1 Institut de Génétique et de Biologie Moléculaire et
Cellulaire, CNRS/INSERM/ULP/Collège de France, BP 10142, 67404 Illkirch
Cedex, CU de Strasbourg, France
2 Departments of Medicine and Molecular and Cellular Biology, Center for
Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza,
Houston, Texas 77030, USA
* Author for correspondence (e-mail: dolle{at}igbmc.u-strasbg.fr)
Accepted 24 February 2003
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SUMMARY |
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Key words: Retinoids, Branchial arches, Pharyngeal endoderm, DiGeorge syndrome, Hirschprung's disease, Mouse mutant
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INTRODUCTION |
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Interestingly, Raldh2/ null mutant
embryos, which are severely impaired in their capacity to synthesize RA, die
at midgestation (E9.5-10.5) because of severe defects of early heart
morphogenesis (Niederreither et al.,
1999; Niederreither et al.,
2001
). These mutant embryos also exhibit an altered development of
trunk mesoderm derivatives, as well as growth and patterning defects of the
posterior hindbrain region and an apparent lack of development of all
branchial arches, with the exception of the first one
(Niederreither et al., 1999
;
Niederreither et al., 2000
).
Several of these abnormalities have been shown to be rescued through maternal
RA supplementation from embryonic day 7.5 (E7.5) to at least E8.5
(Niederreither et al., 1999
;
Niederreither et al., 2002
).
These rescued Raldh2/ mutants consistently
exhibit outflow tract septation defects (PTA), which most probably account for
their death prior to (or at) birth, and extending the duration of RA
supplementation (e.g. until E10.5 or 12.5) has no effect on the septation
defect (Niederreither et al.,
2001
).
We have determined here the defective developmental events that lead to PTA in the RA-supplemented Raldh2/ mutants, and have characterized a number of additional abnormalities exhibited by these rescued mutants. Most notably, we show for the first time that RA deficiency can lead to a Hirschprung disease-like phenotype (agenesis of the enteric ganglia) due to vagal crest deficiency.
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MATERIALS AND METHODS |
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Whole-mount in situ hybridizations were performed as described previously
(Décimo et al., 1995),
using template plasmids cloned in our Institute or kindly provided by Drs G.
Barsh (Stanford University, CA; kreisler/Mafb), P. Gruss (MPI,
Göttingen; Pax1, Pax9), R. Krumlauf (Stowers Institute, Kansas
City, MI; Hoxa2) G. Martin (UC San Fransisco, CA; Fgf8).
Whole-mount X-gal assays of embryos carrying a RARE-hsp68-lacZ
reporter transgene, which harbors a tetrameric repeat of the
RARß2 RARE linked to the hsp68 minimal
promoter, were performed as described previously
(Rossant et al., 1991
).
Anti-neurofilament staining with the 2H3 monoclonal antibody (Developmental
Studies Hybridoma Bank, Iowa City, IA) and in situ hybridization on
cryosections were performed as described previously
(Mark et al., 1993
;
Niederreither and Dollé,
1998
).
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RESULTS |
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Interestingly, this expression pattern did not really match the spatial
activity of a RA-inducible reporter transgene
(Rossant et al., 1991) (see
Materials and Methods). In wild-type E8.5 embryos, the reporter transgene was
expressed at high levels along the foregut wall, up to the posterior edge of
the developing 2nd arch (Fig.
2H). Furthermore, the RA-reporter transgene was activated in both
the endodermal and mesodermal layers of the foregut pocket
(Fig. 2H). RA-reporter activity
also extended further rostrally in the dorsal (hindbrain-adjacent) mesenchyme
up to the otocyst level (Fig.
2H), whereas Raldh2 transcripts did not reach the otocyst
(Fig. 2E,F).
RA-reporter transgene activity was clearly weaker in the RA-rescued Raldh2/ mutant embryos (Fig. 2I,J) although its spatial distribution was comparable to that seen in wild-type embryos (Fig. 2H). Downregulation was seen in both the endodermal and mesodermal layers of the foregut. In the most severe cases, expression was restricted to scattered cells in the branchial region and the hindbrain mesenchyme (Fig. 2J). However, these cells extended almost as rostrally as in wild-type embryos (Fig. 2H).
Impairment of endodermal and mesodermal foregut gene expression in
rescued Raldh2-null mutants
The homeobox genes Hoxa1 and Hoxb1 are known to be
RA-regulated, both in vitro and in vivo, through RAREs located in their
regulatory regions (Gavalas et al.,
1998). Expression of both genes was selectively downregulated in
the foregut region of the RA-rescued Raldh2/
embryos (Fig. 3A-F).
Downregulation was seen in both the endoderm and mesoderm of the posterior
foregut (compare Fig. 3C,E and
D,F). Expression of both genes in the tail bud and posterior trunk
tissues, as well as Hoxb1 expression in the 4th rhombomere (r4), was
not detectably altered in the mutant embryos
(Fig. 3A,B, and data not
shown).
FGF8 is a signaling molecule expressed in specific regions of the wild-type
branchial arch ectoderm and endoderm
(Crossley and Martin, 1995;
Wall and Hogan, 1995
). Within
the endoderm, Fgf8 expression is highest at the level of the
developing pharyngeal pouches (Fig.
3I). Fgf8 was expressed at abnormally low levels along
the posterior branchial arch region of E9.5
Raldh2/ embryos, and its spatial
distribution was altered. Scattered ectodermal Fgf8-expressing cells
were observed in mutant embryos from the level of the 2nd-3rd branchial cleft
down to ectopic posterior locations, almost reaching the level of the forelimb
bud rudiment (compare Fig. 3G and
H, bracket). Furthermore, there was almost no detectable
Fgf8 expression in the mutant pharyngeal endoderm, except at the
level of the developing 2nd pouch (compare
Fig. 3I and J). The
distribution and levels of expression of Fgf8 were unaltered in the
first branchial arch, as well as in other craniofacial regions, of the mutant
embryos (Fig. 3H,J, and data
not shown).
We also analyzed Pax1 and Pax9 transcript distributions
in mutant embryos, as these genes are differentially expressed along the
endoderm of the developing pharyngeal pouches
(Müller et al., 1996).
Both Pax1 (data not shown) and Pax9
(Fig. 3K,L) expression patterns
confirmed the lack of a distinct 3rd pharyngeal pouch and the formation of a
single, enlarged 2nd pouch in E9.5 mutant embryos
(Fig. 3L, `p2'). Despite this
abnormality, Pax9 was differentially expressed along the dorsoventral
axis of the mutant 2nd pouch, in a pattern similar to that seen in the
wild-type 2nd and 3rd pouches (compare Fig.
3K and L). Note that the overall size of the pharyngeal pouch
region (from the anterior aspect of the 1st pouch to the posterior aspect of
the abnormal 2nd pouch) was clearly reduced in E9.5 mutant embryos
(Fig. 3K,L, brackets). Mutants
collected at E10.5 after RA supplementation (from E7.5 to E9.5 or E10.5)
similarly showed fused pouch-like rudiments caudally to their 2nd branchial
arches (compare Fig. 3K and L, insets).
Neural crest cell migration is abnormal in rescued
Raldh2-null mutants
Several neural crest markers were used to investigate whether the abnormal
development of posterior branchial arches in rescued
Raldh2/ embryos correlated with NCC defects.
The EphA4 gene is normally expressed in r3 and r5, and in NCC
emanating from the latter rhombomere
(Nieto et al., 1992)
(Fig. 4A). EphA4 was
expressed at normal levels in r3 and r5 of
Raldh2/ embryos (compare
Fig. 4A and B). However, the
stream of NCC that colonized the 3rd arch in wild-type embryos had no
counterpart in mutants (Fig.
4B). The EphA2 gene is expressed in wild-type embryos in
both NCC and mesodermal cells of the post-otic region and 3rd-6th pharyngeal
arches (Ruiz and Robertson,
1994
) (Fig. 4C).
EphA2-expressing cells were detected in
Raldh2/ embryos, but these cells remained
confined dorsally to the foregut pocket
(Fig. 4D, arrowhead).
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Abnormal development of posterior cranial nerves in rescued
Raldh2-null mutants
The patterning of cranial nerves, which develop within specific branchial
arches, was analyzed at E11.5 in Raldh2/
mutants that were RA-rescued from E7.5-E9.5, using anti-neurofilament
immunostaining (Fig. 5).
Patterning of the nerves that develop in the 1st and 2nd branchial arches (5th
and 7th cranial nerves, respectively) was normal in most of the mutant embryos
(Fig. 5B-D). All mutants,
however, showed impaired development of the 9th (glossopharyngeal) and 10th
(vagus) nerves, which normally develop within the 3rd and 4th branchial
arches. Three examples of phenotypes of increasing severity are shown in
Fig. 5B-D. In the less severe
cases, separate 9th and 10th nerve tracts were formed, but their connections
with the hindbrain were mingled (Fig.
5B). In addition, the distal sensory ganglia of these nerves,
which normally derive from the 2nd and 3rd epibranchial placodes, were
abnormally fused (Fig. 5B). In
more severe cases, the axon bundles of presumptive 9th and 10th nerves merged
in a single rudimentary trunk that followed an aberrant route
(Fig. 5C) or failed to extend
towards the periphery (Fig. 5D,
arrowhead). In such severe cases, a putative distal ganglion was formed (d9/10
in Fig. 5C,D), which had no
connection with the proximal axonal trunk. This indicates that neuronal
differentiation could proceed within the mutant epibranchial placodes, but
that these neurons were unable to establish a connection with the
hindbrain-derived nerve tracts. Altered outgrowth of the 11th (spinal
accessory) and 12th (hypoglosseal) nerve tracts was also evident in mutants
(Fig. 5B-D). The same range of
abnormal phenotypes was observed in Raldh2/
embryos when RA supplementation was extended up to E11.5 (data not shown).
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At later stages, Ret is specifically expressed in various NCC
populations of neural fate, including the vagal NCCs that will give rise to
the ganglia of the enteric nervous system
(Pachnis et al., 1993). This
cell population was analyzed in Raldh2/
mutants by in situ hybridization of serial histological sections. At E10.5,
Ret-positive prospective enteric ganglioblasts are migrating along
the wall of the fore- and midgut of wild-type embryos
(Fig. 7A). Only few
Ret-positive presumptive ganglioblasts were seen in
Raldh2/ embryos after RA rescue from E7.5 to
E9.5, and these cells were confined to the pharyngeal region and/or the nearby
foregut wall (Fig. 7B). By
E12.5, the vagal nerves are strongly labeled
(Fig. 7C) and the enteric
ganglioblasts are beginning to coalesce along the stomach and gut wall to form
ganglia in wild-type embryos (Fig.
7E,G). In contrast, the stomach and gut wall of
Raldh2/ embryos was devoid of
Ret-expressing cells (Fig.
7F,H). A few c-ret-expressing cells, arranged as
rudimentary tracts, were detected at the expected location of the vagal nerves
in mutants (compare Fig. 7C and
D). Other domains of Ret expression were unaltered in
Raldh2/ embryos, both in the case of non-NCC
(e.g. the ureteric bud or spinal cord motoneurons:
Fig. 7A,B and C-F,
respectively) and NCC-derived populations (e.g. the dorsal root or trigeminal
ganglia: Fig. 7C-F and I,J,
respectively). This abnormal phenotype was confirmed by analyzing another
marker of the developing enteric nervous system (Mash1)
(Blaugrund et al., 1996
) (data
not shown). Extending the RA supplementation until E12.5 did not rescue the
formation of enteric ganglia in Raldh2/
mutants. In the best case, labeled cells were found along part of the foregut
and stomach wall, but these cells did not colonize more posterior gut segments
(data not shown).
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DISCUSSION |
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Using several hindbrain markers, we show that growth and patterning of the
posterior rhombomeres, which is highly abnormal in unrescued
Raldh2/ embryos
(Niederreither et al., 2000),
is rescued by the present maternal RA supplementation. It is therefore likely
that the abnormal NCC migration patterns observed in RA-rescued
Raldh2-null mutants are secondary to the abnormal development of the
pharyngeal region, rather than being the result of an intrinsic hindbrain or
NCC defect.
Our data show that RALDH2 is responsible for producing RA which is required
for proper development of the posterior branchial arch region. Previous
studies have indicated that this embryonic region is particularly sensitive to
RA deficiency. Incubation of early somite-stage (E8.0-8.5) cultured mouse
embryos with a pan-RAR antagonist led to defects of the 3rd to 6th branchial
arch region (Wendling et al.,
2000), which are consistent with those seen in RA-rescued
Raldh2-null mutants. Furthermore, vitamin A-deficient (VAD) quail
embryos exhibit deficits in the posterior pharyngeal region
(Quinlan et al., 2002
), which
are reminiscent of the mouse phenotype in these experiments. For instance,
both the VAD quail embryos and the rescued Raldh2 mouse mutants
develop a rather normal first pharyngeal pouch, whereas only a single,
abnormal second pouch is formed posteriorly. In agreement with these studies
(Wendling et al., 2000
;
Quinlan et al., 2002
), our
data point to the pharyngeal endoderm as one of the main target tissues whose
patterning is altered by conditions of impaired RA signaling.
We have shown that Raldh2 expression is mesoderm-specific, and is restricted to the posteriormost pharyngeal region during development of the posterior branchial arches. We propose that RALDH2 function is to produce locally high amounts of RA, which are indispensable to correctly pattern these branchial arches. The mesodermally produced RA would then diffuse and signal within the pharyngeal endoderm. This is illustrated by the fact that activity of a RARE-lacZ reporter transgene, as well as endogenous expression of RA target genes (such as Hoxa1 and Hoxb1), is induced in both the mesoderm and endoderm of the posterior pharyngeal region. In the rescued Raldh2-null mutants, RA brought transplacentally cannot mimic the levels and distribution resulting from endogenous, RALDH2-mediated synthesis, leading to region-specific defects. Interestingly, these mutants exhibit a decrease of RA-reporter transgene activity in both the pharyngeal mesoderm and endoderm. Expression levels of Hoxa1 and Hoxb1 are decreased in mesoderm and endoderm as well, demonstrating that both layers are deficient in their response to the RA signal.
We have also found that development of the 2nd branchial arches, which is
deficient in the Raldh2-null mutants
(Niederreither et al., 1999),
is efficiently rescued by maternal RA supplementation. This indicates that 2nd
arch development may require lower RA levels, which can be supplied maternally
in the absence of RALDH2 function. Other lines of evidence, involving analysis
of RAR compound mutant mice (Lohnes et
al., 1994
), VAD rat embryos
(White et al., 2000
) or
pan-RAR antagonist-treated mouse embryos
(Wendling et al., 2000
), have
indicated that development of the 2nd branchial arches is not as critically
dependent on RA signaling as that of more posterior arches. Whether this
differential requirement reflects binding to a different subset of receptors
has been discussed elsewhere (Wendling et
al., 2000
). We postulate that RA produced by RALDH2 in the
posterior pharyngeal mesoderm diffuses up to the level of the 2nd branchial
arches, where its acts at relatively lower concentrations. This is supported
by the pattern of activity of the RARE-lacZ reporter transgene which,
in wild-type embryos, extends up to the developing 2nd arches, albeit at a
much lower level than in the posterior pharyngeal region.
The rescued Raldh2-null phenotype resembles human DiGeorge
syndrome and mouse Tbx1 knockout phenotypes
Conotruncal abnormalities are prevalent human birth defects occurring at a
frequency as high as four per 10,000 births. As many congenital defects, the
origins of PTA are often unknown. Poor nutrition during pregnancy
including vitamin A deficiency may contribute to these malformations
(Underwood and Arthur, 1996).
The most frequent genetic cause of human conotruncal defects consists of
heterozygous microdeletions of the chromosome 22q11 region, which lead to a
spectrum of abnormalities of variable expressivity, known as
DiGeorge/Velocardiofacial syndromes (DGS/VCFS) (reviewed by
Scambler, 2000
; Emanuel, 2001;
Lindsay, 2001
). Several
engineered deletions of the corresponding mouse locus have implicated the
T-box gene Tbx1 as a major determinant of the DGS/VCFS phenotypes
(Jerome and Papaioannou, 2001
;
Lindsay et al., 2001
;
Merscher et al., 2001
). Both
haploinsufficient and null (Tbx1/) mutant
mice fail to form the 3rd and 4th pharyngeal arches and have conotruncal
defects (Lindsay et al., 2001
;
Jerome and Papaioannou, 2001
;
Merscher et al., 2001
).
Alterations in thymus and parathyroid morphology are also seen in these
mutants (Jerome and Papaioannou,
2001
; Merscher et al.,
2001
). According to its expression which is essentially restricted
to the pharyngeal pouch endoderm, Tbx1 appears to function in a
non-cell autonomous manner for branchial arch outgrowth, and NCC defects in
these mutants have been attributed to a lack of guidance from the pouch
endoderm (Vitelli et al.,
2002
).
The defects reported in the present study are clearly similar to those
observed in posterior branchial arches (and their derivatives) in
Tbx1 mutant mice, and therefore represent a new mouse model of the
human DGS abnormalities. The pharyngeal region appears to be highly sensitive
to alterations in RA levels, as a hypomorphic mouse Raldh2 mutation
was found to selectively lead to DGS-like defects
(Vermot et al., 2003), albeit
less severe than in the present Raldh2-null mutants. As Tbx1
expression is not (or only mildly) affected in both the null (data not shown)
and hypomorphic (Vermot et al.,
2003
) mutants, we do not consider it as a critical determinant of
the Raldh2 phenotype. It rather seems that RA may act downstream (or
in combination with) TBX1 to regulate expression of signaling molecules
required for proper pharyngeal development. FGF8 could represent such a
critical common downstream signal, as (i) its expression is altered in both
Tbx1/ and
Raldh2/ mutants
(Vitelli et al., 2002
) (this
study), and (ii) its hypomorphic mutation also leads to a DGS-like phenotype
(Abu-Issa et al., 2002
;
Frank et al., 2002
).
Lack of vagal outgrowth leads to absence of the enteric nervous
system
Retinoic acid has been implicated in the regulation of many aspects of
neuronal development including specification of neuronal cell fate
(Sockanathan and Jessell, 1998) and stimulation of neurite outgrowth
(Hunter et al., 1991;
Plum and Clagett-Dame, 1996
;
Corcoran and Maden, 1999
). RA
has also been found to promote survival and proliferation of neuronal
progenitors in NCC populations (Henion and
Weston, 1994
; Gale et al.,
1996
). We find that axonal growth is variably affected at the
level of the posterior (9th-12th) cranial nerves in RA-rescued
Raldh2/ mutants (see
Fig. 4), consistent with the
idea that RA produced locally by RALDH2 in the pharyngeal mesoderm is required
to stimulate their neurite outgrowth.
The enteric nervous system (ENS) is mainly derived from vagal NCCs, which
migrate along the foregut mesenchyme to colonize the entire length of the gut
and give rise to the majority of neurons and glia of the enteric ganglia
(Le Douarin and Teillet, 1973;
Young et al., 1998
;
Burns and Le Douarin, 1998
).
Among the signaling pathways involved in ENS development (for reviews, see
Gershon, 1998
;
Taraviras and Pachnis, 1999
),
the RET receptor tyrosine kinase and its ligand GDNF (glial cell line-derived
neurotrophic factor) are of critical importance. Both Ret and
Gdnf knockout mice exhibit semi-dominant hypo- or aganglionosis of
the gastrointestinal tract (Schuchardt et
al., 1995
; Pichel et al.,
1996
; Shen et al.,
2002
). RET mutations are also most frequently involved in cases of
human Hirschprung's disease (congenital megacolon or aganglionosis), the most
frequent hereditary cause of intestinal obstruction
(Gabriel et al., 2002
). Here
we show that the vagal defects in Raldh2/
embryos lead to a similar gastrointestinal aganglionic phenotype. While few
Ret-positive ENS progenitor cells are detected along the foregut wall
at E10.5, they are apparently unable to colonize the gastrointestinal tract,
leading to an absence of enteric ganglia. This is the first report of
intestinal agangliogenesis caused by an alteration in the retinoid signaling
pathway. The possibility that such alterations could be involved in the
pathogeny of human Hirschprung's disease, which is both variable in its
expressivity and complex in its inheritance pattern, should therefore be
considered.
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ACKNOWLEDGMENTS |
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