1 Department of Molecular and Cellular Biology, Harvard University, Cambridge,
MA 02138, USA
2 Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3
7BN, UK
3 Department of Microbiology and Immunology, Stanford University School of
Medicine, Stanford, CA 94305, USA
4 Department of Microbiology, Columbia University College of Physicians and
Surgeons, New York, NY 10032, USA
¶ Authors for correspondence (e-mail: Elizabeth.Bikoff{at}well.ox.ac.uk or Elizabeth.Robertson{at}well.ox.ac.uk)
Accepted 14 January 2005
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SUMMARY |
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Key words: Blimp1/Prdm1 (Blimp-1), Mouse, Branchial arches, Vasculature, Primordial germ cells
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Introduction |
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Considerable evidence suggests that Blimp1 acts to control
anteroposterior axis formation and development of the head structures in early
vertebrate embryos. In Xenopus and zebrafish, Blimp1
transcripts localize to the signaling centers that pattern the forebrain,
namely the leading anterior mesendoderm and prechordal plate
(Baxendale et al., 2004;
de Souza et al., 1999
).
Overexpression of Blimp1 in Xenopus embryos downregulates
Xbra and Myf5 activities, which are required for formation
of trunk mesoderm, and consequently causes axis truncations. Blimp1
also activates anterior mesendodermal markers such as goosecoid and
cerberus in animal cap explant assays
(de Souza et al., 1999
).
Similarly, zebrafish embryos treated with Blimp1 antisense morpholino
oligonucleotides show loss of anterior structures and display a foreshortened
body axis (Baxendale et al.,
2004
). The analogous anterior signaling centers in mouse, namely
the anterior visceral endoderm (AVE) and anterior definitive endoderm
(ADE)/prechordal plate, have been shown to express Blimp1 transcripts
(de Souza et al., 1999
). Thus
it has been widely assumed that Blimp1 also plays a crucial role in
anterior patterning during mammalian development.
Blimp1 activity is also required for lineage specification in two
additional tissues in zebrafish. A hypomorphic allele of the Blimp1
ortholog u-boot (ubo) results in viable animals lacking
slow-twitch muscle fibers (Baxendale et
al., 2004; Roy et al.,
2001
). Molecular analysis reveals muscle precursors fail to
differentiate into slow-twitch fibers in response to Hh. ubo
activates expression of the slow myosin heavy chain, and represses expression
of the fast myosin heavy chain. Interestingly, ubo also acts
downstream of BMP signaling in specification of the trunk and cranial neural
crest precursors (Roy and Ng,
2004
). Whether Blimp1 similarly controls muscle
development and/or formation of neural crest derivatives in the mammalian
embryo remains unknown.
Here, we describe for the first time the defects caused by Blimp1
loss of function in the mouse. Blimp1-deficient embryos die at
mid-gestation, but surprisingly early axis formation, anterior patterning and
neural crest formation proceed normally. Rather loss of Blimp1
expression disrupts morphogenesis of the caudal branchial arches and leads to
a failure to correctly elaborate the labyrinthine layer of the placenta.
Blimp1 mutant embryos also show widespread blood leakage and tissue
apoptosis. Blimp1 transcripts are first detectable in the visceral
endoderm overlying the proximal epiblast prior to gastrulation, and within the
epiblast are restricted to the primordial germ cells (PGCs) at the time they
first appear in the posterior allantois. Blimp1 expression persists
as PGCs migrate anteriorly toward the genital ridges
(Chang and Calame, 2002).
Strikingly, we report here that Blimp1 homozygous mutants entirely
lack PGCs. Quantitative analysis of PGC numbers at sequential embryonic stages
reveals that this loss occurs at the time of their allocation around 7.25 days
post coitum (dpc). Moreover Blimp1 heterozygous embryos exhibit a
dose-dependent decrease in PGC numbers. The present experiments thus identify
Blimp1 as the first transcriptional regulator required for
establishment of the mammalian germ line.
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Materials and methods |
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Whole-mount in situ hybridization and histology
Whole-mount in situ hybridization was performed according to standard
protocols (Nagy et al., 2003).
Two Blimp1/Prdm1 probes were used. The first was derived
from the EST mB3 (IMAGE clone 1165721) specific for the 3'UTR, and the
second, generated by PCR, was specific for exons 4 and 5. No expression
pattern differences were observed between these two probes. Fgf8, Crabp1,
Shh, Hoxb1 and Evx1 probes have been described previously
(Dolle et al., 1989
;
Vincent et al., 2003
). India
ink was injected into the outflow tract of freshly isolated 9.5 dpc embryos to
visualize the major arteries. For histological analysis, embryos fixed in 4%
paraformaldehyde, were dehydrated through an ethanol series, and embedded in
wax before sectioning. Hematoxylin and Eosin staining was performed according
to standard protocols.
Alkaline phosphatase staining and SSEA1 immunostaining
Embryos were dissected from the decidua and Reichert's membrane. Pieces of
the extraembryonic tissue (7.75-8.5 dpc embryos) or yolk sac (9.5 dpc embryos)
were kept for genotyping. Alkaline phosphatase staining was performed as
described previously (Labosky and Hogan,
1999; Lawson et al.,
1999
). SSEA1 immunostaining was performed as previously described
(Gomperts et al., 1994
).
Statistics
Regression analysis and comparison of regression lines were performed using
the F test to compare variances (Snedecor
and Cochran, 1967).
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Results |
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Blimp1 functional loss causes branchial arch defects
Blimp1 is expressed in the anterior definitive endoderm, with
higher levels detected in the lateral region that subsequently gives rise to
the branchial arches (Fig.
3A,B). In mammalian embryos, the six pairs of branchial arches
develop in a cranial to caudal sequence. In the mouse, the first branchial
arch, the precursor of the maxilla and mandible, becomes morphologically
apparent at 8.5 dpc, with the second and third arches emerging over the course
of the next 24 hours. At 9.5 dpc, Blimp1 transcripts are restricted
to the endodermal layer of the proximal-most region, or cleft, of the first
branchial arch (Fig. 3C,D),
whereas, by contrast, expression expands into the endoderm, ectoderm and
mesenchyme of the more caudally situated second and third arches
(Fig. 3C,E). Interestingly
Blimp1 expression is transient, and from 10.5 dpc onwards is barely
detectable in pharyngeal tissues (Fig.
3F,G).
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Specification of the myotome and limb bud patterning is unperturbed in Blimp1 mutant embryos
Blimp1 shows a dynamic pattern of expression from 9.5 dpc onwards.
Interestingly, Blimp1 is expressed at the site where myogenesis is
initiated in the myotome of the most rostral somites (reviewed by
Tajbakhsh and Buckingham,
2000) (Fig. 4A). As
the more caudal somites mature, Blimp1 expression is detected in the
myotomal fibers along the rostrocaudal axis
(Fig. 4B,C), and by 11.5 dpc
becomes restricted to the myotome of the most caudal somites
(Fig. 4D). Expression is
confined to the intercalated mytome, located between the most epaxial and
hypaxial domains, where muscular differentiation is initiated
(Cheng et al., 2004
;
Spörle, 2001
).
Blimp1-deficient embryos die at 10.5 dpc, precluding our ability to
investigate its functional role in the myogenic lineage. However, the expanded
Fgf8 domain in the epaxial dermomyotomal lip of
Blimp1-deficient embryos suggests a potential role for
Blimp1 in regulation of the myogenic program in mouse
(Fig. 3J,M).
|
Embryonic lethality is associated with severe hemorrhage and placental defects
The major vascular structures of the early embryo, including the dorsal
aorta and the yolk sac vasculature form normally in Blimp1 mutant
embryos (Fig. 4). By 9.5 dpc,
the heart tube displays correct patterning, and has undergone normal looping
morphogenesis (Fig. 4G, compare
with 4F) and contracts
rhythmically. Histological analysis shows appropriate formation of the
myocardial and endocardial cell populations. However, one day later, mutant
embryos show widespread apoptosis and become severely hemorrhagic, with blood
pooling in the heart, dorsal aorta and under the surface ectoderm
(Fig. 5G). We wondered whether
the reduced growth rate and mid-gestation lethality might be caused by a
placental defect.
|
The major blood vessels did not display any obvious abnormalities prior to 10.5 dpc (Fig. 4). At 10.5 and 11.5 dpc, Blimp1 transcripts are detectable in the developing intersegmentary arteries and the endothelial cells of the superficial capillary plexus (Fig. 4C,E). PECAM staining of endothelial cells throughout the circulatory network of mutant embryos was unperturbed as assessed by whole mount immunohistochemistry (data not shown). Thus it appears that endothelial cells initially form in Blimp1 mutants, but that the rapid expansion of this cell population necessary to support embryonic growth is compromised. Alternatively, the loss of the caudal branchial arches, which prevents formation of the second and third pharyngeal arteries (Fig. 5C), may secondarily disrupt blood circulation. Conditional deletion of Blimp1 within the endothelial cell lineages is required to distinguish these possibilities.
Blimp1 is required for specification of primordial germ cells
Around 7.0 dpc, Blimp1 expression identifies committed PGCs as
they first appear at the base of the incipient allantois
(Fig. 1B). Expression persists
in PGCs as they proliferate and migrate anteriorly along the hindgut toward
the genital ridges (Chang and Calame,
2002). To evaluate whether Blimp1 is required for
specification and/or maintenance of the mammalian germ line, we compared PGC
numbers in wild-type, heterozygous and homozygous mutant embryos. PGCs are
easily identified due to their high endogenous levels of alkaline phosphatase
(AP) activity (Ginsburg et al.,
1990
; Lawson and Hage,
1994
). Intercross embryos were collected around 9.0-9.5 dpc. In
Blimp1 null mutant embryos (n=12), we failed to observe
AP-positive PGCs, and the number of PGCs in similarly staged heterozygous
embryos (n=58) was significantly reduced, when compared with wild
type (n=34) (Fig. 6B).
These results were confirmed by immunohistochemical staining with the SSEA1
monoclonal antibody (Gomperts et al.,
1994
). We failed to detect any migrating PGCs within the hindgut
epithelium of Blimp1 mutant embryos, and there were reduced numbers
of SSEA1-positive PGCs in heterozygotes, when compared with wild type
(Fig. 6C).
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Discussion |
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The identical phenotype results from two independent targeting strategies
that deleted different regions of the locus. Heart development per se proceeds
normally, but at around 10.5 dpc, we observe blood leakage from the
superficial capillaries, and accumulation of blood within the heart and dorsal
aorta. Mutations causing hemorrhaging phenotypes have been extensively
described in the various signaling pathways that control endothelial cell
function and formation (reviewed by Sato
and Loughna, 2002). Our experiments demonstrate that
Blimp1 is expressed in the endothelium and intersegmental arteries.
Specification of endothelial cells proceeds normally, as assessed by
histological examination and PECAM expression, suggesting that Blimp1
is not required during formation of the vasculature but probably acts later to
regulate angiogenesis and/or vascular remodeling. It will be interesting to
test this possibility in conditional mutants selectively lacking
Blimp1 in the endothelium.
The growth retardation and rapid death of the Blimp1-deficient embryos is most likely due to placental insufficiency. All of the specialized placental cell types are correctly specified in Blimp1 mutant embryos. However the labyrinth region, the site of major maternal/fetal exchange, is poorly developed at 9.5 dpc, and by 10.5 dpc, mutant placentas display striking morphogenetic defects coincident with rapid growth of the embryo. At this stage the essential nutrient and oxygen exchange functions provided by the visceral yolk sac normally shift to the mature placenta. Blimp1 transcripts are undetectable in the placenta, suggesting the labyrinth defects arise as a secondary consequence of abnormalities restricted to the embryonic vasculature. The importance of blood flow in shaping the vasculature is well documented. Reduced blood flow due to hemorrhage thus potentially disrupts the mechanical signals necessary for villous branching in the placental labyrinth.
Organogenesis and tissue patterning are largely unaffected. However,
Blimp1-deficient embryos display striking branchial arch defects. The
branchial arches form from four distinct cell subpopulations. The core,
comprising lateral mesenchymal cells and neural crest cells, interacts with
the adjacent endoderm and surface ectoderm tissues. Blimp1 is
expressed in the dorsal anterior regions of the emerging branchial arches,
specifically in the pharyngeal endoderm. In the first arch, Blimp1
transcripts are only present in the endoderm, whereas in the second and third
arch expression is more widespread, extending into the mesenchyme. Formation
of the second and third arches correctly initiates around 9.5 dpc, but in
Blimp1 mutant embryos these structures deteriorate shortly
thereafter. Reduced Blimp1 activity in the hypomorphic zebrafish
mutant ubo similarly leads to pectoral fin defects, implicating an
evolutionarily conserved role for Blimp1 in patterning branchial arch
derivatives (van Eeden et al.,
1996).
In fish, BMP signals induce Blimp1 expression at the boundary
between neural and non-neural ectoderm, which in turn promotes formation of
neural crest and sensory neuron progenitors
(Roy and Ng, 2004). However,
the caudal branchial arch defects described here cannot be explained as a
deficiency in neural crest because Crabp1 expression in
Blimp1 mutant embryos is unperturbed. Thus, neural crest cells are
correctly specified and efficiently migrate into the forming arches. Rather,
branchial arch defects closely resemble those caused by reduced Fgf signaling.
Fgf8 is expressed in both the branchial arch ectoderm and endoderm,
and is required for survival of the neural crest. Localized cell death has
been observed in the branchial arches of Fgf8 hypomorphs and
conditional mutants (Abu-Issa et al.,
2002
; Frank et al.,
2002
; Macatee et al.,
2003
; Trumpp et al.,
1999
). Blimp1 mutants similarly display numerous
apoptotic cells with pyknotic nuclei in caudal branchial arches. These results
suggest that Blimp1 positively regulates Fgf8 in the
pharyngeal endoderm. The pharyngeal endoderm is thought to play a crucial role
in coordinating branchial arch outgrowth (reviewed by
Graham, 2003
;
Graham et al., 2004
). Cell
death in the arches probably compromises continued arch outgrowth, and
disrupts the survival or mitogenic cues necessary to create a permissive
environment for incoming neural crest and paraxial mesenchyme.
Interestingly these defects are restricted to branchial arches 2 and 3,
whereas the first arch develops normally, a phenotype reminiscent of the
Raldh2 mutants and those rescued by maternal retinoic acid (RA)
supplementation (Niederreither et al.,
1999; Niederreither et al.,
2003
). Expression of the RA-responsive genes Hoxa1 and
Hoxb1, normally present in the foregut endoderm, is entirely absent
in Raldh2 mutants, and these transcripts are expressed at reduced
levels in the rescued embryos. Interestingly, the first arch does not express
either of these Hox genes. By contrast, formation of the posterior arches is
sensitive to fluctuating Hox levels (Rijli
et al., 1993
; Rossel and
Capecchi, 1999
). Here, we observe that Blimp1 is
co-expressed with Hoxa1/Hoxb1 in the foregut endoderm. An attractive
idea is that the focal defects in arch formation reflect selective
Blimp1 requirements upstream of Hox gene expression. It will be
interesting to learn more about Blimp1 targets in the branchial
arches and the extent to which these pathways overlap with those governing
terminal B cell differentiation and germ cell specification.
Here, we demonstrate for the first time that the zinc-finger
transcriptional repressor Blimp1 is required for specification of the
mammalian germ line. Blimp1 transcripts appear to tightly localize to
PGCs, coincident with their emergence in the extra-embryonic mesoderm.
Blimp1 is initially expressed in a subpopulation of VE overlying the
proximal region of the epiblast adjacent to the distal extra-embryonic
ectoderm. It is well known that Bmp4 plays an essential role during germ-cell
specification. Bmp4 signals from the extra-embryonic ectoderm
(Lawson et al., 1999),
together with Alk2, which is expressed in the VE
(de Sousa Lopes et al., 2004
),
and the intracellular effectors Smad1, Smad5 and Smad4
(Chang and Matzuk, 2001
;
Chu et al., 2004
;
Tremblay et al., 2001
) are
required to promote both germ cell and posterior mesoderm/allantoic fates in a
dose-dependent fashion. As for neural crest progenitors in zebrafish
(Roy and Ng, 2004
), we suggest
that the Bmp4 pathway also governs Blimp1 induction during germ-cell
specification. Relatively little is known about transcriptional control at the
Blimp1 locus, but we speculate that Blimp1 expression in
PGCs in part depends on Bmp4 signals acting upstream of Smad effector
proteins. Consistent with this idea Smad1, Smad5 and Smad4 mutant embryos
display germ-cell defects (Chang and
Matzuk, 2001
; Chu et al.,
2004
; Tremblay et al.,
2001
).
A recent screen identified two candidate genes potentially involved in the
establishment of germ-cell competence in the proximal epiblast
(Saitou et al., 2002).
Fragilis/Ifitm3, an interferon-inducible transmembrane protein, is broadly
induced in proximal epiblast cells adjacent to the extra-embryonic ectoderm
(Tanaka and Matsui, 2002
;
Tanaka et al., 2004
), and is
activated in response to Bmp4 signaling in a dose-dependent fashion.
Expression rapidly resolves to the proximal posterior side of the embryo, and
becomes confined to the PGCs, but its functional role in germ-cell
specification has yet to be characterized. The gene stella
(Dppa3 - Mouse Genome Informatics), encodes a novel intracellular
protein, activated later within the PGCs, that is nonessential for germ-cell
specification (Payer et al.,
2003
; Bortvin et al.,
2004
). It has been proposed that genes such as fragilis and stella
act to turn off genes that promote somatic cell fates, including transcription
factors such as Hoxb1 and Evx1, and thus create a niche for
PGC specification (Saitou et al.,
2002
).
The present data suggests that Blimp1 turns off the default pathway that allows epiblast cells to adopt a somatic cell fate and shifts the transcriptional profile so that Blimp1-expressing cells become exclusively allocated into the germ-cell lineage. Germ-cell specification involves the repression of region-specific homeobox genes such as Hoxa1/Hoxb1, Lim1 and Evx1 in adjacent somatic cells. Evx1 and Hoxb1 expression domains were not expanded in Blimp1-deficient embryos (data not shown), but this might reflect our inability to assess expression at single-cell resolution via WISH. Interestingly, we observe pronounced dose-dependent Blimp1 requirements, which suggests that a relatively high threshold of Blimp1 activity is required for germ-cell differentiation and survival. An important future goal is the identification of Blimp1 targets downstream in the molecular program responsible for specification of germ cells.
In Xenopus, Blimp1 activates Cerberus expression and
antagonizes TGFß and Wnt signals (de
Souza et al., 1999). However TGFß antagonists play more a
subtle role in axis patterning in mouse embryos. Indeed, mutants lacking
cerberus (Cer1 - Mouse Genome Informatics) are viable, most
likely as a result of redundancy in these signaling pathways. Cerberus
activities in mice were only uncovered in double-mutant embryos also lacking
Lefty1, a second TGFß family antagonist
(Perea-Gomez et al., 2002
).
Cerberus is thus also a candidate Blimp1 target in early mouse
embryos.
Blimp1 contains five consecutive Krüppel-type zinc fingers in the
C-terminal region, and a positive-regulatory (PR) domain at the N terminus
that is necessary for chromatin remodeling. The middle proline-rich region
recruits members of the Groucho family of co-repressors and members of the
histone deacetylase families (Ren et al.,
1999; Yu et al.,
2000
). These various functional modules coordinate the ability of
Blimp1 to function as a master regulator of gene expression.
Considerable evidence suggests that Blimp1 acts as a DNA-binding
scaffold protein capable of directly recruiting multiple chromatin-modifying
enzymes to targeted promoters. The molecular mechanisms underlying
Blimp1 activities during plasma cell differentiation have been
extensively characterized. As a master regulator of the B-cell lineage,
Blimp1 functions upstream of transcription factors such as CTIIA and
Pax5, which govern antigen presentation and receptor signaling
(Lin et al., 2002
;
Piskurich et al., 2000
).
Blimp1 also represses genes, such as Myc, which are involved
in cell cycle progression (Lin et al.,
1997
). In contrast, Blimp1 activates expression of XBP, a
transcription factor in the unfolded-protein-response pathway that is required
for plasma cell differentiation (Lin et
al., 2002
; Shaffer et al.,
2002
; Shapiro-Shelef et al.,
2003
). The present study demonstrates that Blimp1 is an
essential regulator of branchial arch formation and germ cell specification.
Future experiments aim to characterize how Blimp1 promotes programmed
differentiation and/or survival of these distinct cell types in the developing
mammalian embryo.
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ACKNOWLEDGMENTS |
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Footnotes |
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Present address: ES Cell International, Singapore
Present address: Department of Molecular Genetics and Cell Biology,
University of Chicago, Chicago, IL, USA
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