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First published online 17 October 2007
doi: 10.1242/dev.010991
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Research Report |
1 National Research Centre `Frontiers in Genetics', Department of Zoology and
Animal Biology, University of Geneva, Sciences III, Quai Ernest Ansermet 30,
1211 Geneva 4, Switzerland.
2 School of Life Sciences, Ecole Polytechnique Fédérale, Lausanne,
Switzerland.
* Author for correspondence (e-mail: Denis.Duboule{at}zoo.unige.ch)
Accepted 23 August 2007
SUMMARY
The digestive tract is made of different subdivisions with various functions. During embryonic development, the developing intestine expresses combinations of Hox genes along its anterior to posterior axis, suggesting a role for these genes in this regionalization process. In particular, the transition from small to large intestine is labelled by the transcription of all Hoxd genes except Hoxd12 and Hoxd13, the latter two genes being transcribed only near the anus. Here, we describe two lines of mice that express Hoxd12 ectopically within this morphological transition. As a consequence, budding of the caecum is impeded, leading to complete agenesis in homozygous individuals. This effect is concurrent with a dramatic reduction of both Fgf10 and Pitx1 expression. Furthermore, the interactions between `anterior' Hox genes and ectopic Hoxd12 suggest a model whereby anterior and posterior Hox products compete in controlling Fgf10 signalling, which is required for the growth of this organ in mice. These results illuminate components of the genetic cascade necessary for the emergence of this gut segment, crucial for many vertebrates.
Key words: Hox target genes, Budding morphogenesis, Genetic analysis, Gut regionalization, Mouse organogenesis
INTRODUCTION
The caecum is a pouch of the digestive tube, located at the junction
between the small and the large intestine, which is essential for many
vertebrate species to digest dietary cellulose. In herbivorous species, where
it represents a crucial gastrointestinal (GI) organ, the relative size of the
adult caecum is much larger than that of carnivores. In addition, there is
variation in the presence or absence of the caecum even among mammals
(Langer, 2001
), hence
discovering genetic determinants of caecum growth may contribute to diverse
types of investigations into both ontogenesis and phylogenesis of the
gastrointestinal system.
The role of Hox genes in patterning the mammalian GI tract in addition to
the skeleton, the nervous system and the genitals has been documented for some
time, in particular with respect to the differentiation of both the muscular
layer and the epithelium. While systematic analyses of expression patterns in
mice have revealed a coordinated expression strategy
(Sekimoto et al., 1998;
Pitera et al., 1999;
Kawazoe et al., 2002), more
recent studies employing various methodologies of gene expression profiling
have also supported the involvement of many Hox genes, including those in the
HoxD cluster, in regionalization
(Bates et al., 2002;
Choi et al., 2006).
Furthermore, examination of mice with modified Hox gene expression levels
has provided decisive evidence for their function during development, as
ranges of anatomical defects were discovered along the anteroposterior axis of
the GI tract. Hox deficiencies due to the inactivation of single genes such as
Hoxc4 and Hoxa5, as well as overexpression of either
Hoxc8 or Hoxa4, were shown to affect the oesophagus, stomach
or intestine, respectively (Boulet and
Capecchi, 1996; Aubin et al.,
2002; Pollock et al.,
1992; Wolgemuth et al.,
1989). We had previously shown that, in the absence either of all
Hoxd genes, or of the Hoxd4 to Hoxd13 genomic interval, the
genesis of both the ileo-caecal and anal sphincters was severely impaired,
even though the gross anatomy was normal
(Zakany and Duboule, 1999;
Zakany et al., 2001).
Furthermore, targeted inactivation of Hoxd12 or Hoxd13
affected the proper morphology of the anal sphincter selectively
(Kondo et al., 1996).
The caecum forms at the limit between the ileum and the colon; in mice, it
begins to grow at day 10 of embryonic development, and one day later it
protrudes out of the abdominal cavity and is included in the intestinal
hernia. A large number of Hox genes are co-expressed in posterior midgut, in a
region that coincides with the future budding of the caecum
(Dolle et al., 1991;
Kawazoe et al., 2002;
Levin et al., 1997;
Pitera et al., 1999;
Roberts et al., 1995;
Sekimoto et al., 1998). By
contrast, the expression of the most `posterior' Hox genes, such as
Hoxd12 and Hoxd13 is excluded from this precise region
(Dolle et al., 1991;
Kmita et al., 2000).
Interestingly, the expression of the HoxD cluster genes in this
particular region, the transition from the ileum to the colon, did not appear
to follow the rule of collinearity, unlike that seen for the expression of
these genes in other axial structures. Indeed, several genes belonging to the
HoxD cluster were reported to be co-expressed at around the position
of the future caecum, probably in response to a global regulatory mechanism
located in 3' of (telomeric to-) the cluster
(Kmita et al., 2000;
Spitz et al., 2005),
suggesting that these transcription factors may be instrumental in the
development of this organ.
In this report, we further investigate the importance of the embryonic Hox expression domains for the proper formation of the ileo-caecal transition. First, we confirm that HoxD cluster genes are excluded from the anterior small bowel and we show that all Hoxd genes, with the exception of Hoxd12 and Hoxd13, are heavily co-expressed in a limited segment of the posterior midgut. Next, by investigating novel mutant lines involving partial deficiencies of the HoxD cluster, we show that a robust gain of expression of Hoxd12 in the posterior midgut correlates, in time and place, with the absence of caecum budding originating from this region. In these foetuses, however, specific expression of Hoxa genes was maintained. We also show that Hoxd12 gain of function inhibits the outgrowth of the caecum, probably by interfering with fibroblast growth factor signalling, in particular Fgf10, which normally depends upon the activity of anterior Hox gene products. These results strongly suggest that several Hox gene(s) are required for the proper formation of the ileum-to-colon transition and concurrent budding of the caecum.
MATERIALS AND METHODS
Mouse stocks, TAMERE, crosses and genotyping
In order to obtain the various genotypes shown in
Table 1, mice heterozygous for
the
HoxDDel(1-10)
allele (Zakany et al., 2004)
[referred to as `Del(1-10)'] were crossed with either
del(1-13) (Zakany et
al., 2001), del(4-13)
(Zakany and Duboule, 1999),
del(8i-13) (Tarchini et
al., 2005) or del(11-13)
(Zakany and Duboule, 1996). To
produce the novel Del(4-11) allele, we used targeted meiotic
recombination (TAMERE) (Hérault et
al., 1998) after a cross between the del(4-13)
allele and the md11f allele
(Beckers and Duboule, 1998).
Heterozygous Hoxd1/lac mice
(Zakany et al., 2001) were
crossed together in order to monitor the expression of Hoxd1/lac
reporter gene by X-Gal assay or to detect lacZ transcript
accumulation. For the production of the novel Del(4-11)
allele, `transloxer' males were produced containing the two HoxD
alleles del(4-13) and md11f, along with the
Sycp1CRE transgene. Three recombinant pups were obtained after
genotyping 171 progeny (1.7%), one of which carried the intended allele, and
the two others the predicted reciprocal allele (see
Fig. 3).
|
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),
Hoxd3 (Condie and Capecchi,
1993), Hoxd4
(Featherstone et al., 1988),
Hoxd8 (Izpisua-Belmonte et al.,
1990), Hoxd9
(Zappavigna et al., 1991),
Hoxd10 and Hoxd11
(Gerard et al., 1996),
Hoxd12 (Izpisua-Belmonte et al.,
1991), Hoxd13 (Dolle
et al., 1991). The remaining RNA probes were Hoxa6
(Sekimoto et al., 1998),
Hoxa10 (Favier et al.,
1996), Fgf10 (Bellusci
et al., 1997) and Pitx1
(Logan et al., 1998). For the
complementation assay, newborns were recovered, their full GI was dissected,
documented and genotyped. RESULTS AND DISCUSSION
Posterior specificity of the HoxD cluster
We first established the expression pattern of all nine gene members of the
HoxD cluster in wild-type embryos at mid-gestation (E12), at a time
when the caecum is located in the intestinal hernia
(Fig. 1A,B). Consistent with
earlier observations, we found that Hoxd4, Hoxd8 and Hoxd9
are co-expressed in the developing caecum, in addition to Hoxd1, Hoxd3,
Hoxd10 and Hoxd11. From Hoxd1 to Hoxd10,
expression was detected up to the ileo-caecal transition. By contrast,
Hoxd11 transcripts were restricted to the posterior half of the
caecum bud (Fig. 1E), whereas
the more `posterior' genes Hoxd12 and Hoxd13
(Fig. 1C,D) were transcribed
only in the most caudal part of the GI tract
(Dolle et al., 1991;
Kondo et al., 1996).
Despite the expression of most Hoxd and other Hox genes in the developing
caecum, foregut derivatives appeared to be devoid of Hoxd transcripts. For
instance, while expression of all three Hox4 paralogous genes was
scored in E12 stomach mesenchyme (Kawazoe
et al., 2002; Pitera et al.,
1999), we were unable to detect either Hoxd1, or
Hoxd4, transcripts in embryonic stomach. Because of the rapid
degradation of Hoxd1 mRNA (Zakany
et al., 2001), we performed in situ hybridization with a
Hoxd1 probe on wild-type foetuses, and explored
lacZ-specific transcript accumulation in embryos carrying the
Hoxd1/lacZ knock-in allele. In contrast to the robust lacZ
expression in the caecum (Fig.
1C), staining was not seen in stomach. Similarly, Hoxd3
was weakly expressed in stomach, compared with midgut, indicating a relative
restriction of Hoxd gene expression to the posterior gut.
Ectopic expression of Hoxd genes
Over recent years, a collection of mouse lines carrying rearrangements at
the HoxD locus were produced by targeted meiotic recombination
(TAMERE) (Hérault et al.,
1998), in order to study gene regulation at this locus. In several
lines harbouring deletions of one or multiple Hoxd genes, the remaining genes
usually changed their expression patterns, in agreement with their new
respective position within the Hox cluster. Accordingly, mice carrying such
deletions usually showed both loss-of-function and gain-of-function
phenotypes. In particular, severe alterations were obtained when `posterior'
Hoxd genes such as Hoxd12 or Hoxd13 were expressed in more
anterior territories, either in the trunk
(Kmita et al., 2000), or in
the limbs (Zakany et al.,
2004), due to the antagonizing effect of the most posterior HOX
products over anterior ones, a property referred to as `posterior prevalence'
(Duboule, 1991;
Duboule and Morata, 1994).
Mice homozygous for a deletion of the anterior part of the cluster, from Hoxd1 to Hoxd10 including [the Del(1-10) allele], were born in mendelian proportions and newborns appeared overtly normal, yet none of them survived due to acute respiratory failure. Interestingly, all homozygous animals showed a severe agenesis of the caecum. We investigated whether this defect was due to the combined loss of function of several Hoxd genes in cis by analysing mice homozygous for a complete deficiency of the HoxD cluster [the del(1-13) allele]. In del(1-13) homozygous mice, however, the caecum was never absent. This observation indicated that the absence of caecum in Del(1-10) homozygous individuals was caused by a gain-of-function mechanism involving either Hoxd11, Hoxd12 or Hoxd13, rather than by a combined loss of function.
|
We then investigated whether the absence of caecum was due to a deficit in budding or to a more global problem of gut (mis-)specification, due to aberrant regulation of those Hox genes labelling the ileum-to-colon transition. To this aim, we used the Hoxa10 and Hoxa6 probes. In wild-type animals, Hoxa10 is expressed in the anterior colon up to the ileo-caecal valve, including the budding caecum. In Del(1-10) heterozygous animals, Hoxa10 expression was not importantly modified and still labelled the ileum- to-colon transition, reminiscent of the ectopic patterns of both Hoxd11 and Hoxd12 (Fig. 2J-L), suggesting that caecum agenesis was not due to a transcriptional effect of the gained genes over other Hox genes transcription. In contrast to Hoxa10, Hoxa6 signal is normally restricted to the budding caecum. Whereas in heterozygous Del(1-10) embryos, the signal was expectedly reduced, homozygous mutant GI tracts still showed a Hoxa6 signal, but only in a small group of cells located at the expected position for the caecum bud (Fig. 2M-O). From these observations we conclude that the overall molecular GI tract specification, as indicated by the HoxA-cluster-specific probes, was maintained even in homozygous mutants that did not develop a caecum. Consequently we searched for other genetic constitutions that result in caecum agenesis or hypoplasia, but without known involvement of general regionalization.
The development of the caecum is strongly impaired in mice, where either
fibroblast growth factor genes (Fairbanks
et al., 2004; Zhang et al.,
2006) or receptors (Burns et
al., 2004) are inactivated, in particular Fgf10, which is
selectively expressed in the mesenchyme of the wild-type budding caecum
(Fairbanks et al., 2004)
(Fig. 2P). In the
Del(1-10) mutant embryos, we found that Fgf10
transcript accumulation was reduced in heterozygotes and almost completely
absent in homozygotes, leaving a small cluster of Fgf10-expressing
cells in the ileo-colonic loop (Fig.
2Q-R). These observations suggest that caecum outgrowth is under
the control of Fgf10, the expression of which may require the
activity of several Hox genes in a defined region of the developing intestinal
tract. In the absence of all Hoxd genes [del(1-13)], Hox
genes from other clusters can still instruct presumptive cells to activate
Fgf10 signalling, thus leading to the budding of a caecum. By
contrast, the presence of ectopic Hoxd12 in this precise intestinal
segment will abrogate the functions of more `anterior' gene products from all
clusters, via posterior prevalence. Accordingly, Fgf10 will fail to
be produced and caecum budding will be suppressed. Interestingly, this
situation is analogous to that recently reported to happen during early limb
budding, where ectopic expression of both Hoxd12 and Hoxd13
could abrogate the Fgf10-dependent growth of forelimb buds
(Zakany et al., 2007).
|
)
and, as shown here, accumulate selectively in the mesenchyme of the growing
caecum (Fig. 3H). Here again,
this specific expression of Pitx1 was severely reduced in caecum
mesenchyme of heterozygotes, whereas it was absent from homozygous specimens
(Fig. 3I-J). Posterior midgut
development was thus similarly compromised in both Del(1-10)
and Del(4-11) homozygous animals. There was a robust
correlation between all aspects of the caecum defect, on the one hand, and the
ectopic expression of Hoxd12 and concurrent dose-dependent
suppression of Fgf10 and Pitx1 transcripts in prospective
caecum bud mesenchyme, on the other hand. We thus concluded that the induction
and/or growth of the caecum are affected by ectopic expression of
Hoxd12. Whether the loss of Fgf10, Hoxa6 and Pitx1
expression reflects the loss of the corresponding `presumptive caecal cells'
or, alternatively, the downregulation of these genes in these cells remains to
be addressed. We did not fully assess the genetic cascade underlying the
suppressive effect of HOX proteins on Pitx1 and Fgf10
transcription in developing caecum mesenchyme. However, Pitx1
expression was gained in the second branchial arch of mice lacking
Hoxa2 following Hox interference with Fgf signalling
(Bobola et al., 2003). Also,
the data from the genetic and molecular embryological analysis presented here,
together with those concerning early limb budding
(Zakany et al., 2007), suggest
that the Hox genes Fgf10 and possibly Pitx1 are components
of a mesenchyme-specific genetic hierarchy that controls caecum budding.
These observations support an instructive role for `anterior' Hox genes in
the definition of a restricted territory from where the caecum will emerge.
This precise area corresponds to an important morphological transition in the
intestine, the position of which is probably also dependent upon the coherent
expression of these same Hox genes. Induction of caecum budding and its
elongation require a localized source of growth factors, as provided by
Fgf10 signalling, downstream of Hox gene expression. We interpret our
results in the context of posterior prevalence, according to which the
function of a given Hox gene may be impeded by the presence of more posterior
Hox product in the same cells (Duboule and
Morata, 1994), in particular from the most posterior
Hox12 and Hox13 groups. Because the absence of the whole
HoxD cluster induced only a relatively mild posterior midgut
malformation, we think that the expression of Hox genes left in the other
clusters is equally capable of promoting posterior midgut development.
However, in the case of internal HoxD cluster deletions, the ectopic
expression of Hoxd12 abrogates the functions of several co-expressed
`anterior' Hox genes, leading to the inability to transcribe Fgf10
and consequent absence of budding.
Hoxd genes and the posterior midgut
In order to further document this conclusion, we produced a set of genetic
configurations to fine-tune the doses of various Hox gene products. Because
the Del(1-10) allele arguably delivers less ectopic activity
of Hoxd12 than the Del(4-11) allele, we used the
former together with selected HoxD cluster deficiencies, which by
themselves do not induce ectopic gene expression. The rationale of these
crosses was to manipulate doses of `anterior' genes on the top of a fixed,
standard level of ectopic Hoxd12 in the presumptive region for caecum
budding (Table 1). First, we
produced compound mutants with the del(1-13) allele, i.e. a
full deletion of the HoxD cluster. Interestingly, a proportion of
Del(1-10)/del(1-13)
trans-heterozygous individuals showed a phenocopy of the
Del(1-10) homozygous phenotype, pointing to a strong
influence of gene dose balance: in the absence of one haplotype of the
HoxD cluster, half the dose of ectopic Hoxd12 gene product
was sufficient to induce caecum agenesis. The occurrence of caecum agenesis in
Del(1-10)/del(1-13) mice, compared with
Del(1-10)/+ heterozygous mice, demonstrated that
caecum development depends on the presence of `anterior' Hoxd genes, capable
of counterbalancing the deleterious effect of ectopic Hoxd12. In
other words, higher doses of anterior HOXD gene products make a full posterior
prevalence by HOXD12 difficult to achieve.
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Two doses of ectopic Hoxd12, in Del(1-10) homozygous, were capable of inactivating all the non-HoxD-derived caecum-promoting Hox activity, in all homozygous animals tested. Furthermore, even a single dose of gained Hoxd12 was capable of abrogating the HoxA, HoxB and HoxC gene function in a number of Del(1-10)/del(8i-13) individuals, in addition to an activity possibly provided by Hoxd1, Hoxd3 and Hoxd4 (Fig. 4A-C). From this, we conclude that in posterior midgut, the HoxA, HoxB and HoxC clusters together provide no more function than a single haplotype of the HoxD cluster does.
Hox function and postnatal growth
Quantitative modulation in the balance between `anterior' Hox genes and
ectopic Hoxd12 led to a phenotypic series involving more or less
affected individuals, some of which survived for several weeks. In particular,
most Del(4-11) heterozygous and some
Del(1-10)/del(8i-13) compound mutants
survived postnatally having either no, or reduced, caeca
(Fig. 4B). In the
Del(4-11) pedigree, we noticed a marked variation, and
heterozygous mice proved lighter than their wild-type littermates. We took
individual body mass readings of four litters sired by the same third
generation backcross male with wild-type C57Bl6 females, and two litters of
heterozygous parents. Of a total of 39 typed progeny, 17 were wild type and 22
were of Del(4-11) heterozygous genotype. At 4 weeks of age,
the average body mass was 10.9 and 9.2 g, respectively, indicating
approximately 20% deficit in Del(4-11) heterozygotes. This
statistically significant body mass deficit persisted into adulthood.
Similar observations carried out on mice heterozygous for a full
HoxD deficiency showed less than 10% body mass reduction, a figure
statistically non-significant. In conclusion, Del(4-11)
heterozygous mice do not thrive as well as wild-type littermates, which may
indicate reduced digestion efficacy due to a shorter gut. We believe that this
effect would be even more substantial on a less complete and mostly vegetal
chow, as caecum and upper colon are sites of bacterial cellulose decomposition
of nutritional importance. Therefore, these HoxD cluster mutants
represent a valuable genetic resource to investigate gut patterning in
general, and postnatal adaptive responses to environmental factors in
particular (Wostmann and Bruckner-Kardoss,
1959), as well as the concurrent effects on body mass control
(Backhed et al., 2004;
Samuel and Gordon, 2006).
ACKNOWLEDGMENTS
We thank N. Fraudeau for technical assistance, M. Kmita, S. Bellusci, M. Logan, K. Yamamura and B. Favier for sharing probes and J. Beckers and B. Tarchini for mice. This work was supported by funds from the canton de Genève, the Louis-Jeantet foundation, the Claraz foundation, the Swiss National Research Fund, the National Center for Competence in Research (NCCR) `Frontiers in Genetics' and the EU programmes `Cells into Organs' and `Crescendo'.
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