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Molecular and Cellular Biology, December 2001, p. 8184-8188, Vol. 21, No. 23
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.23.8184-8188.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
The Mouse Snail Gene Encodes a Key Regulator of the
Epithelial-Mesenchymal Transition
Ethan A.
Carver,
Rulang
Jiang,
Yu
Lan,
Kathleen F.
Oram, and
Thomas
Gridley*
The Jackson Laboratory, Bar Harbor, Maine
04609
Received 2 August 2001/Accepted 28 August 2001
 |
ABSTRACT |
Snail family genes encode DNA binding zinc finger proteins that act
as transcriptional repressors. Mouse embryos deficient for the Snail
(Sna) gene exhibit defects in the formation of the mesoderm
germ layer. In Sna
/ mutant embryos, a
mesoderm layer forms and mesodermal marker genes are induced but the
mutant mesoderm is morphologically abnormal. Lacunae form within the
mesoderm layer of the mutant embryos, and cells lining these lacunae
retain epithelial characteristics. These cells resemble a columnar
epithelium and have apical-basal polarity, with microvilli along
the apical surface and intercellular electron-dense adhesive junctions
that resemble adherens junctions. E-cadherin expression is retained in
the mesoderm of the Sna/ embryos. These
defects are strikingly similar to the gastrulation defects observed in
snail-deficient Drosophila embryos, suggesting that the mechanism of repression of E-cadherin transcription by Snail
family proteins may have been present in the metazoan ancestor of the arthropod and mammalian lineages.
| |
INTRODUCTION |
Genes of the Snail family encode
zinc finger proteins that function as transcriptional repressors in a
variety of experimental systems (8, 10, 12, 16, 17, 21;
reviewed in reference 11). The first gene of this family
studied was the Drosophila snail gene, which is one of two
genes required zygotically for mesoderm formation during
Drosophila embryogenesis (1, 5, 9, 13, 24;
reviewed in reference 19). Embryos homozygous for null
mutations of snail exhibit defects in mesoderm formation, gastrulation movements, and germ band retraction (9, 24). The snail protein is a transcriptional repressor which acts to maintain
proper germ layer boundaries by repressing the expression within the
mesoderm of regulatory genes involved in ectodermal development
(18). Snail family genes are evolutionarily conserved, and
studies have implicated Snail family proteins in the regulation of
epithelial-mesenchymal transitions in tissue culture systems and in
both vertebrate and invertebrate embryos (3, 7, 17, 19, 20, 23,
26, 27).
Two mouse homologs of snail, termed Sna
and Slug, have been cloned (15, 22, 28, 30). It
has been previously demonstrated that mice homozygous for a null
mutation of the Slug gene are viable, although they exhibit
postnatal growth deficiency (15). We describe here the
construction and analysis of a targeted mutation of the Sna
gene. During gastrulation, Sna is expressed in the primitive
streak and the mesoderm germ layer (22, 30).
Sna-deficient mouse embryos die early in gestation,
exhibiting defects in gastrulation and mesoderm formation.
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MATERIALS AND METHODS |
Gene targeting.
The Sna targeting vector was
constructed from an 18-kb genomic clone containing the entire
Sna gene (14). The 5' arm was a 2.5-kb
SalI-NruI genomic fragment subcloned upstream of
a PGK-neo expression cassette. The 3' arm was a
1.2-kb XbaI-EcoRI fragment. This resulted in the
deletion of a 1.6-kb genomic fragment containing exons 1 and 2 of the
Sna gene, which deletes the translation initiation site and
amino acids 1 to 203 of the Sna protein, including degenerate zinc
finger 1 and zinc fingers 2 and 3 of the DNA binding domain. A herpes
simplex virus (HSV)-tk cassette was introduced for negative selection. Embryonic stem (ES) cell electroporation and selection and
blastocyst injections were performed as previously described (31). DNAs from individual ES cell colonies were
prescreened by PCR, and positive colonies were then screened by
Southern blotting, using a 0.5-kb EcoRI-SphI
genomic fragment as a probe on SphI-digested genomic DNA.
Germ line transmission of the Sna mutant allele was obtained
for two independently targeted clones. The official nomenclature for
this mutant allele is Snatm1Grid.
Histology, in situ hybridization, and immunofluorescence.
Embryos were dissected at embryonic day 7.5 (E7.5) from timed matings
of Sna+/ heterozygotes. Mutant homozygotes
were identified by allele-specific PCR or by their characteristic
morphology. A strict correlation was observed between genotype and the
characteristic Sna/ mutant phenotype. Some
embryos were sectioned in their decidua for histological analysis.
Decidua and isolated embryos were fixed in Bouin's fixative for
histological analysis. Fixed embryos were dehydrated through graded
alcohols, embedded in paraffin, sectioned, and stained with hematoxylin
and eosin. Embryos for in situ hybridization were fixed overnight at
4°C in 4% paraformaldehyde in phosphate-buffered saline. Whole-mount
in situ hybridization was performed as previously described
(15). At least three Sna/
mutant embryos were analyzed for each of the probes. For analysis of
E-cadherin RNA expression, embryos were embedded in plastic resin after
whole-mount in situ hybridization and sectioned.
Sna/ mutant embryos and control littermates
were stained at E7.5 in whole mount with a monoclonal anti-E-cadherin
antibody (Zymed). Antibody staining was detected with
fluorescein-conjugated anti-rat immunoglobulin G (Jackson
ImmunoResearch). Whole-mount embryos were cut into thick sections using
electrolytically sharpened tungsten needles, mounted in Vectashield
mounting medium (Vector Laboratories), and examined with a fluorescent microscope.
Transmission electron microscopy.
Embryos were fixed
overnight in 2.5% glutaraldehyde in 0.1 M phosphate buffer (pH 7.2).
After being washed, embryos were postfixed in 1% osmium tetroxide in
0.1 M phosphate buffer. Embryos were washed, dehydrated in an ethanol
series, and treated with propylene oxide. Embryos were infiltrated with
Epon-araldite, and ultrathin sections were cut. Specimens were imaged
on a JEOL 100CXII transmission electron microscope.
| |
RESULTS |
Disruption of the mouse Sna gene.
To analyze the
role of the Sna gene during embryogenesis in mice, we used
gene targeting to construct a mutant allele from which exons 1 and 2 of
the Sna gene had been deleted (Fig.
1A). This deletion removes the exons
encoding the translation initiation site and amino acids 1 to 203 of
the 264-amino-acid Sna protein, including degenerate zinc finger 1 and
zinc fingers 2 and 3 of the DNA binding domain. Germ line transmission
of the Sna mutant allele was obtained for two independently
targeted clones (Fig. 1B). Heterozygous Sna+/
mice appeared normal.
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FIG. 1.
Targeted disruption of the mouse Sna gene.
(A) Targeting scheme. The upper line shows the genomic organization of
the Sna gene (14). The three exons are
indicated by boxes. The region encoding the amino terminus of the Sna
protein is indicated by gray boxes, the region encoding the zinc
fingers is indicated by black boxes, and the 3' untranslated region is
indicated by a white box. The middle line represents the structure of
the targeting vector. The lower line represents the predicted structure
of the Sna locus following homologous recombination of the
targeting vector. The probe used for Southern blot analysis is
indicated. N, NruI; R, EcoRI; S, SalI;
Sp, SphI; X, XbaI; TK, thymidine kinase. (B) DNAs
isolated from targeted ES cells were digested with SphI,
blotted, and hybridized with the indicated probe. Wild-type (wt) and
mutant hybridization bands are indicated. Three independently targeted
ES cell clones are shown. (C) Whole-mount morphology of a
Sna/ embryo (right) and a control littermate
embryo (left) at E7.5. In all figures, normal littermate embryos were
either Sna+/ or Sna+/+
and are indicated with a plus sign.
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No homozygous
Sna/ mice were found among the
progeny of the intercross of heterozygous
Sna+/ mice, indicating that our
Sna
mutant allele is a recessive lethal
mutation. To determine when
homozygous mutant embryos were dying,
embryos were isolated from timed
matings. At E6.5,
Sna/ mutant embryos were
not distinguishable from the embryos of heterozygous
and wild-type
littermates. At E7.5, however, the homozygous mutant
embryos were
smaller than the embryos of their littermates (Fig.
1C). By E8.5, the
Sna/ embryos were severely retarded compared
to those of littermates
and were being resorbed (data not
shown).
Sna/ mutant embryos form a mesoderm
cell layer.
Histological analysis of
Sna/ mutant embryos at E7.5 demonstrated the
presence of three germ layers (see below), indicating that a mesoderm
layer had formed in the mutants. This was confirmed by analysis of the
expression of several marker genes (Fig.
2). In wild-type embryos, the Brachyury
(T) gene is expressed in the primitive streak and in the
rostral axial mesoderm (32). In the
Sna/ embryos, expression levels of the
T gene were reduced compared to those of the controls and
expression did not extend as far rostrally in the embryo (Fig. 2A and
B). The Lim1 gene in wild-type embryos is expressed in the
primitive streak and the mesodermal wings (2).
Lim1 was expressed in both of these structures in the
Sna/ embryos (Fig. 2C and D). In wild-type
embryos at the prestreak and early streak stages, the Otx2
gene is expressed throughout the epiblast but its expression gradually
becomes restricted to the anterior neuroectoderm (29). In
Sna/ mutants, Otx2 expression did
not become anteriorly restricted (Fig. 2E and F). The Cer1
gene is expressed in wild-type embryos in the anterior visceral
endoderm and the definitive endoderm (4). Cer1
was expressed in these tissues in Sna/
embryos, but expression levels were reduced compared to those of the
controls (Fig. 2G and H). These marker studies confirm that the
mesoderm, ectoderm, and endoderm all differentiate in Sna/ mutant embryos, although some
differences in expression levels or details of the expression patterns
were detected in the mutants.
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FIG. 2.
Analysis of marker gene expression in
Sna/ mutant embryos at E7.5. (A and B)
T expression. T is expressed in axial mesoderm
cells, and expression extends rostrally from the node (A). In the
Sna/ embryo, T is expressed, but
at lower levels than in the control embryos, and does not extend
as far rostrally in the embryo (B). (C and D) Lim1
expression. Lim1 is expressed in the primitive streak and
the mesodermal wings (C). Lim1 is expressed in these tissues
in the Sna/ embryo (D). (E and F)
Otx2 expression. Otx2 is expressed in the
visceral endoderm and epiblast, and expression is gradually restricted
to the anterior third of the embryo as the primitive streak extends
(E). In the Sna/ mutant, Otx2
expression is not restricted to the anterior portion of the embryo (F).
(G and H) Cer1 expression. Cer1 is expressed in
the anterior visceral endoderm and the definitive endoderm (G). In the
Sna/ embryos, Cer1 expression is
reduced (H). All embryos are oriented with the anterior side towards
the left.
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The Sna/ mutant mesoderm retains
epithelial characteristics.
While histological and marker analyses
clearly indicated that a mesoderm cell layer differentiated in the
Sna/ mutant embryos, morphological
abnormalities were apparent in the mutant mesoderm. In wild-type and
heterozygous embryos by E7.5, the mesoderm cell layer had delaminated
from the primitive streak and had migrated anteriorly between the
embryonic ectoderm and the visceral endoderm to form the mesodermal
wings (Fig. 3A, C, and E). Cells in the
mesoderm layer of these embryos had a morphology characteristic of that
of mesenchymal cells. In Sna/ mutant
embryos, a primitive streak and a mesoderm layer formed and the cells
migrated anteriorly to form the mesodermal wings. However, many of the
mutant mesoderm cells did not have a characteristic mesenchymal
morphology (Fig. 3B, D, and F). In most Sna/
mutant embryos, cavities or lacunae formed in the mesoderm layer (Fig.
3D and F) and the mesoderm cells abutting these lacunae exhibited an
epithelial morphology. The cells lining these lacunae had the
appearance of a columnar epithelium (Fig. 3F and
4B). Transmission electron microscopic
analysis revealed that the mutant mesoderm exhibited apical-basal
polarity, which is typically observed in an epithelial cell layer.
These cells contained microvilli along the apical surface (i.e., the
surface facing into the lacunae) (Fig. 4C) and contained electron-dense
adhesive junctions that resembled adherens junctions (Fig. 4C and D).
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FIG. 3.
Morphological abnormalities in the
Sna/ mutant mesoderm. (A and B) Sagittal
sections of embryos at E7.5. In the Sna/
mutant embryo (B), a posterior amniotic fold forms (arrow) but no
amnion or chorion is formed. (C to F) Transverse sections of embryos at
E7.5. In Sna/ mutant embryos, lacunae form
within the mesoderm layers (arrows in D and F). Mesoderm cells lining
these lacunae exhibit an epithelial morphology. (A to D)
Hematoxylin-and eosin-stained paraffin sections. (E and F) Toluidine
blue-stained plastic sections. Abbreviations: am, amnion; ch, chorion;
ee, embryonic ectoderm; m, mesoderm; ps, primitive streak.
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FIG. 4.
Apical-basal polarity and adhesive junctions in the
Sna/ mutant mesoderm. Transmission electron
microscopic images for analysis of wild-type (A) and
Sna/ (B to D) embryos at E7.5. are shown.
(A) Mesoderm cells in wild-type embryos exhibit a typical mesenchymal
morphology. (B) In Sna/ embryos, mesoderm
cells lining the lacunae exhibit an ordered, columnar morphology. (B to
D) The lumens of the lacunae are indicated with asterisks. (C) Mesoderm
cells in the mutant embryos have microvilli (arrowheads) at the apical
surface and exhibit electron-dense adhesive junctions (arrow) between
the cells. (D) Adhesive junctions are numerous in the
Sna/ mutant mesoderm. The positions of
intercellular adhesive junctions are indicated by arrows. Approximate
magnifications: (A and B) ×4,000, (C) ×20,000, (D)
×3,000.
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E-cadherin expression is not downregulated in the
Sna/ mutant mesoderm.
Recent work has
shown that Sna expression represses E-cadherin transcription
in cultured epithelial cell lines by binding to E boxes present in the
E-cadherin promoter region and that Sna overexpression
causes epithelial cell lines to adopt a fibroblast-like morphology and
to acquire tumorigenic and invasive properties (3, 7).
E-cadherin protein is a component of adherens junctions, and
downregulation of E-cadherin expression in cells in the primitive streak is believed to be important for gastrulation in vertebrates (6). We therefore analyzed expression of the E-cadherin
gene by in situ hybridization of Sna/ mutant
embryos and littermate controls (Fig. 5A to
C). In the control embryos, E-cadherin
expression was downregulated in the mesoderm (Fig. 5A and B). In
Sna/ embryos, E-cadherin RNA expression was
maintained in the mesoderm layer (Fig. 5A and C). However, the levels
of E-cadherin RNA observed in the mutant mesoderm were lower than those
observed in the embryonic ectoderm. We also examined whether E-cadherin
protein expression was maintained in the mesoderm of
Sna/ embryos. This analysis revealed that,
as we observed with E-cadherin RNA, expression of E-cadherin protein
was retained in the mesoderm of the Sna/
embryos but at lower levels than were observed in the embryonic ectoderm (Fig. 5D to G).
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FIG. 5.
E-cadherin expression is retained in the mesoderm of
Sna/ mutant embryos. (A) Whole-mount in situ
hybridization with E-cadherin antisense riboprobes of a control
littermate (left) and a Sna/ embryo (right).
(B and C) Plastic sections of embryos treated as described for panel A. E-cadherin RNA expression is downregulated in the mesoderm of the
control littermate embryo (B), but expression is retained (arrows) in
the mesoderm of the Sna/ embryo (C). (D to
G) Immunofluorescence with anti-E-cadherin monoclonal antibody. (D and
E) Nomarski optics. (F and G) Fluorescence optics. In the
Sna/ embryo (G), E-cadherin protein
expression is retained in the mesoderm layer (arrows). Abbreviations:
ee, embryonic ectoderm; m, mesoderm; ps, primitive streak.
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| |
DISCUSSION |
We describe here the construction and analysis of a targeted null
mutation of the mouse Sna gene. Although previous work had demonstrated that the related Slug gene is not essential for
embryogenesis in mice (15),
Sna/ mutant embryos die early in gestation.
The mutant embryos exhibit defects in gastrulation and in the
epithelial-mesenchymal transition required for generation of the
mesoderm cell layer. Our data indicate that formation of the mesoderm
cell layer can occur despite the retention of E-cadherin expression.
However, many cells in the mesoderm of Sna/
mutant embryos retain apical-basal polarity and an epithelial morphology, presumably due to the retention of adherens junctions between the mesoderm cells in the mutant embryos. The phenotypic defects we observe in the Sna/ mutant mouse
embryos are strikingly similar to the gastrulation defects observed in
snail mutant Drosophila embryos
(25). The Drosophila E-cadherin gene is
normally expressed in the epithelial cells of the
cellular-blastoderm-stage embryo but is then downregulated in mesoderm
precursor cells prior to invagination. In Drosophila embryos
homozygous for a snail null mutation, E-cadherin
downregulation does not occur and mesoderm precursors in the ventral
region of the embryo retain adherens junctions and apical-basal
polarity (25). As noted by Wolpert (33), the
morphogenetic movements of gastrulation are more highly conserved than
the establishment of the body plan during evolution. The similarity of
the gastrulation defects in mutant Snail genes of both
Drosophila and mice indicates that the molecules regulating
mesoderm formation and gastrulation movements are conserved over an
extremely wide evolutionary distance. This observation suggests that
repression of E-cadherin transcription by Snail family proteins may
have been an ancestral condition in the metazoan precursor to the
arthropod and mammalian lineages.
Our studies provide the first genetic evidence that the Sna
gene functions as a key regulator of the epithelial-mesenchymal transition in mice. Our data show that, as was found in cultured cells
and in metastatic carcinomas (3, 7), the E-cadherin gene
is a target for repression by the Sna protein. However, the level of
expression of E-cadherin in the mesoderm of
Sna/ mutant embryos is considerably less
than the level of E-cadherin RNA expression in the embryonic ectoderm
of these embryos. This finding suggests that other regulators of
E-cadherin transcription may not be maintained in the mesoderm of
Sna/ mutant embryos. For example, the
embryonic ectoderm may express a positive regulator of E-cadherin
transcription and this positive regulator might not be expressed in the
mesoderm of the Sna/ mutant embryos.
It is intriguing that despite the retention of E-cadherin expression
and intercellular adherens junctions, a primitive streak forms and the
mesoderm layer delaminates in Sna/ mutant
embryos. This may be due to the fact that these regions express
distinctly lower levels of E-cadherin RNA than are expressed in the
embryonic ectoderm. It would be interesting to overexpress E-cadherin
in the primitive streak and the mesoderm to test whether higher levels
of E-cadherin expression would entirely prevent streak formation and
mesoderm delamination.
| |
ACKNOWLEDGMENTS |
We thank B. Holdener, J. Mercer, and M. Shen for helpful
discussions; L. Bechtold and P. Finger for transmission electron microscopic analysis and plastic sectioning; G. Martin for help with
fluorescent microscopy; C. Norton for technical assistance; S. Ang, R. Behringer, B. Hermann, and R. Kemler for in situ probes; and S. Ackerman and T. O'Brien for reading the manuscript.
This work was supported by a grant (HD34883) from the NIH to T.G. and a
subcontract to T.G. under NIH Project Center grant DE13078 from Johns
Hopkins University. This work was also supported by a training grant
(CA09217) (E.A.C. and Y.L.) and a Core grant (CA34196) from the
National Cancer Institute to the Jackson Laboratory.
E.A.C. and R.J. contributed equally to this work.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: The Jackson
Laboratory, 600 Main St., Bar Harbor, ME 04609. Phone: (207) 288-6237. Fax: (207) 288-6077. E-mail: gridley{at}jax.org.
Present address: Center for Oral Biology and Department of Biology,
University of Rochester, Rochester, NY 14642.
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Molecular and Cellular Biology, December 2001, p. 8184-8188, Vol. 21, No. 23
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.23.8184-8188.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
