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*
School of Pathology, University of New South Wales, Sydney, Australia; and
Departments of Biochemistry and Microbiology and Centre for Molecular and Cellular Biology, University of Queensland, Queensland, Australia
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, S100ß,
calbindins, and calcyclins (6) and forms a cluster of
linked genes in the mouse and human genomes (1). Human
S100A8 (also known as MRP8, calgranulin A, L1 light chain, cystic
fibrosis Ag, and calprotectin) is the most closely related member of
the human S100 family to mouse S100A8, although the level of homology
is <60%, and the human protein lacks chemotactic activity
(3). In both species, S100A8 forms complexes with S100A9
(MRP14) in the cytoplasm of neutrophils and macrophages in various
states of differentiation and activation and has been implicated in
calcium-dependent regulation of myeloid cell function (7).
In other studies in the laboratory we have found that S100A8 mRNA and
protein is massively induced in the lung in response to i.v. injection
of bacterial LPS (our unpublished data). The first isolation of the mouse S100A8 and S100A9 gene reported upon the restricted expression of the two genes in the fetal liver (8). More recently, we have demonstrated that both genes are expressed exclusively in this location from around 10.5 days of embryological development (10.5 days postcoitum (dpc)3). Expression was not observed during yolk sac hematopoiesis and was also absent from mature macrophages that leave the liver in very large numbers during development (9). This pattern was consistent with in vitro studies in which both S100A8 and S100A9 mRNAs were induced transiently in bone marrow cultures stimulated with the macrophage-specific growth factor, CSF-1 (10). In this study we sought to define the possible roles of S100A8 by targeted disruption of the mouse gene. Given the very restricted pattern of expression of S100A8 during embryogenesis and its biological activities, we anticipated that a targeted disruption of the gene might cause a late embryonic lethality if macrophage/granulocyte production by the liver was perturbed, or it might compromise some aspect of inflammation or LPS responsiveness in adult animals if fetal expression was redundant. Because of the large size of the S100 family, it was possible that the function of S100A8 might be substituted by some other family member and no phenotype would be evident. A more extensive examination of sites of expression of S100A8 during embryogenesis herein revealed that the gene is also expressed in extra-embryonic tissues immediately following implantation, where it might regulate fetal-maternal interactions. In keeping with this hypothesis, we show that 100% of null embryos are resorbed by the mother at exactly the time that S100A8 is expressed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Whole mount in situ hybridization using digoxygenin-labeled
(DIG) riboprobes was performed on embryos at the stages indicated as
described previously (11). S100A8 (CP10/MRP8) and S100A9
(MRP14) cDNA plasmids are detailed in Hu et al. (12). In
each case sense and antisense mRNA probes were produced; any signal
detected with the sense probes is noted in the figure legends. For the
analysis of the implantation sites, individual decidua were hemisected
along the longest axis using a scalpel under a dissecting microscope
before fixation in 4% paraformaldehyde and processing as described
previously for embryos (11). Following hybridization and
extensive washing, the DIG was detected using
alkaline-phosphatase-conjugated anti-DIG Abs followed by
histochemical staining which yields a blue-purple color. The pattern of
expression of S100A8 and c-fms observed in Fig. 2
was
observed in at least four independent litters at each developmental
age; the approximate gestational age (dpc) was confirmed by examination
of the stage of development of the embryos. Typically, multiple litters
of each gestational age were combined, then 8–10 embryos were stained
for expression of each marker examined. The timing of gestational age
is based upon the assumption that coitus occurred at midnight on the
evening before confirmation of a vaginal plug.
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The S100A8 targeting vector described in Fig. 1 is based upon a positive-negative
selection strategy in which cells are initially selected for
recombination using G418 resistance and then nonhomologous insertions
are selected against because of their retention of the viral thymidine
kinase gene using ganciclovir (13). Following homologous
recombination at the S100A8 locus, the coding sequence is replaced by
1.8 kb of neomycin phosphotransferase (neo) gene driven by
the phosphoglycerate kinase 1 (pgk1) promoter. Transfection of R1
embryonic stem (ES) cells (a gift from Dr. A. Nagy; Samuel Lunenfeld
Research Centre, Toronto, Canada) by electroporation, selection of
candidate homologous recombinants, screening by Southern blotting, and
generation of chimeras by the morula aggregation method were performed
as described by Monkley et al. (14). We selected two
independent targeted ES cell lines (clone 52 and clone 79) for further
study.
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Identification of the targeted allele in mice was based upon detection of the neo gene using the primers described (14), and identification of the wild-type, S100A8 allele using the primers 5'-GCTCCGTCTTCAAGACATCGT-3' (+22 to +41) and 5'-GGCTGTCTTTGTGAGATGCC-3' (+898 to +880). For genotyping of preimplantation embryos, the uterus was flushed at 3.5 dpc and blastocysts were placed into 200 µl microcultures in DMEM + 10% FBS for up to 7 days. During this time the blastocysts hatched, and trophoblast migration was observed. Genotyping was performed on DNA isolated from hatched blastocyst cells.
Immunolabeling of disaggregated decidual cells
For immunostaining, embryos were removed and decidua were washed in PBS, cut into small pieces, and drawn through a 23-guage needle. Decidua were incubated in Petri dishes in 0.1% collagenase, 0.2% dispase (Boehringer Mannheim, Indianapolis, IN), 20% FCS in PBS for 60 min at 37°C. The digest was drawn through the 23-guage needle, pelleted, and washed. The single cell suspension was blocked with 5% rat serum, then incubated with PE-conjugated anti-Mac-1 Ab (Caltag, South San Francisco, CA), washed, and analyzed on a FACSCalibur (Becton Dickinson, Mountain View, CA) flow cytometer.
Transfer of embryos into lacZ-expressing mothers
For the investigation of infiltration of embryos by maternal cells, 3.5-dpc embryos were collected from S100A8 (+/-) matings and transferred into pseudopregnant 253 strain female mice, which express nuclear lacZ in all cells under the control of the HMG-CoA reductase promoter (15). The mice were sacrificed at 6.5–9.5 dpc. Decidua and embryos were bisected as for in situ hybridization, fixed, and stained for lacZ expression as described (15). They were then embedded in paraffin wax, sectioned at 8 µ and counterstained with Neutral Red.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies indicated S100A8 is expressed for the first time
in the mouse embryo together with S100A9 in presumptive myeloid cells
in developing liver around 11.5 dpc (8, 9). As a prelude
to performance of targeted disruption of the gene, we examined the
expression of S100A8 mRNA at earlier stages of development. This study
revealed a second site of S100A8 expression in extraembryonic tissue.
Following initial attachment and implantation of the mouse embryo, the
polar trophectoderm proliferates to form the EPC and extraembryonic
ectoderm, from which the various differentiated secondary trophoblast
cell types arise. In many respects, EPC-derived trophoblasts resemble
granulocytes and macrophages. They are capable of extensive
phagocytosis (16) and like macrophages, express the gene
encoding the receptor for CSF-1, the c-fms protooncogene
(11). Whole mount in situ hybridization on hemisected
decidua at 6.5–8.5 dpc provides a three-dimensional perspective of
gene expression in the implantation site. The application of this
method, which is used routinely on mouse embryos, to gene regulation in
the implantation site has not been reported previously to our
knowledge. The c-fms mRNA was detected within primary
trophoblasts infiltrating surrounding tissues from the full perimeter
of implanted embryos at 6.5 dpc, throughout the EPC and extending
outwards from that pole into the deciduum. By contrast, S100A8 mRNA was
only detected in very small subsets of cells that seemed to delineate
the external perimeter of the EPC (not shown). By 7.5 dpc, the
c-fms positive cells were more extensively infiltrated into
the deciduum surrounding the embryo, particularly around the EPC (Fig. 2
A). S100A8 was clearly
restricted to a halo of cells surrounding the EPC. The distribution
apparently partly overlaps the distribution of c-fms but the
method is not amenable to double-labeling to confirm identity (Fig. 2B). Sections of in situ-stained embryos demonstrated that
the S100A8-positive cells flanking the EPC were large mononuclear cells
with abundant cytoplasm (Fig. 2C). The S100A8-positive cells
were indistinguishable from cells expressing the CSF-1R
(c-fms) in sections (data not shown, see Ref.
8), though less numerous, but one cannot distinguish
unequivocally between maternally derived decidual cells and
trophoblasts at this stage. A separate intense S100A8 signal at the
very tip of the EPC was present in all decidua (though visible to
varying extents in individual half-decidua depending upon the plane of
hemisection). Histological examination of this region confirmed the
presence of large numbers of neutrophils (not shown). Maternally
derived neutrophils are present within the uterine lumen
(17), and these, together with activated macrophages, may
contribute to the localized inflammatory response during initiation of
blastocyst implantation (18). Murine neutrophils
(19) and activated macrophages (9) express
high levels of S100A8 mRNA.
The induction of S100A8 mRNA of the expected size in decidua was
confirmed by Northern blot analysis (data not shown), indicating that
the signal was unlikely to be attributable to cross hybridization with
any other S-100 gene. At 8.5 dpc, S100A8 mRNA expression in the
vicinity of the EPC was no longer detectable by in situ hybridization
or Northern blot analysis (data not shown). Whereas c-fms
mRNA was maintained at very high levels in trophoblasts and trophoblast
giant cells (Fig. 2D) at later stages of embryonic
development (10.5–11.0 dpc), S100A8 mRNA expression was only detected
in cells associated with the vasculature at the maternal face of the
placenta (Fig. 2E). In contrast to the situation in the
liver, where S100A9 was co-expressed with S100A8 in myeloid cells
(14), S100A9 mRNA was not detected in the vicinity of the
EPC at any stage except in decidual neutrophils (data not shown).
Although most studies in human and mouse have indicated coexpression of
the two S100 proteins, at least one other precedent for expression of
secreted S100A8, in the absence of S100A9, occurs in mature macrophages
responding to bacterial LPS (9). The cells expressing
S100A8 and S100A9 in the fetal liver are also not necessarily
coincident and appear morphologically distinct (8),
although double labeling is required to confirm this proposal.
Resorption of S100A8 null embryos occurs between 9.5 and 13.5 dpc
To address the possible functions of S100A8 in myeloid and
trophoblast cells, we created a disruption of the S100A8 gene in the
mouse genome. The mouse S100A8 (MRP8) genomic DNA sequence reported by
others (20) has been confirmed in our laboratory. The
targeting strategy is outlined in Fig. 1. Because the gene is
comparatively small, the introduced mutation removed the majority of
the coding sequence and no functional protein product was possible. The
targeting vector was transfected into embryonic stem cells, and after
positive-negative selection (for G418 resistance and
ganciclovir-resistance respectively) the transfectant clones were
screened for correct targeting of the S100A8 gene. Two homologous
recombinants were used to produce chimeras by morula aggregation, and
male chimeras from both lines transmitted the null allele with high
frequency to their progeny. Heterozygous animals revealed no obvious
gross phenotype, and mated normally. After
S100A8+/- mice were interbred, analysis of the
progeny derived from both of the two independent targeting events in
separate ES cell lines revealed homozygous normal (+/+) and
heterozygous (+/-) offspring in the ratio 1:2 (Table I), indicating that the null mutation was
embryonic lethal. Additional timed matings were conducted for each of
the lines and the progeny genotyped at various times during embryonic
development. Combining the results for all embryos examined from 10.5
to 13.5 dpc, homozygous normal, heterozygous (+/-) and resorbing
embryos that could not be genotyped (presumably null) occurred in the
expected ratios of 1:2:1 (Table II).
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At 6.5 and 7.5 dpc, intact embryos could be extracted from all decidua. PCR genotyping revealed an excess of apparent heterozygotes over the expected 1:2:1 ratio, which is probably an artifact due to the sensitivity of PCR and the difficulty of completely avoiding maternal tissue which could result in both +/+ and -/- decidua being scored as +/-. Any detectable signal was scored as positive. The problem could be avoided with quantitative PCR, but the key point is that the ratio of definite homozygous wild-type to null mutants is one, indicating that there is no selective loss of S100A8-deficient embryos. This conclusion is supported independently below. The definitive S100A8 null embryos were completely indistinguishable from their wild-type or heterozygous littermates in terms of size or developmental stage at 7.5 dpc.
To confirm that pre-implantation development and trophoblast
development was normal, blastocysts were isolated at 3.5 dpc, hatched
in vitro, and subsequently genotyped. This experiment detected the
expected 1:2:1 ratio of wild-type, heterozygote, and homozygous mutant
embryos (Table II). The hatched blastocysts, including the (-/-)
embryos, were indistinguishable from one another, and large
trophoblasts were adherent to the substratum surrounding the inner cell
mass in each case (data not shown).
Infiltration of the embryo by maternal cells and of the deciduum by fetal cells
By 8.5 and 9.5 dpc, despite the lack of any obvious gross
abnormality, the ratio of embryos genotyped as null compared with wild
type was significantly less than one. This pattern suggests that
homozygous null embryos contain greater numbers of cells of maternal
genotype that can be detected by PCR, possibly presaging the overt
resorption that becomes visibly obvious only 24 h later (9.5–10.5
dpc; Table II). Transplacental leukocyte infiltration occurs in normal
pregnancies (21) but appears to be strictly controlled
(22) and is presumably below the limits of detection by
PCR in wild-type embryos.
To seek evidence that the apparent excess of heterozygotes detected by
PCR was indeed due to infiltration by maternal cells, we transplanted
3.5-dpc embryos from heterozygous matings into mothers in which a
nuclear lacZ transgene is expressed in all cells
(15). This experiment also permits the detection of cells
of fetal origin infiltrating the deciduum in normal implantation sites.
Fig. 3A shows a normal
implantation site at 8.5 dpc, the maternal cells expressing nuclear
lacZ are excluded from the EPC region, whereas fetal cells
with red nuclear staining (i.e., absence of lacZ) can be
detected infiltrating the deciduum, corresponding in location to the
S100A8-positive cells detected by in situ hybridization in Fig. 2.
Conversely, Fig. 3B shows an embryo in early stages of
resorption, at 8.5 dpc, demonstrating extensive infiltration by
lacZ-positive maternal cells. Apart from this embryo, where
there is macroscopic evidence of early resorption, and others in which
resorption was already complete, in eight litters examined we did not
detect lacZ-positive cells infiltrating morphologically
normal embryos using this approach and thus did not provide a clear
explanation for the PCR genotyping. It may be that maternal leukocytes
are contributed from extraembryonic sources during dissection, or the
number detectable by PCR is below the limits of detection by
lacZ staining or the cells infiltrating initially express
lacZ at low levels.
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Apart from direct genotyping, the only alternative approach to
identify S100A8-/- embryos is to examine
expression of the S100A8 gene. Whole-mount in situ detection of S100A8
mRNA on hemisected decidua from a series of 7.5-dpc embryos from
heterozygous crosses (Fig. 4A)
showed no S100A8 signal in regions flanking the EPC in 11/46 decidua
examined, whereas the signal was detected in every one of the embryos
from wild-type matings examined in the course of localization of the
gene in Fig. 2. The disappearance of the S100A8 signal in the expected
25% of embryos from a heterozygous (+/-) cross further argues that
the cells expressing the S100A8 gene in the region flanking the EPC
(Fig. 4) are of fetal origin and confirms the evidence based upon PCR
genotyping that null embryos develop normally to this point.
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The decidua of S100A8-/- embryos
identified based upon the absence of S100A8 mRNA, and the embryos
within them, were indistinguishable from the (+/?) embryos and decidua
of littermates. No gross deficiency in the EPC was evident, and decidua
were the same size and shape as those of wild-type embryos (Fig. 4A). It is possible to obtain further differentiation of
trophoblasts in vitro by taking explant cultures of the EPC
(23). A series of heterozygous matings was performed, and
7.5-dpc EPC explants were cultivated for 4–7 days as described without
exogenous growth stimulus. All cultures formed adherent
trophoblast-like cells, and there was no clear difference in the extent
of growth or spreading that would identify a subset of putative S100A8
null EPC cultures.
To assess the decidual reaction further, we digested 29 individual
decidua from three separate heterozygous matings with
collagenase/dispase and identified myeloid cells by flow cytometry. A
representative profile is shown in Fig. 4B. Two populations
of cells of different size and light scattering properties expressed
the type 3 complement receptor (CD11b, Mac-1 Ag) present on
granulocytes and macrophages. There was remarkably little variation in
the numbers or proportions of the two cell populations between
littermates (Fig. 4B). The data indicate that there is no
gross effect of the null mutation on the initial myeloid cell
infiltration of the decidua.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and the data in Fig. 4 confirm that the
S100A8-positive cells are of fetal origin. Indeed, it would be
difficult to see a mechanism for early embryonic loss in the S100A8
null if the cells expressing the gene were maternal. One gene that does
resemble S100A8 in expression pattern is urokinase plasminogen
activator, which is induced around 7 dpc surrounding the EPC, in a halo
of cells presumed to be migrating trophoblasts (34).
Given the lack of any overt defect in either embryo or trophoblast
development in vivo or in vitro before resorption of the
S100A8-/- embryo we propose that S100A8 is
secreted, as occurs in activated macrophages, and contributes to the
regulation of fetal-maternal interaction. In support of this
hypothesis, recent studies in our laboratory (S. Leung and C. L.
Geczy, unpublished data) have shown that although abundant S100A8
protein can be detected in decidual extracts at 8.5 dpc, S100A8
apparently does not accumulate within cells in the vicinity of the EPC
(as evidenced by immunocytochemistry in which decidual neutrophils
provide a positive control). As noted in the Introduction, we have
shown that S100A8 mRNA is massively inducible in mouse organs following
i.v. LPS injection (our unpublished data) indicating that expression in
mice, as in humans, is associated with inflammation. The decidual
reaction to embryo implantation is essentially a form of acute
inflammation (17, 18, 35). The data in Fig. 4 indicate
that the primary decidual reaction occurred normally in S100A8 null
mice, not surprisingly because much of the process occurs in response
to blastocyst hatching, well before S100A8 is expressed maximally at
7.5 dpc.
The actual process of resorption in S100A8 null embryos must occur very
rapidly, because among the hundreds of implantation sites we have
examined (Table II), the one shown in Fig. 3B is the only
one in which the embryo was not either completely normal, or completely
destroyed. A similar pattern of resorption is observed in a natural
model of early embryo loss, the CBA/J x DBA/2 cross. In this
model, embryonic development is also completely normal until 8 dpc, and
embryo loss has been attributed to activation of macrophages and/or NK
cells, or to ischemia due to vascular thrombosis (36) and
inflammation (36, 37). S100A8 could contribute to the
prevention of such pathology in a normal implantation site. It is
chemotactic at low concentrations and the macrophages elicited have a
particular phenotype including efficiency of uptake of lipid
(38) and a high phagocytic index (our unpublished data),
properties similar to those described for circulating monocytes in
normal pregnancy (39). Hence the S100A8 secreted in the
vicinity of the EPC could regulate the state of macrophage activation
and procoagulant activities, thus protecting the embryo from immune
attack by maternal cells. Alternatively, or in addition, high levels of
S100A8 may be protective by virtue of its ability to be readily
oxidized by reactive oxygen intermediates including hypochlorite, the
major oxidant produced by activated granulocytes (40). By
analogy, the anti-oxidant defense provided by thioredoxin functions
is an essential protective factor against oxidative stress to embryos,
though the thioredoxin null mutant dies earlier than the S100A8 null
(41). In the future it will be of interest to compare the
S100A8 null with the CBA/J x DBA/2 cross as a model for early
embryo loss, particularly once the null allele has been crossed onto
the appropriate inbred genetic backgrounds. PGE2, CSF-1, leukemia
inhibitory factor, FasL, IL-1ß, TGF-ß, and IL-10, have variously
been attributed roles in regulating infiltration of the embryo by
maternal cells and the latter two prevent resorption in the CBA/J
x DBA/2 model (22, 36, 42). Among these candidate
regulators, S100A8, a known regulator of myeloid cell function and
inflammation (2, 3, 38, 40, 43), is unique in being
expressed at precisely the critical time and place where infiltration
of the embryo by maternal cells must be regulated.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. D. A. Hume, Department of Microbiology, University of Queensland, Q4072 Queensland, Australia. E-mail address:
3 Abbreviations used in this paper: dpc, days postcoitum; CSF-1, macrophage colony-stimulating factor; ES cell, embryonic stem cell; EPC, ectoplacental cone.
Received for publication March 26, 1999. Accepted for publication June 3, 1999.
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G. R. Thomas, E. A. Costelloe, D. P. Lunn, K. J. Stacey, S. J. Delaney, R. Passey, E. C. McGlinn, B. J. McMorran, A. Ahadizadeh, C. L. Geczy, et al. G551D Cystic Fibrosis Mice Exhibit Abnormal Regulation of Inflammation in Lungs and Macrophages J. Immunol., April 1, 2000; 164(7): 3870 - 3877. [Abstract] [Full Text] [PDF]
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