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First published online 30 August 2006
doi: 10.1242/dev.02552
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1 Laboratory of Reproductive and Developmental Toxicology, National Institute of
Environmental Health Sciences, 111 T. W. Alexander Drive, PO Box 12233, MD
C4-10, C458, Research Triangle Park, NC 27709, USA.
2 Department of Cell Biology, Duke University Medical Center, Durham NC 27710,
USA.
* Author for correspondence (e-mail: mishina{at}niehs.nih.gov)
Accepted 26 July 2006
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Epiblast, Primitive streak, Paraxial mesoderm, Somites, BMP, FGF, Mouse
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In this case, `proximal' refers to the end of
the primitive streak closest to the extra-embryonic tissues. At the early to
mid streak stage, primarily future extra-embryonic mesodermal cells are
recruited to the proximal primitive streak and they are committed to yolk sac
mesoderm (Kinder et al., 1999;
Lawson et al., 1991;
Parameswaran and Tam, 1995).
By the late streak stage, prospective lateral plate mesoderm (LPM) and
paraxial mesoderm (PXM) cells are recruited to the middle and anterior
primitive streak, respectively, and become committed to trunk mesoderm
(Kinder et al., 1999;
Parameswaran and Tam, 1995;
Tam and Quinlan, 1996).
However, the molecular mechanisms involved in recruitment of the epiblast
cells are largely unknown (Tam and
Behringer, 1997).
It is now well established that BMP signaling regulates the development of
many embryonic cell types, including the heart and hematopoietic tissues
(Kishigami and Mishina, 2005;
Mishina, 2003). The
development of the lateral plate is also regulated by BMP signaling. Hensen's
node or the BMP antagonist Noggin can generate somites from lateral plate
cells (Hornbruch et al., 1979;
Tonegawa and Takahashi, 1998).
Thus, BMP signaling plays a role in patterning the LPM. In addition to BMPs,
other growth factors are crucial for somitic development. For example,
fibroblast growth factor receptor 1 (Fgfr1) deficient embryos do not
form somites, and FGF signaling is involved in the development of the PXM
lineage (Ciruna and Rossant,
2001; Yamaguchi et al.,
1994). Thus, one can speculate that there is a high potential for
interaction between BMP and FGF signaling during mouse mesoderm development.
However, little is known about how they might interact to regulate paraxial
versus other mesodermal tissues.
Bmpr1a encodes the type 1 BMP receptor BMPR1A, which is known to
be a receptor for BMP2 and BMP4 (Mishina,
2003). These molecules constitute a major BMP signaling component
in early mouse development. However, because Bmpr1a-null mutant
embryos do not initiate gastrulation
(Mishina et al., 1995), the
function of Bmpr1a during gastrulation in mice is largely unknown. To
elucidate functions of BMP signaling through BMPR1A during and after
gastrulation, we have generated a conditional allele of Bmpr1a
(Mishina et al., 2002). The
Mox2-Cre (MORE) strain drives mosaic Cre-mediated
recombination in the epiblast, providing a useful tool for reducing but not
completely abolishing gene expression in the epiblast
(Hayashi et al., 2002;
Tallquist and Soriano, 2000).
For simplicity, we refer to embryos in which Bmpr1a is ablated as a
result of MORE activity as Bmpr-MORE embryos. Our previous studies
using Bmpr-MORE embryos showed that the anterior neural ectoderm was
enlarged at the expense of surface ectoderm, and that endodermal morphogenesis
was defective (Davis et al.,
2004). Here, the development of mesodermal tissues is studied in
Bmpr-MORE embryos. The results indicate that Bmpr1a in the
epiblast is required to regulate the recruitment of prospective PXM cells
correctly and consequently to direct normal somite development. Our results
also indicate that BMP and FGF signaling interact for proper development of
the mesoderm during gastrulation.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). All mouse
experiments were performed in accordance with NIH and institutional guidelines
covering the humane care and use of animals in research.
Whole-mount in situ analysis
Whole-mount in situ was performed as described
(Belo et al., 1997). Probes
used were brachyury (Wilkinson et al.,
1990), Lefty2 (Meno
et al., 1999), Foxf1
(Mahlapuu et al., 2001),
Bmp4 (Winnier et al.,
1995), Lim1 (Tsang et
al., 2000), Mox1
(Candia et al., 1992),
Uncx4.1 (Leitges et al.,
2000), Pax1 (Wallin
et al., 1996), Foxa2
(Sasaki and Hogan, 1994),
Tbx6 (Chapman et al.,
1996), Pcdh8
(Yamamoto et al., 2000),
Epha4 (Durbin et al.,
1998) and noggin (McMahon et
al., 1998).
Cell lineage analysis
Embryos were harvested in dissecting medium
(Miura and Mishina, 2003).
Cell lineage analysis was carried out as described previously
(Wilson and Beddington, 1996).
Briefly, a 0.5% stock solution of
1,1'-dioctadecyl-3,3,3',3'-tetramethy-indocarbocyanine
perchlorate (DiI) (Molecular Probes) in 100% ethanol was diluted tenfold with
0.3 M sucrose before use. DiI solution (0.05%) was sucked into a glass needle
of 25 µm diameter (HUMAGEN). The tip of the needle softly touched the
posterior region of the embryo, tore through the visceral endoderm and then
DiI was released to label the mesoderm. These embryos were cultured with DR50
in a rotating glass bottle (BTC engineering) supplied with 5% O2
and CO2 balanced with N2 at 37°C. After culture,
embryos were placed in phosphate-buffered saline (PBS) and observed with a
stereo-dissection microscope (Leica) under visible or ultra violet light, and
imaged.
Inhibition of FGF signaling
SU5402 (CALBIOCHEM) was suspended in dimethyl sulfoxide (DMSO) (Sigma) as a
10 mM solution and kept at -20°C until use. E6.5-6.75 embryos were
cultured with DR50 containing either SU5402 or DMSO for indicated lengths of
time in rotating glass bottles.
Immunohistochemistry
Cultured embryos were washed in cold PBS and fixed with 4% paraformaldehyde
overnight, dehydrated and embedded in paraffin. Sections (7 µm) were
deparaffinized and stained with anti-phosphoErk1/2 antibody (Cell Signaling
Technology) using an ABC kit (Vector Laboratories) according to manufacturers'
protocols.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). However,
morphological defects were apparent in Bmpr-MORE embryos starting at
E7.5. At the allantoic bud stage, control embryos had a distinctly formed
amnion and chorion (Fig. 1A),
while mutant embryos were characterized by a poorly formed amniotic fold and
acute posterior curvature (Fig.
1A'). Amnion and chorion were not formed yet at the
head-fold stage in Bmpr-MORE embryos
(Fig. 1B'). In addition,
a typical cardiac crescent did not develop in Bmpr-MORE embryos
(Fig. 1C,C' arrowheads).
At E8.5, multiple defects were observed, including a striking lateral
expansion of somites (Fig.
1D',F').
Histological sectioning at E8.5 revealed important aspects of these and
other mesodermal phenotypes. In control embryos, somites developed as a single
column on each side of the neural tube
(Fig. 1F,G). In
Bmpr-MORE embryos, ectopic mutant somites developed and extended
laterally to form multiple irregular columns
(Fig. 1F',G'). The
mutant somites formed typical ball-like epithelialmesenchymal structures
(Fig. 1F',G'). In
control embryos, LPM formed lateral to somites and medial to visceral yolk sac
(Fig. 1E,G). In
Bmpr-MORE embryos, lateral plate was apparently lacking, but cell
masses were observed anterior and lateral to the paraxial somites and medial
to the yolk sac, suggesting abnormal development of LPM
(Fig. 1F',G'). The
heart formed at the most anterior end of normal embryos, but no analogous
structure formed in Bmpr-MORE embryos
(Fig. 1G,G'). Notochord
was formed and expressed markers such as sonic hedgehog
(Fig. 1G')
(Davis et al., 2004). The
amnion was formed at this stage, but the allantois was notably small in the
mutant embryos (Fig.
1H').
Bmpr-MORE embryos were mosaic for recombined
Bmpr1a-/- (mutant) cells and heterozygous cells
(Davis et al., 2004). It is
therefore important to know if both cell types distribute evenly or unevenly
during development among all three germ layers. If there were a bias in their
distribution, it might affect the mutant phenotype. We used a mouse line
R26R to visualize mutant and heterozygous cells
(Soriano, 1999). This is a
reporter line for Cre recombinase, which marks those cells that have
undergone recombination by expression of lacZ. As observed
previously, both cell types were distributed evenly among tissues in control
and mutant embryos (Fig. 1I-L)
(Davis et al., 2004). These
results indicate that Bmpr1a signaling in the epiblast did not
restrict cells to or from any germ layer or major tissue in the early embryo.
Thus, both mutant and heterozygous cells simultaneously traversed the
primitive streak and ingressed into mesodermal tissues, resulting in a loss of
BMPR1A signaling in most, but not all, epiblast-derived cells.
By contrast, Sox2-Cre mice catalyze complete recombination of
loxP sequence in the epiblast
(Fig. 1M,O)
(Hayashi et al., 2002),
allowing us to obtain embryos with total loss of BMPR1A signaling in the
epiblast-derived tissues (Fig.
1N,P). Many of such mutant embryos showed a remarkably similar
phenotype to Bmpr-MORE embryos, namely lateral expansion of somites
(Fig. 1N,P). Having the similar
phenotype both in Bmpr-MORE and Sox2Cre;
Bmpr1aflox/null embryos implies that downstream targets of
BMPR1A signaling act in a non-cell-autonomous manner to regulate early mouse
epiblast development.
Correct patterning of ectopic somites and improper patterning of lateral plate mesoderm
To further explore how mutant somites were patterned, the expression for
several markers for PXM development was examined. Normally, Uncx4.1
(a marker for the caudal region of each somite)
(Leitges et al., 2000) or
Dll1 (Bettenhausen et al.,
1995) (a marker for caudal somite and presomitic mesoderm) was
expressed as a column on each side of the embryo
(Fig. 2A; data not shown). In
mutant embryos, Uncx4.1 or Dll1 was expressed in multiple
irregular columns on each side of the embryo, forming short mediolateral rows
of expression domains (Fig.
2A'; data not shown). Uncx4.1 was correctly
expressed in caudal region of each somite in both control and mutant embryos
(Fig. 2B,B'). The
expression domain of Epha4 (Durbin
et al., 2000) or Mesp2
(Saga et al., 1997) (markers
of rostral presomitic mesoderm) was laterally broadened, indicating the
expansion of presomitic mesoderm (Fig.
2C'; data not shown). Mox1 (a paraxial mesoderm
marker) (Candia et al., 1992),
which is normally expressed in the somites
(Fig. 2D,E), was not only
expressed in expanded somites but also in cells of the LPM domain
(Fig. 2D',E'),
suggesting the LPM had acquired PXM fate. The expression domain of
Pax1 (a marker for sclerotome)
(Wallin et al., 1996) was also
expanded in mutant embryos (Fig.
2F'). These data show that somites extended abnormally to
the lateral edges of the embryo but individual somite were largely patterned
correctly in Bmpr-MORE embryos.
By contrast, mutant LPM was very poorly patterned. Foxf1 was
normally expressed in LPM starting at E8.5
(Fig. 2G)
(Mahlapuu et al., 2001). In
Bmpr-MORE embryos, expression of Foxf1 was patchy and often
weak (Fig. 2G'). Some
mutants did not express Foxf1 at all, suggesting some variability of
phenotype; this is possibly a result of the mosaic nature of the mutant
embryos. Bmp4 was expressed in allantois, the posterior primitive
streak and LPM at E8.5 (Fig.
2H) (Winnier et al.,
1995). In Bmpr-MORE embryos, Bmp4 was expressed
in allantois and the primitive streak but not in LPM
(Fig. 2H'). Lim1
expression was normally observed in LPM at E7.75
(Fig. 2I)
(Tsang et al., 2000). In
Bmpr-MORE embryos, Lim1 expression was either not expressed
or lower than normal (Fig.
2I'; data not shown). These data indicate that
Bmpr1a is required for proper patterning of LPM in normal
development.
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). In
the notochord, the expression reached the anterior end of embryos
(Fig. 3A). However, in
Bmpr-MORE embryos, the most anterior domain of brachyury
expression was in the distal region of the embryo
(Fig. 3A'). In a control
embryo at the allantoic bud stage, Foxa2 was expressed in the node,
notochord and anterior definitive endoderm
(Fig. 3B)
(Sasaki and Hogan, 1994). The
node is formed at the most distal region of the primitive streak. In
Bmpr-MORE embryos, the node was formed more proximally than
in control embryos (Fig.
3B'). Similar observations were made using probes for noggin
(Fig. 3C') and
Lim1 (see Fig. S1A' in the supplementary material)
(McMahon et al., 1998;
Tsang et al., 2000). These
results indicate that the distoanterior extension of the primitive streak was
defective in Bmpr-MORE embryos. However, by the head-fold stage, the
primitive streak of Bmpr-MORE appeared to be fully elongated
(Fig. 3D'; see Fig.
S1B' in the supplementary material). Thus, primitive streak extension
was temporally delayed in Bmpr-MORE embryos during gastrulation.
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;
Meno et al., 1999). In
Bmpr-MORE embryos, the expression domain for Lefty2
was decreased and observed only in the proximal embryonic region
(Fig. 3E'). Tbx6
was also expressed in LPM and PXM at the late streak stage (see Fig. S1C in
the supplementary material) (Chapman et
al., 1996), but its expression was also decreased and observed in
only the proximal embryonic region in Bmpr-MORE embryos (see Fig.
S1C' in the supplementary material). Thus, a reduced amount of LPM
and/or PXM was induced in Bmpr-MORE embryos by the late-streak stage.
These results suggest that the recruitment of prospective LPM and/or PXM to
the primitive streak was delayed. This, in turn, caused a delay in the
extension of the primitive streak in Bmpr-MORE embryos. To further probe the temporal nature of mesoderm formation, we performed a cell lineage experiment using DiI, a tracer of living cells; this allowed us to label mesodermal cells with DiI, then to analyze their fate after culturing them for a defined period. DiI was injected into the proximal region of the primitive streak to label mesoderm cells of control or Bmpr-MORE embryos at the late streak stage (Fig. 4A,B). The embryos were then cultured for approximately 30 hours until the organogenesis stage (Fig. 4A',B'). As expected, in control embryos, labeled cells contributed to lateral plate (3/3) and yolk sac (3/3) (Fig. 4A',A''). Similarly, in all mutant embryos (5/5), labeled cells were distributed in regions of the embryo anterior and lateral to the paraxial region, but not to the somites (Fig. 4B',B''). Labeled cells were also distributed in the yolk sac (3/5) (Fig. 4B',B''). DiI was also injected into the anterior and distal region of the primitive streak of control or Bmpr-MORE embryos at the late streak stage (Fig. 4C,D). In control embryos, labeled cells contributed to somites and an axial tissue, which was probably axial mesoderm (3/3) (Fig. 4C',C''). However, in the mutant embryos, labeled cells did not contribute to the paraxial region but rather to the anterior region and an axial tissue of the embryo (4/4) (Fig. 4D',D''). These results indicate that the recruitment of prospective PXM had not occurred yet at the late streak stage in Bmpr-MORE embryos.
At the allantoic bud stage, Lefty2 was normally expressed in
migrating LPM and PXM cells (Fig.
3F). The two domains of expression were basically contiguous,
suggesting that recruitment of prospective LPM and PXM occurs continuously. In
Bmpr-MORE embryos, we found two domains of expression for
Lefty2 that were separated (Fig.
3F'). The more anterior domain most probably represented
migrating LPM (Fig. 3F').
The other domain revealed mesoderm more recently recruited at the anterior and
middle region of the primitive streak (Fig.
3F'). The same observations were made for the expression of
paraxial procadherin (PCDH8), a trunk mesoderm marker at this stage
(Fig. 3G')
(Yamamoto et al., 2000).
Lefty2 was actively transcribed even at the head-fold stage in
Bmpr-MORE embryos (Fig.
3H'). These results further suggest that production of
presumptive PXM was delayed in Bmpr-MORE embryos relative to control
littermates of the same stage.
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Inhibition of FGF signaling restores proper recruitment of prospective PXM and partially rescues the abnormal expansion of somites in Bmpr-MORE embryos
Embryos deficient for fibroblast growth factor receptor type 1 (FGFR1) do
not form somites, indicating that FGF signaling is involved in the development
of the PXM lineage (Ciruna and Rossant,
2001; Yamaguchi et al.,
1994). In Bmpr-MORE embryos, LPM acquired PXM character
(Fig. 2D',E').
These observation led us to hypothesize that BMP signaling protects LPM from
FGF signaling, which otherwise might cause the LPM to acquire PXM character.
This hypothesis was tested by culturing E6.5-6.75 embryos in the presence of
the FGFR1 antagonist SU5402 (Mohammadi et
al., 1997). We reasoned that if the essential function of
Bmpr1a in terms of LPM development is to antagonize FGF signaling,
SU5402 should be able to mitigate the abnormal patterning of LPM in
Bmpr-MORE mutants.
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), we also tested the effect of 20 µM of SU5402. Control
embryos developed normally at this concentration. By contrast, mutant embryos
developed an amnion, chorion and allantois (12/12)
(Fig. 5B,F). Moreover, the
primitive streak appeared to extend normally in such embryos
(Fig. 5B), suggesting that the
recruitment of prospective PXM had occurred normally in Bmpr-MORE
embryos in culture. Next, cultured embryos were tested for their expression of
phosphorylated Erk1/2 to evaluate the level of signaling transduced by FGFR1
(Corson et al., 2003). The
expression was observed most strongly in extraembryonic ectoderm derived
tissues and ectoplacental cone (Corson et
al., 2003). In embryos cultured with DMSO, strong expression was
observed in the chorion or amniotic fold and ectoplacental cone
(Fig. 5C,D). When cultured with
20 µM SU5402, expression was still observed strongly in the ectoplacental
cone. However, the expression in the chorion was significantly reduced,
indicating that signaling from FGFR1 was inhibited in both control and
Bmpr-MORE embryos (Fig.
5E,F). We then examined the expression of Lefty2 in
cultured embryos. As observed in vivo, the expression of Lefty2 in
mutant embryos cultured with DMSO was abnormal; the expression was shifted
proximally and decreased (3/3) (Fig.
6B). However, when cultured with 20 µM SU5402, Lefty2
was expressed at a normal level in mutant embryos (2/2)
(Fig. 6D). These results
indicate that inhibition of FGF signaling via reduction of FGFR1 activity
rescued the delayed recruitment of prospective PXM in Bmpr-MORE
embryos.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Bmpr-MORE embryos at the allantoic bud stage showed a
characteristic morphology: an acute curvature in the posterior side, which was
due to a delay of primitive streak extension. Our results indicate that
recruitment of prospective PXM that normally occurs during the mid to late
streak stage was delayed and took place during the allantoic bud to head fold
stage in Bmpr-MORE embryos. Normally, the prospective PXM population
arises mainly at the anterior primitive streak. Our results indicate mesoderm
cells with PXM character arise in the middle in addition to the anterior part
of the primitive streak. The distoproximal order of the prospective mesoderm
cells within the primitive streak is maintained during ingression of cells
from the primitive streak into the mesoderm
(Smith et al., 1994).
Presumably, PXM cells in the middle part of the primitive streak migrate more
laterally and PXM cells at the distal part of the primitive streak migrate
more medially, thus causing an altered morphogenesis of somites in
Bmpr-MORE embryos.
We propose two possible models to explain the mechanism of how ectopic somites develop in Bmpr-MORE mutant embryos. The first model proposes that loss of BMP signaling causes a fate change of epiblast cells passing through the middle primitive streak, which would normally form the LPM, and that these cells consequently form ectopic somites (Fig. 7B, yellow arrow). The second model posits that the delay of recruitment in Bmpr-MORE embryos causes abnormal morphogenetic movement of prospective PXM cells upon recruitment to the primitive streak (Fig. 7C). Normally, these cells are recruited to the anterior primitive streak and exit from the anterior primitive streak (Fig. 7A, red arrow). In the mutant embryos, these cells are abnormally recruited to the middle primitive streak to form ectopic somites (Fig. 7C, yellow arrow).
FGF signaling induces PXM patterning via expression of brachyury and
Tbx6 (Ciruna and Rossant,
2001). However, inhibition of FGF signaling in Bmpr-MORE
embryos restored normal timing of prospective PXM recruitment. Together, these
data indicate that FGF signaling negatively regulates recruitment of
prospective PXM cells but is required for their patterning. Interestingly, we
found that BMPs do not regulate the recruitment of prospective LPM cells, but
they are essential for LPM patterning (this study). These observations suggest
that a mechanism(s) might be present that are responsible for controlled
allocation of mesoderm and thus for successful establishment of mouse body
plan.
Control embryos treated with 20 µM SU5402 developed apparently normally
up to the allantoic bud stage. However, Fgf8-deficient mice exhibit a
marked decrease in migration of mesoderm cells out of the primitive streak
during gastrulation (Sun et al.,
1999). Probably, the concentration of SU5402 used here does not
sufficiently inhibit FGF signaling to elicit this migratory defect.
It is unlikely that BMP signaling directly inhibits FGF signaling. In Bmpr-MORE embryos, the phosphorylation of ERK1 and ERK2, major signal transducers of FGF signaling appears at the normal level. In addition, Snai1, one of target genes of FGF signaling, is expressed normally in mutant embryos (data not shown). Rather, downstream targets of BMP and FGF signaling are probably involved in antagonistic effects.
Through the analyses of Bmpr-MORE embryos, we identified novel functions of BMP signaling in gastrulation. However, many issues remain to be addressed. The mechanism that explains delayed recruitment of epiblast cells (prospective PXM) is unknown, although we showed that BMP and FGF signaling have antagonistic effects on this process. The identification of such mechanisms and the assessment of their functions are crucial for a more thorough understanding of mouse gastrulation.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/133/19/3767/DC1
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ACKNOWLEDGMENTS |
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