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First published online 11 February 2009
doi: 10.1242/dev.027979
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Research Report |
1 Department of Craniofacial Development, Dental Institute, King's College
London, London SE1 9RT, UK.
2 Department of Cell Biology, University of Alabama at Birmingham, Birmingham,
AL 35294-0005, USA.
3 Department of Craniofacial Development and Orthodontics, Dental Institute,
King's College London, UK.
4 Department of Embryology, Carnegie Institution of Washington 3520 San Martin
Drive, Baltimore, MD 21218, USA.
5 Department of Teratology, Institute of Experimental Medicine, Academy of
Sciences of the CR, Prague, Czech Republic.
6 INSERM UMR977, Dental School, Strasbourg University, Strasbourg, France.
* Author for correspondence (e-mail: paul.sharpe{at}kcl.ac.uk)
Accepted 21 January 2009
SUMMARY
Primary cilia mediate Hh signalling and mutations in their protein components affect Hh activity. We show that in mice mutant for a cilia intraflagellar transport (IFT) protein, IFT88/polaris, Shh activity is increased in the toothless diastema mesenchyme of the embryonic jaw primordia. This results in the formation of ectopic teeth in the diastema, mesial to the first molars. This phenotype is specific to loss of polaris activity in the mesenchyme since loss of Polaris in the epithelium has no detrimental affect on tooth development. To further confirm that upregulation of Shh activity is responsible for the ectopic tooth formation, we analysed mice mutant for Gas1, a Shh protein antagonist in diastema mesenchyme. Gas1 mutants also had ectopic diastema teeth and accompanying increased Shh activity. In this context, therefore, primary cilia exert a specific negative regulatory effect on Shh activity that functions to repress tooth formation and thus determine tooth number. Strikingly, the ectopic teeth adopt a size and shape characteristic of premolars, a tooth type that was lost in mice around 50-100 million years ago.
Key words: Intraflagellar transport, Cilia, Shh, Supernumerary tooth, Tooth development, Tooth number, Orpk, Tg737, Gas1, Epithelium, Mesenchyme, Mouse
INTRODUCTION
Tooth number is highly regulated in mammals. Species such as mice have a
highly reduced dentition consisting of only molars and incisors, whereas the
development of other mammalian tooth types has been lost during evolution.
Evidence from three-dimensional reconstructions of early tooth development in
mouse embryos has identified tooth primordia in the diastema, a toothless
region between the incisors and molars, which are initiated but are later
suppressed by apoptosis (Tureckova et al.,
1996
; Peterkova et al.,
2002). These primordia are believed to be the vestiges of teeth
lost during mouse evolution and suggest that a mechanism for suppression of
tooth formation in the diastema involves selective apoptosis of tooth
primordia (Peterkova et al.,
2003). In the early oral cavity, Shh expression is
restricted to the thickenings of oral epithelium (dental placodes), from which
the tooth germs arise (Bitgood and McMahon,
1995; Dassule and McMahon,
1998; Hardcastle et al.,
1998). A loss of Shh activity in these regions at embryonic day
(E)10 results in a lack of epithelial cell proliferation and a failure of
tooth bud formation (Cobourne et al.,
2001). Once the early tooth bud has formed, continued Shh activity
is required within discrete regions of the tooth germ epithelium and
mesenchyme for normal growth and morphogenesis of the developing tooth
(Dassule et al., 2000;
Gritli-Linde et al., 2002;
Jeong et al., 2004).
Significantly, Shh transcriptional activity is lacking in the
diastema and, thus, during normal development of the murine dentition,
suppression of Shh pathway activity in the diastema may play an important role
in controlling primary tooth number
(Cobourne et al., 2004).
Primary cilia have recently been shown to play a crucial role in Shh
signalling (Rohatgi et al.,
2007; Caspary et al.,
2007; Singla and Reiter,
2006; Huangfu and Anderson,
2005). The Shh receptor Ptch1, its activator Smo and the
transcriptional effector Gli1 are all found to localize in cilia, suggesting
that the Shh signalling pathway is active in cilia and that cilia are required
for Shh signal transduction (Rohatgi et
al., 2007; Haycraft et al.,
2005). Intraflagellar transport (IFT) proteins are highly
conserved in all ciliated eukaryotic cells, and mutation of the proteins that
comprise the IFT process result in defects in cilia formation in all organisms
studied to date (Rosenbaum and Witman,
2002; Pan et al.,
2005; Scholey and Anderson,
2006). Mice with null mutations in Ift88, which encodes
the IFT protein polaris, lack cilia on all cells and die mid-gestation with
severe defects in neural tube patterning and closure, polydactyly, and
left-right axis determination (Murcia et
al., 2000; Zhang et al.,
2003). Defects in the neural tube have been associated with loss
of Shh signalling regulation through disruption of Gli activation, whereas the
limb patterning defects are associated with a gain of Shh activity as a result
of a loss of Gli3 repression (Huangfu and
Anderson, 2005; Haycraft et
al., 2005; Michaud and Yoder,
2006). Similar defects have also been reported for mice with
severe mutations in other IFT proteins
(Huangfu and Anderson, 2005;
Liu et al., 2005;
May et al., 2005).
Tg737orpk is a hypomorphic allele of polaris; homozygous
Tg737orpk mice exhibit a complex pathology, including
kidney and pancreatic cysts, preaxial polydactyly, and supernumerary teeth
(Zhang et al., 2003).
We examined the development of vestigial diastema tooth primordia in Tg737orpk mice and found ectopic tooth formation that correlates with ectopic Shh signalling activity in the diastema mesenchyme. Using Wnt1-Cre and keratin(K)5-Cre to conditionally inactivate polaris in tooth mesenchyme and epithelium, respectively, we show that this cilia-mediated Shh signalling is required only in the mesenchyme. We further show that mutants in the Shh regulatory protein Gas1 also develop diastema teeth as a result of ectopic Shh activity in diastema mesenchyme. Therefore, in the context of control of tooth number, cilia are involved in the repression of Shh activity in diastema mesenchyme cells.
MATERIALS AND METHODS
Production and analysis of mice
Tg737orpk and
Tg737
2-3β-gal
were produced as described previously
(Moyer et al., 1994).
Gas1 mutant mice, polarisLoxP mice, K5-Cre and Wnt1-Cre
mice were produced as described previously
(Chai et al., 2000;
Lee et al., 2001;
Ramirez et al., 2004;
Haycraft et al., 2007).
In situ hybridisation
Radioactive section in situ hybridisation using 35S-UTP
radiolabelled riboprobes was carried out as described previously
(Ohazama et al., 2008).
Whole-mount in situ hybridisation was carried out as described previously
(Pownall et al., 1996).
Micro-CT analysis
Heads were scanned with Explore Locus SP (GE Pre-clinical imaging) high
resolution Micro-CT with a voxel dimension of 8 µm. Three-dimension
reconstruction was performed by the three structure analysis software
Microview (GE Pre-clinical imaging).
β-Galactosidase (β-gal) staining
Embryo heads were processed as previously described
(Taulman et al., 2001).
|
).
Transmission electron microscopy (TEM) analysis
Heads were fixed in 2.5% glutaraldehyde (phosphate buffer) overnight at
4°C and postfixed in 2% osmium tetroxide (Millonigs buffer) after washing
by buffer. Specimens were dehydrated through a graded series of ethanols and
embedded in Epon 812-equivalent (TAAB Lab). Semithin sections (1 µm) were
stained with Toluidine Blue for light microscopy analysis. Ultrathin sections
(40-90 nm) were cut, stained with uranyl acetate and lead citrate and examined
with a Hitachi H7600 transmission electron microscope.
Immunohistochemistry
Sections were incubated with antibody to acetylated 
-tubulin or
-tubulin (Sigma). Alexa488 or Alexa594 was used (Molecular probe) for
detecting primary antibody. Immunohistochemistry for Polaris or Shh were
performed as previously described
(Rosenbaum and Witman 2002;
Martinelli and Fan, 2007;
Gritli-Linde et al.,
2001).
RESULTS AND DISCUSSION
Shh activity in the diastema
Primary cilia have been shown to be important mediators of Shh activity
and, as Shh controls tooth initiation, we examined tooth development in
Tg737orpk adult mice, which contain a hypomorphic mutation
in the IFT protein polaris. We identified teeth mesial to the first molar in
all four jaw quadrants with 100% penetrance that were not present in wild-type
animals (Fig. 1A-D)
(Zhang et al., 2003). Because
the development of ectopic digits in Tg737orpk mutants is
due to alternations in Shh signalling in the limb bud, we examined the
expression of Ptch1 and Gli1, which are upregulated in
response to Shh signal transduction, in the region of ectopic tooth
development in the Tg737orpk homozygous mutants at E12.5
and E13.5. To determine the expression pattern of Ptch1, we generated
Tg737orpk homozygous mutants that were also heterozygous
for a Ptch1-lacZ allele and examined the activity of β-gal. At
E13.5, Ptch1-lacZ staining was increased in the incisor and molar
areas of Tg737orpk homozygous mutants and expanded into
the diastema, which is normally devoid of Shh signalling activity
(Fig. 1E,F). Gli1
expression was also expanded into the diastema region
(Fig. 1G-H') and
expression of Gas1, a Shh antagonist in tooth development that is
downregulated by Shh activity, was reduced
(Fig. 1I-J')
(Cobourne et al., 2004;
Martinelli and Fan, 2007). The
expansion of Ptch1 and Gli1 expression into the diastema
correlates with the placement of premolar-like tooth buds that develop in the
Tg737orpk mutants. These observations suggest that an
absence of the IFT protein polaris results in a Shh gain-of-function
phenotype. In limb buds, hypomorphic mutation of polaris leads to a series of
changes in Shh signalling that include disruption of Gli3 processing,
resulting in severe polydactyly similar to that found in Gli3 mutants
(Haycraft et al., 2005;
Litingtung et al., 2002). The
expression of Shh is downregulated in the midline of polaris null
mutants, which show severe midline defects
(Murcia et al., 2000). It has
been suggested that the loss of Gli activators, which play a major role in
neural tube patterning, is consistent with the loss of ventral neural tube
cells in the IFT protein mutant mice, whereas loss of Gli3 repressor function,
which is more important in digit patterning, is consistent with the formation
of extra digits in the IFT protein mutants
(Huangfu and Anderson, 2005;
Michaud and Yoder, 2006). The
absence of an IFT protein can therefore affect both positive and negative
aspects of Shh signalling, depending upon the particular Gli activity. In the
context of the control of tooth number, increased Shh activity is thus
consistent with loss of Gli3 repressor which is prominently expressed in the
wild-type diastema (see Fig. S1 in the supplementary material)
(Huangfu and Anderson, 2005;
Haycraft et al., 2005;
Michaud and Yoder, 2006).
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-tubulin and a marker of basal bodies of
cilia, -tubulin. Cilia were found in tooth epithelium and mesenchyme
cells at early stages of development (Fig.
2A,B,D). Cilia were observed on both epithelial and mesenchymal
cells of supernumerary and endogenous tooth germs in
Tg737orpk mice (Fig.
2C,E). Transmission electron microscopy (TEM) was performed to
investigate the structure of the cilia on tooth cells. Cilia were found on
dental epithelial and mesenchymal cells and no obvious morphological
differences were visible between Tg737orpk and wild-type
cells (Fig. 2F-I). We next
examined Tg737 expression and polaris protein localisation in tooth
development to confirm that this protein is a component of cilia on dental
cells. Tg737 was expressed throughout the dental epithelium and in
the underlying mesenchyme, as determined by expression of β-gal in
embryos heterozygous for the
Tg7372-3β-gal
allele (Fig. 2J,K). In
agreement with the β-gal expression pattern, immunolocalisation of
polaris showed cilia were present on both tooth epithelial and underlying
dental mesenchyme cells (Fig.
2L,K).
Polaris in epithelial and mesenchymal cells of tooth germs
As cilia are present on both epithelial and mesenchymal cells of early
tooth germs, the effect of reduction in polaris in
Tg737orpk mice could be mediated in either or both cell
types. Conditional loss-of-function of polaris in epithelial cells was
investigated by crossing polaris floxed mice with K5-Cre mice. The
K5-Cre/polarisflox/flox mice survived but there was no evidence of
supernumerary teeth, although they did show polydactyly
(Fig. 3A,B; data not shown). To
test whether polaris is required in dental mesenchyme, we crossed polaris
floxed mice with Wnt1-Cre mice. Wnt1-Cre/polarisflox/flox mice died
at birth and showed severe craniofacial abnormalities (data not shown).
Supernumerary tooth germs were observed mesial to first molars in the
Wnt1-Cre/polarisflox/flox mice
(Fig. 3C,D). The expansion of
Gli1 expression into the diastema was seen in the
Wnt1-Cre/polarisflox/flox mice as also observed in
Tg737orpk mice (Fig.
3E-F'). This confirmed that the formation of supernumerary
teeth results from loss of polaris in dental mesenchyme. Although Shh
is only expressed in the epithelium during tooth development, Ptch1
and other Shh pathway molecules are expressed in both epithelial and
mesenchymal cells in early tooth primordia. Moreover, a role for Shh in dental
epithelial cells is confirmed by abnormal cell differentiation in K14-Cre/Shh
and K14-Cre/Smo conditional mutant mice; however, the teeth that develop in
K5-Cre/polarisflox/flox mice undergo apparently normal
morphogenesis and cytodifferentiation
(Dassule et al., 2000;
Gritli-Linde, 2002). This suggests that cilia-mediated Shh activity mediated
by polaris is dispensable in dental epithelial cells, whereas Shh signalling
in early dental mesenchyme requires polaris-mediated cilia function. Despite
the expectation that cilia would be absent in tooth mesenchymal cells in
Wnt1-Cre/polarisflox/flox mice, -tubulin
immunohistochemistry did show cilia present but in reduced numbers (see Fig.
S2 in the supplementary material). This may represent incomplete expression of
Cre or a contribution of non-neural crest cells
(Chai et al., 2000).
Tooth phenotype in Gas1 mutant mice
In order to confirm that ectopic Shh signalling in the diastema was the
direct cause of supernumerary tooth formation, we examined the dentition of
mice with a targeted disruption in the Gas1 gene, which we has
previously identified as an inhibitor of Shh in diastema mesenchyme.
Gas1 is expressed in diastema mesenchyme and non-dental mesenchyme,
but not in tooth germs (Fig.
4G,H) (Cobourne et al.,
2004). Supernumerary teeth in the diastema region of both the
maxilla and mandible were observed with 100% penetrance in Gas1
mutants (Fig. 4A-F). These
teeth, positioned mesial to the first molars, were identical to those observed
in Tg737orpk mice. The presence of these teeth was
associated with ectopic Shh signalling activity within the diastema region,
demonstrated by analysis of Ptch1, Gli1 and Shh expression,
and Shh protein localization, as observed in the Tg737orpk
mutants (Fig. 4I-U).
Significantly, we also found that Gas1 expression was downregulated
in diastema mesenchyme of Tg737orpk mutant embryos
(Fig. 1I-J'). Ectopic Shh
activity in the diastema mesenchyme was thus observed in two different
mutants, both resulting in ectopic tooth formation mesial to the first molars.
In Gas1 mutants, the effect on Shh signalling can be attributed to a
direct consequence of loss of an antagonist, whereas
Tg737orpk may be indirect following reduction in polaris
that results in loss of Gas1.
|
;
Cobourne et al., 2001); in the
diastema, Shh signalling is normally specifically inhibited by Gas1
(Cobourne et al., 2004). When
Gas1 is lost either directly, or indirectly in the mesenchyme of
Tg737orpk mice, Shh signalling is increased. As a result,
the vestigial tooth rudiments mesial to the first molar do not undergo
apoptosis, but survive and develop into a functional tooth. This suggests that
modulation of Shh signalling has played an important part in the evolution of
dental patterns by regulating tooth number. Interestingly, in the
talpid2 chick mutant, ectopic activation of Shh signalling
in the developing oral cavity correlates with the formation of reptile-like
teeth [reminiscent of avian ancestors
(Harris et al., 2006)]. The
requirement for Shh signalling in the mesenchyme to regulate events in the
epithelium also identifies a mesenchyme-to-epithelium interaction in this
process.
|
; Kassai et al.,
2005; Tucker et al.,
2004). In both these cases, development of the molars is impaired.
The formation of diastema teeth in the context of normal molar development is
observed in Sprouty2 and Sprouty4 mutant mice, and has been
interpreted as a role for suppression of FGF signalling in suppression of
diastema tooth formation. In Sprouty4 mutants, ectopic teeth are
restricted to one quadrant with low penetrance; in Sprouty2 mutants,
92% have bilateral, 5% have unilateral and 3% have no ectopic teeth in the
mandible, whereas ectopic teeth are observed in less than 5% of the maxilla
(Klein et al., 2006) (J.-M.
Courtney and P.T.S, unpublished). We show here that ectopic Shh signalling in
the diastema produces ectopic teeth with 100% frequency in all four jaw
quadrants without affecting molar development and thus we propose that Shh is
the direct determinant of tooth initiation and that the roles of FGF, BMP and
other signalling pathways in tooth suppression are mediated through Shh.
Premolar formation in the diastema
Mouse first molar tooth buds form from a fusion of four epithelial
swellings, the most mesial of which is excluded from the first molar tooth bud
and undergoes apoptosis (Peterkova et al.,
2002). We used histology and 3D reconstruction of E15.5 embryos to
show that the supernumerary tooth primordia were observed in the position of
the former mesial swellings, indicating that rather than being suppressed,
these swellings continued to develop into independent teeth
(Fig. 1K-N). The
cyclin-dependent kinase inhibitor p21 provides a marker for diastema
bud apoptosis and in Tg737orpk homozygous embryos we found
that p21 expression was downregulated in diastema epithelial buds
(see Fig. S3 in the supplementary material). The premolar-like teeth in
Tg737orpk thus form from the survival of vestigial
swellings.
To verify whether the supernumerary teeth developed with a molar-like or
incisor-like programme, we performed in situ hybridisation at E15.5 for
Barx1, which is specifically expressed in developing molars, in
addition to dHAND (Hand2 – Mouse Genome Informatics)
and Islet1 (Isl1–Mouse Genome Informatics), which are
expressed in incisors (Thomas et al.,
1998; Tucker et al.,
1998; Mitsiadis et al.,
2003). The supernumerary teeth expressed Barx1 in a
similar manner to the developing first and second molars, but did not express
Hand2 or Isl1 (see Fig. S4 in the supplementary material).
These data support the identification of these ectopic teeth as molar-like,
and confirm they develop from oral epithelium in the molar region.
In several other mouse mutants that have been reported to develop extra
teeth, the form and position of the molars are highly abnormal, which makes
analysis of the morphology of diastema teeth difficult
(Mustonen et al., 2003;
Kassai et al., 2005).
Interestingly, the molar and incisor teeth of homozygous
Tg737orpk mutants showed no major abnormalities in shape,
size or position. The supernumerary teeth were smaller than the first molars,
had fewer cusps and a cusp pattern that was consistent with a premolar-like
identity. The lingual cusps of maxillary supernumerary teeth were more
prominent in comparison with the lingual cusps of mandibular supernumerary
teeth (Fig. 1O-T). Furthermore,
the supernumerary teeth in the maxilla showed a concave-shape root, whereas
those in the mandible had a round root shape
(Fig. 1U,V). These differences
in root and cusp shapes are a consistent feature of human premolars
(Ash and Nelson, 2003;
Berkovitz et al., 2002).
The fact that the extra teeth that develop as a result of ectopic Shh form
a shape that is appropriate for their position indicates that despite having
lost the ability to form a premolar tooth shape over 50-100 million years ago,
the mouse embryo has retained all the genetic information necessary to make
this tooth type (Meng et al.,
1994; Ji et al.,
2002). This supports the concept that loss of tooth types during
evolution results from suppression of tooth initiation. This is also
consistent with the specification of tooth shape being provided by expression
of specific homeobox genes such as Dlx and Barx1 in the
mesenchyme prior to initiation (Tucker and
Sharpe, 2004). These gene expression domains in the mesenchyme of
the facial primordia provide cells with positional information. This
information is used to direct cells to follow particular pathways of hard
tissue morphogenesis. In animals where tooth development is suppressed, such
as birds or the mouse diastema, this information is still required for bone
and cartilage morphogenesis. Thus, what has been `lost' in the evolution of
mice is the ability to initiate and maintain epithelial tooth buds, mesial to
the first molars. When ectopic tooth development is stimulated as a result of
ectopic Shh signalling, the tooth primordia develop from mesenchyme cells with
the information appropriate for that position.
Footnotes
We thank Karen Liu and Isabelle Miletich for critical reading of the manuscript, Deepak Srivastava for dHAND plasmid, Andrew McMahon for Shh plasmid, Ken Brady for TEM analysis, and Chris Healy for micro-CT analysis. Maisa Seppala is a European Union Marie Curie Early Stage Fellow (grant number MEST-CT-2004-504025). Funding for this work was provided by the Medical Research Council, The Wellcome Trust, GACR-304/07/0223 and MSM 0021620843. Atsushi Ohazama is an Research Councils UK Fellow. Deposited in PMC for release after 6 months.
Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/136/6/897/DC1
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