C). Though abducens
nerves and nuclei are reported to be responsible for the abnormal eye
movements in Okihiro syndrome (Al-Baradie
et al., 2002; Kohlhase et al.,
2002), the abducens nuclei in adult heterozygous mice
(n=6) were properly formed, and oculomotor and trochlear nuclei, eye
and ocular muscles were also unaffected
(Fig. 4D and data not shown).
Inner ear structures at E17.5 (n=9) and in adults (n=6) were
not impaired (Fig. 4E; data not
shown). Thus, in mice, not all Okihiro phenotypes were caused by Sall4
haploinsufficiency.
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Sall4 genetically interacts with Sall1
Compound heterozygotes were generated to investigate functional redundancy
among members of the Sall family. Surprisingly, no Sall1/4
compound heterozygotes survived after birth, whereas mice having other genetic
combinations (Sall1/2, Sall1/3, Sall2/3, Sall2/4 and
Sall3/4) survived. The Sall1/4 heterozygotes exhibited uni-
or bilateral renal agenesis (Fig.
5A), exencephaly (data not shown), anorectal malformations
(Fig. 5B) and ventricular
septum defects (data not shown); the incidence of these phenotypes was
significantly increased in comparison with Sall4 heterozygotes
(Table 4), suggesting a genetic
interaction of Sall4 and Sall1 in vivo. Next, we determined
if the expression of Sall4 and Sall1 overlapped in the
affected organs. At E8.5, a stage at which the neural tubes close, both
Sall4 and Sall1 were expressed in the mesenchyme of the
anterior portion (Fig. 5C,
filled arrowhead) and in all tissues of the tail region
(Fig. 5C, open arrowhead). At
E11.5, Sall4 and Sall1 were expressed in the anorectal
region (Fig. 5D, arrowhead). In
the heart at E11.5, Sall4 was detected in the myocardium, including
the developing interventricular septum, while Sall1 was expressed not
only in the myocardium but also in the endocardium, thus overlapping with
Sall4 in the myocardium (Fig.
5E). We further checked to determine if Sall1 and Sall4 were
colocalized in ES cells. Endogenous Sall4 was localized in the punctate
nuclear foci that colocalized with 4,6-diamidino-2-phenylindole (DAPI)
(Fig. 5F), indicating that
Sall4 is localized in the constitutive heterochromatin. Endogenous Sall1 was
also localized in the heterochromatin and overlapped with Sall4.
Immunoprecipitation using lysates from ES cells showed that endogenous Sall4
binds to Sall1 (Fig. 5G).
Therefore, these two genes probably form heterodimers in the developing brain,
heart and anorectal regions. However, in the developing kidney, the two genes
did not overlap (data not shown). Thus, heterodimer-independent mechanisms may
exist in kidney development.
Truncated Sall1 disturbs heterochromatin localization of Sall4, and functions in a dominant-negative manner
When various Sall4 and Sall1 constructs with mutations in
the zinc-finger domains were generated, we observed that the most C-terminal
double zinc-finger domain (Zn4) of Sall4 was essential and sufficient for
localization to the heterochromatin (Fig.
6A). In the case of Sall1, two double zinc fingers (Zn 4 and 5)
were required, and were sufficient for heterochromatin localization
(Fig. 6B). Thus, these
C-terminal double zinc fingers constitute heterochromatin localization
domains. SALL1 mutations in Townes-Brocks syndrome are likely to
produce C-terminally truncated proteins. Truncated Sall1 fused to
DsRed (Sall11-435-DsRed) was ubiquitously located
throughout the cytoplasm and euchromatin
(Fig. 6C), as this mutant
lacked the C-terminal heterochromatin localization domain. Co-transfection of
Sall11-435-DsRed and Sall4-GFP showed disturbance
in Sall4 localization in the heterochromatin. Thus, the C-terminally truncated
SALL1 proteins in Townes-Brocks syndrome probably dimerize with SALL4 in a
dominant-negative manner, resulting in mislocalization of SALL4 in the
heterochromatin. Considering the anal and heart anomalies and exencephaly in
Sall1/4 double heterozygotes, the phenotypes observed in Sall1
truncations could be explained by the functional reduction of Sall4.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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)], Sall4
could also bind HDAC complexes and deacetylate the histone lysine residues,
followed by recruitment of histone-methylating and DNA-methylating complexes.
Centromeric and pericentromeric regions, which comprise constitutive
heterochromatin, are required for spindle formation in mitosis, and it is
possible that the absence of Sall4 affects these structures. Alternatively,
Sall4 could suppress downstream genes, including cell cycle inhibitors, by
inducing heterochromatin formation in the euchromatic promoters (known as
facultative heterochromatin formation). More detailed examination in the
heterochromatin structure in Sall4 mutant ES cells, as well as
identification of downstream target genes of Sall4, is required for further
elucidation of Sall4 functions. It is interesting that Nanog and
Eras were slightly decreased in Sall4-deficient cells.
Nanog heterozygous cells show no reduction in proliferation, and
Nanog-deficient cells differentiate into primitive endoderm
(Mitsui et al., 2003). Though
Eras could be partly responsible for impaired proliferation of
Sall4-null ES cells, Eras-null mice had no abnormalities in
vivo (Takahashi et al., 2003).
Thus, it is unlikely that a reduction of these genes could explain the
phenotypes of Sall4 deficiency. As ES cells are suitable for
quantitative biochemical approaches, we expect to apply the detailed analysis
of Sall4 function in ES cells to the study of organ formation during later
stages of development. We demonstrated that Sall4 and Sall1 form heterodimers and that truncated Sall1 proteins altered Sall4 localization in a dominant-negative manner. Townes-Brocks syndrome caused by SALL1 mutations exhibits limb, anal, ear, kidney and heart anomalies, and mice retaining truncated Sall1 proteins show similar phenotypes as well as exencephaly. As human families with severe phenotypes are unlikely to survive, exencephaly could be one of the phenotypes of SALL1 truncations. Considering the anal and heart anomalies and exencephaly in Sall1/4 double heterozygotes, at least these three phenotypes observed in Sall1 truncations can be explained by the functional reduction of Sall4. Thus, we propose that some symptoms of Townes-Brocks syndrome caused by SALL1 truncations result from the inhibition of SALL4 functions that is due to heterodimer formation.
SALL4 mutations in humans cause the autosomal dominant disorder
Okihiro syndrome, which is characterized by limb deformity, eye movement
(abducens nerve) abnormalities, and anorectal, ear, heart, and kidney
anomalies. Some Sall4 heterozygous mice had anal and heart anomalies,
suggesting that these phenotypes are caused by Sall4
haploinsufficiency. This is important because most phenotypes in Townes-Brocks
syndrome could be caused by the dominant-negative effect of the truncated
Sall1, but not by haploinsufficiency of Sall1. However, other anomalies to
limbs, abducens nuclei, inner ears and kidneys were not detected in
Sall4 heterozygous mice; thus, these phenotypes are not explained by
Sall4 haploinsufficiency in mice. In humans, C-terminally truncated
SALL4 proteins could function in a dominant-negative manner, as is the case
for SALL1 truncations. Recently, a gene trap allele retaining truncated
Sall4 was reported and this strain exhibited digit and heart
anomalies (Koshiba-Takeuchi et al.,
2006). If this allele serves as a dominant-negative form, it is
possible that this trap allele has more severe phenotypes than ours, although
other phenotypes are not described. Direct comparison of the two mouse strains
on the same genetic background would test this possibility.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/133/15/3005/DC1
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ACKNOWLEDGMENTS |
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Footnotes |
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