1 Division of Anatomy and Cell Biology, Department of Biomedicine, University of
Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
2 Department of Experimental Medicine and Cancer Research, The Hebrew
University, Jerusalem, 91120, Israel
3 Laboratories of Integrated Biology, Graduate School of Frontier Biosciences,
Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
4 Group of Developmental Neurobiology, Division of Biological Science, Nagoya
University Graduate School of Science, Chikusa-ku, Nagoya, 464-8602,
Japan
5 Biocenter Oulu and Department of Biochemistry, Faculties of Science and
Medicine, University of Oulu, 90014, Finland
6 Department of Biochemistry and Molecular Biology, Graduate School of Medicine,
University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
* Author for correspondence (e-mail: keijo.luukko{at}pki.uib.no)
Accepted 20 October 2004
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SUMMARY |
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Key words: Odontogenesis, Tissue interactions, Tooth, Axon growth, Mouse
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Introduction |
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The developing tooth is a useful model in which to analyze the molecular
mechanisms of organ formation. The teeth develop in the oral side of the
maxillary and mandibular processes, and their formation is regulated by
sequential and reciprocal interactions between the odontogenic epithelium and
neural crest derived ectomesenchymal cells
(Miletich and Sharpe, 2003;
Thesleff, 2003
). Signaling
molecules have been shown to mediate inductive tissue interactions during
odontogenesis. In particular, early oral epithelium- and oral
epithelium-expressed signaling molecules regulate dental mesenchymal
expression of signaling genes and transcription factors that are essential for
tooth formation (Miletich and Sharpe,
2003
; Thesleff,
2003
). Trigeminal axon pathfinding and nerve fiber patterning, in
particular in the murine lower first molar, takes place in a strictly
spatiotemporally controlled manner and is tightly linked to tooth formation
(Loes et al., 2002
;
Luukko et al., 1997b
;
Mohamed and Atkinson, 1983
).
The early developing tooth is innervated by nerve fibers originating from the
sensory trigeminal ganglion. Because new axons do not emerge from the
trigeminal ganglia after E13 (Davies,
1988
), axon navigation and their survival around the embryonic
tooth germ during the period of programmed cell death (E13-E18)
(Davies, 1988
) are essential
for the proper development of the sensory innervation of the dental pulp and
periodontal ligament (Luukko et al.,
1997a
). The sympathetic innervation of the tooth develops
postnatally after the onset of root formation
(Fristad et al., 1994
).
Some light has been shed on the molecular mechanisms that regulate the
development of tooth nerve supply. It appears that this process is regulated
by set of neuroregulatory molecules of different families (for a review, see
Fried et al., 2000;
Luukko, 1998
). However, as
yet, no gene has been shown to be essential for pioneer dental axon guidance
or the establishment of early tooth innervation. The finding that the
developing tooth is able to promote its reinnervation when implanted in
ectopic locations (Erdelyi et al.,
1987
) and that the expression of neurotrophins and their receptors
persists in vitro, without peripheral nerve fibers cultured tooth explants has
suggested that the developing tooth is able to control the formation of its
own innervation and that the synthesis of the neuroregulatory molecules is
regulated locally and is an intrinsic property of the tooth germ
(Luukko et al., 1996
;
Luukko et al., 1997a
).
We have recently reported developmentally regulated mRNA expression of
semaphorin 3a (Sema3a) in the developing tooth in sites that are devoid of
nerve fibers, suggesting functions in dental axon guidance and tooth formation
(Loes et al., 2001). Sema3a, a
secreted repulsive axon guidance molecule, shows broad developmentally
regulated expression in the peripheral tissues and organs of the embryo
including the first branchial arch (BA1) and tooth
(Taniguchi et al., 1997
;
Wright et al., 1995
). Targeted
inactivation of the Sema3a gene leads to abnormal fasciculation and patterning
of a set of peripheral nerves, including the cranial trigeminal, facial and
glossopharyngeal nerves, indicating the importance of Sema3a in the
establishment of axonal trajectories
(Taniguchi et al., 1997
;
Ulupinar et al., 1999
). In
addition, Sema3a serves an organogenetic function, e.g. in bone and heart
formation (Behar et al., 1996
),
and controls vascular morphogenesis by inhibiting integrin function
(Serini et al., 2003
). In the
current study, we analyzed the functions and regulation of Sema3a during
early, crucial stages of tooth organogenesis and the formation of its
trigeminal nerve supply. We found that Sema3a is an essential signal for
proper tooth innervation, and that the oral epithelium and dental epithelium
expressed Wnt4 induce Sema3a in the mandibular presumptive molar
mesenchyme area before the arrival of first nerve fibers. Later, during
pioneer dental axon navigation, Wnt4 and Tgfß1 control Sema3a
expression in the dental mesenchyme. Thus, epithelial-mesenchymal interactions
may provide a central mechanism for coordination of axon navigation and
patterning with the mandibular process and tooth formation.
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Materials and methods |
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Antibodies and immunohistochemistry
To detect nerve fibers in paraffin sections, immunohistochemistry with
rabbit polyclonal anti-peripherin (Chemicon International, CA, USA) and
neuropilin 1 antibodies (Kawakami et al.,
1996) (1:150 and 1:1000 dilution) was carried out using the
Vectastain pK4001 kit (Vector Laboratories, Burlingame, CA) according to the
manufacturer's instructions (Luukko,
1997
; Fristad et al.,
1994
). Negative control sections were incubated with normal rabbit
serum instead of the primary antibody. No specific immunoreactivity was
detected.
In situ hybridization
For in situ hybridization on sections the 0.6 kb rat Gdnf, 0.1 kb rat Lanr,
0.9 kb mouse Ncam, 0.4 kb rat Ngf and 2.9 kb mouse Sema3a cDNAs were used for
in vitro transcription of 35S-UTP- and digoxigenin-labeled and
antisense and sense probes. Sectional and whole mount in situ hybridization
was performed as described previously
(Luukko et al., 1996;
Henrique et al., 1995
). No
specific hybridization signals were detected in tissues hybridized with
control sense probes (not shown).
Three-dimensional reconstruction
Three-dimensional (3D) computer reconstruction of the tooth germ was
generated from 7 µm serial frontal bright- and dark-field
phototomicrographs (180 sections from each field). The processing of the
images was done using custom scripts and programs written with Java Advanced
Imaging and Java 3D (Sun Microsystems, CA, USA)
(http://java.sun.com).
Three-dimensional reconstructions were rendered with a perspective camera view
in Visualization Toolkit (Kitware, New York, USA)
(http://www.kitware.com).
A transparent 3D surface of the inner dental epithelium was generated using
the Marching Cubes function in Visualization Toolkit from the outlines of the
dental epithelium and the cervical loops. A hybridization signal in the
dark-field images with an intensity over 230 was considered to represent
positive Sema3a gene expression. The sections were median filtered to reduce
the background hybridization signal in the 3D image.
Organ and tissue culture, recombinant proteins and cell lines
Organ and tissue cultures were performed as described earlier
(Kettunen et al., 1998).
Explants shown are representatives of at least three independent experiments.
At least six explants of each experimental setup were analyzed. Agarose
(BioRad) and heparin acrylic (Sigma) were used. Beads were incubated in
recombinant human FGF2 (100 µg/ml) and FGF4 (50 or 100 µg/ml); mouse
Fgf8b (50 or 100 µg/ml); human FGF9 (25 or 100 µg/ml); human TGFß1
(10 or 100 µg/ml); mouse Shh (250 µg/ml); human BMP4 (100 µg/ml)
(R&D Systems, Minneapolis, MN); or in BSA (1 mg/ml). All bead experiments
were accompanied by positive controls to confirm the activity of the proteins
used (Fig. 6, G1-I2, P1-Q2;
Fig. 7I).
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Cell proliferation assay
The effect of exogenous proteins on dental mesenchymal cell proliferation
was analyzed as described earlier
(Kettunen et al., 1998). The
explants were labeled for 1.5 hours with 10 mM BrdU (Sigma) after 24 hours'
culture. The incorporated BrdU was detected by indirect immunoperoxidase
method with monoclonal antibody against BrdU (Sigma, CA) and the biotinylated
goat anti-mouse secondary antibody (Jackson ImmunoResearch Laboratories, West
Grove, PA, USA) in wholemounts and tissue sections.
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Results |
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Npn1 mutant mice show defects in axon navigation
The receptor neuropilin 1 (Npn1) mediates Sema3a signaling by forming
receptor complexes with plexins (Bagri and
Tessier-Lavigne, 2002). Experimental and genetic analyses have
provided evidence that Npn1 mediates in vivo effects of Sema3a on trigeminal
axons during their pathfinding (Kitsukawa
et al., 1997
; Rochlin and
Farbman, 1998
). To analyze whether Npn1 is a signaling receptor
for Sema3a in dental axons, we first analyzed its mRNA expression in
trigeminal sensory ganglion. In situ hybridization revealed a prominent
Npn1 expression in the ganglion cells during E12.5-E14.5, i.e. during
the period when the dental axons are navigating to and around the tooth germ
as shown for E13.5 ganglion, while hardly any neuropilin 2
(Bagri and Tessier-Lavigne,
2002
) expression was seen (Fig.
2A1-B2). Immunohistochemical analysis from the E12.5-E13.5 head
sections using Npn1 antibodies showed that dental axons expressed the protein
(Fig. 2C), which is in
agreement with the recent report showing Npn1 in dental axons at E15
(Lillesaar and Fried, 2004
).
To investigate the in vivo roles of Npn1 in tooth, we analyzed Npn1
mutant mouse embryos (Kitsukawa et al.,
1997
). Apparently owing to the defects in the cardiovascular
system, the embryos die at about E12.5 when the molar tooth germ is at the
early bud stage. No defects in tooth formation in the E11.5-E12.5 mutant
embryos were detected compared to corresponding wild-type embryos.
Immunohistochemical analysis of 12.5 Npn1-/- embryos
revealed that nerve fibers were prematurely present next to the dental
epithelium, and some were also ectopically localized in the condensing dental
mesenchyme area (Fig. 2D). This
phenotype resembled the defects observed in corresponding stages of
Sema3a-/- embryos but appeared to be less severe.
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Epithelial Wnt4 and Tgfß1 induces mesenchymal Sema3a expression
Early oral and dental epithelium expressed signals in particular members of
the fibroblast growth factor, bone morphogenetic protein, Wnt and Hedgehog
families control gene expression in the underlying mesenchyme
(Miletich and Sharpe, 2003;
Thesleff, 2003
). To identify
the epithelial signal(s) that induce(s) and regulate(s) Sema3a
expression, we applied protein-soaked beads and protein-producing cells of
different members of these families to the mandibular and dental mesenchyme
explants and cultured them for 24 hours
(Kettunen and Thesleff, 1998
).
The explants were serially sectioned and analyzed for Sema3a
expression by in situ hybridization.
Fgf8 mRNAs are expressed in the E10.5 proximal oral epithelium and later in
the early dental epithelium (Kettunen and
Thesleff, 1998) and are essential for the outgrowth and patterning
of the BA1 and for tooth formation (Trumpp
et al., 1999
). As reported earlier
(Neubuser et al., 1997
), Fgf8
induced a prominent Pax9 expression in the presumptive molar area of
E10 mandibular processes, whereas no Sema3a induction was observed
around the Fgf8 beads (Fig.
6A1-B2). Similarly, beads soaked in Bmp4, Fgf9 and Shh, mRNAs of
which are expressed in the presumptive and early dental epithelium
(Hardcastle et al., 1998
;
Kettunen and Thesleff, 1998
;
Vainio et al., 1993
), had no
effect on Sema3a expression in the molar area of E10.5 or E12.5
mandibular mesenchymes as shown for Fgf9 at E12.5
(Fig. 6N1,N2; not shown).
Furthermore, protein-soaked beads for the enamel knot expressed Fgf4
(Jernvall et al., 1994
) did
not have effects on Sema3a expression in the molar region of E12
mandibular mesenchyme explants (not shown).
The finding that the E10.5 oral epithelium was able to induce
Sema3a suggested that the expression of the putative signaling
molecule(s), which induce(s) the initial mesenchymal Sema3a
expression, is or are not limited to the presumptive dental epithelium. The
Wnts form a large family of conserved secreted signaling molecules that
regulate neuronal and non-neuronal development. Several Wnts are expressed in
the lower jaw and dental epithelia (Sarkar
and Sharpe, 1999). In developing limb, epithelial Wnt4 induces
neurotrophin 3 (Nt3) expression in the adjacent mesenchyme
(Patapoutian et al., 1999
),
the development of which is dependent on epithelial mesenchymal interactions.
Moreover, Wnt4 and Wnt5 regulate commissural axon guidance
(Lyuksyutova et al., 2003
;
Yoshikawa et al., 2003
). To
investigate whether Wnt factors control Sema3a, we placed clusters of
Wnt4-producing cells, mRNAs of which are present in the oral and dental
epithelium during E10.5-E14.5 (Sarkar and
Sharpe, 1999
), onto the presumptive molar mesenchyme area of E10.5
and E11.5 lower jaws as well as onto isolated E12.5 dental mesenchyme.
Wnt4-producing cells upregulated Sema3a expression in the adjacent
mesenchymal cells at all stages studied
(Fig. 6, C1-E2), while cells
producing Wnt6, mRNAs of which are present in the oral epithelium
(Sarkar and Sharpe, 1999
),
showed no effect on mesenchymal Sema3a expression at E10.5 or E11.5
(Fig. 6J1,J2 and not shown).
mRNAs for Tgfß1 appear in the epithelial dental bud at E12.5 (not shown),
and later at the cap stage they also appear in the dental mesenchyme
(Vaahtokari et al., 1991
).
Tgfß1 regulates Ngf and Nt3 mRNA levels in the epithelial and mesenchymal
cells of the maxillary process in culture
(Buchman et al., 1994
). When
Tgfß1-soaked beads were placed onto the molar area of E12.5 mandibular
jaw mesenchyme, a prominent Sema3a expression was observed in the
surrounding cells (Fig.
6G1,G2). No effects on Sema3a was observed in the
mesenchyme cultured with control NIH3T3 cells or beads soaked in BSA (1 mg/ml)
from E10 to E12.5 (Fig. 6K1-M2;
not shown).
Wnt4 stimulates Msx1 expression in the jaw mesenchyme
Because Wnt signaling is essential for tooth formation
(Andl et al., 2002;
van Genderen et al., 1994
), we
investigated whether Wnt4 is involved in odontogenesis by analyzing its
effects on the expression of Msx1 and Pax9 transcription factors. Msx1 and
Pax9 are necessary for tooth morphogenesis beyond the bud stage and their
expression in the early mandibular mesenchyme is induced by and dependent on
epithelial signaling (Ferguson et al.,
2000
; Neubuser et al.,
1997
; Peters et al.,
1998
; Satokata and Maas,
1994
; Vainio et al.,
1993
). We found that Wnt4-producing cells were able to stimulate
endogenous Msx1 in E10 mandibular mesenchyme explants, whereas no
Msx1 was observed around the control NIH3T3 cell clusters
(Fig. 6H1-I2). No effects on
Pax9 expression in E10.5 presumptive dental mesenchyme around the
cells were observed (not shown).
Tgfß1 stimulates dental mesenchymal cell proliferation
Because Tgfß1 is prominently expressed in the highly proliferative
cells in the cervical loops and dental papilla mesenchyme during the cap stage
(Vaahtokari et al., 1991) when
dental axons are growing around the tooth germ, we analyzed the effects of
Tgfß1 on dental cell proliferation. Tgfß1-soaked agarose beads were
applied onto the molar area of isolated dental mesenchyme at E12 when
Tgfß1 is expressed in the epithelial bud but not in the underlying
mesenchyme. The explants were cultured for 24 hours, the last 1.5 hours with
5-bromo-2-deoxyuridine (BrdU). Whole-mount and sectional immunohistochemical
analysis showed that E12 dental mesenchymal cells around Tgfß1 and
positive control Fgf2 (Kettunen et al.,
1998
)-releasing beads had incorporated BrdU markedly
(Fig. 7A-D). This mimicked the
effects of E12 dental epithelia, which also stimulated the proliferation of
adjacent dental mesenchymal cells in homochronic recombinants
(Fig. 7C,D). No elevated BrdU
incorporation was seen in explants cultured with BSA-soaked beads
(Fig. 7E). Thus, besides
controlling the establishment of tooth innervation, Tgfß1 may regulate
tooth morphogenesis by stimulating dental cell proliferation.
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Discussion |
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Analysis of Sema3a knockout mice revealed that Sema3a is an essential signal for the establishment of early tooth innervation, though not for its formation, and that its effects appear to be mediated by the Npn1 receptor expressed in the dental axons. That the nerve fibers prematurely innervate the Sema3a-/- tooth already at the epithelial thickening stage indicates that Sema3a, by forming exclusion areas in the jaw and presumptive dental mesenchyme, regulates the timing of tooth innervation by apparently by preventing ingrowth of other trigeminal nerve fibers such as buccal nerve. At the early bud stage, Sema3a signaling appears to regulate the formation of the single `molar' nerve and channels the growth of pioneer dental axons to the restricted mesenchymal pathway towards the tooth. During subsequent morphogenetic bud, cap and bell stages, Sema3a restricts axon growth into the mesenchymal target field around the tooth and prevents their ingrowth to the condensed dental mesenchyme and the dental papilla. The absence of Sema3a from the sites of the developing secondary apical foramina during E18-PN4 suggests that Sema3a exclusion areas in the base of the dental papilla do not determine the timing of nerve fiber penetration to the dental papilla but are involved in regulation of the sites through which the nerve fibers are able to enter, i.e. through the forming root canals.
We also noticed that many nerve fibers showed largely normal localization
within the tooth target field in Sema3a-/- embryos, and
that errors in dental axon patterning became increasingly corrected as tooth
morphogenesis proceeded, which is in line with the corrections of other
sensory axon projections in Sema3a-/- mice
(White and Behar, 2000). We
found that mRNA expression of Ngf, Gdnf, Lanr, Ncam and Net3 was not affected
in the dental follicle target area of the Sema3a-/- teeth.
This indicates that their expression is not regulated or dependent on Sema3a,
and that they appear to partially rescue tooth innervation phenotype in
Sema3a-/- mice. Thus, these results provide genetic
evidence for the model that axon guidance and establishment of tooth nerve
supply involves redundant and independent signaling of neuroregulatory genes
of different families.
Epithelial-mesenchymal interactions regulate the establishment of tooth nerve supply
The finding that precisely regulated expression domains of Sema3a are
crucial to the timing of tooth innervation as well as dental axon guidance and
patterning led us to use Sema3a as a marker gene for analysis of the basal
regulatory mechanisms behind the establishment of tooth nerve supply. By
performing tissue recombination experiments, we found that the oral epithelium
is necessary for Sema3a expression in the E10.5 and E11 mandibular
mesenchyme, and that E10.5 oral epithelium as well as E11 and E12 dental
epithelia are able to induce Sema3a expression in the presumptive
molar mesenchyme area of the lower jaw lacking Sema3a. Furthermore,
we showed that later at E12 when the first dental axons are about to or are
navigating to the developing tooth, dental epithelium controls Sema3a
in the dental mesenchyme. Thus, these results suggest that local
epithelial-mesenchymal interactions control Sema3a expression and the
establishment of tooth innervation. As tooth formation has been shown to be
controlled by interactions between epithelial and mesenchymal tissues
(Lumsden, 1988;
Mina and Kollar, 1987
), tissue
interactions may therefore provide a mechanism to coordinate axon navigation
and patterning spatiotemporally with tooth formation.
Earlier tissue recombination studies have shown that E10-E11 mouse oral and
dental epithelium possesses instructive information to control tooth formation
as well as the potential to determinate tooth type
(Lumsden, 1988;
Mina and Kollar, 1987
;
Tucker et al., 1998
). Our
tissue recombination experiments showing that the E10.5 oral and E11 dental
epithelia induce mesenchymal Sema3a expression indicate that, besides
the odontogenic information, the presumptive dental epithelium also possesses
the instructive information to control the formation of early tooth nerve
supply and possible tooth-specific sensory innervation that is distinct, in
some aspects, from the adjacent cutaneous sensory system
(Fried et al., 2000
;
Kvinnsland et al., 2004
).
Furthermore, because the formation of teeth of all types is controlled by the
epithelial-mesenchymal interactions, the interactions also appear to provide a
rationale for the fact that the timing and pattern of tooth innervation in
different teeth and species correlate better to the developmental stage of the
individual tooth than the chronological age of the animal.
Epithelial-mesenchymal interactions mediated by Wnt4 and Tgfß1 may coordinate trigeminal axon navigation and patterning with tooth formation
Early oral and dental epithelium expressed signaling molecules have been
implicated in the mediation of organogenetic tissue interactions. We found
that oral and dental epithelium expressed Wnt4 induces Sema3a in the
mandibular presumptive dental mesenchyme and that, later, Wnt4 and Tgfß1,
which are present in the early bud stage dental epithelium during dental axon
growth, stimulate Sema3a expression in the dental mesenchyme. Thus,
Wnt4 and Tgfß1 may act as in vivo epithelial signals that control
mesenchymal Sema3a expression. Of particular interest is the
observation that Wnt signaling has been shown to be essential for tooth
formation, as evidenced by the finding that overexpression of the Wnt
inhibitor Dickkopf1 in the BA1 ectoderm and targeted inactivation of Lef1
transcription factor (which is needed for Fgf4 expression in the
primary enamel knot signaling center) in transgenic mice result in arrest of
tooth formation prior to the bud and cap stages, respectively
(Andl et al., 2002;
van Genderen et al., 1994
;
Kratochwil et al., 2002
).
Epithelial Fgf4 induces Fgf3 expression in the dental mesenchyme
(Kettunen et al., 2000
), which
is required for Shh expression in the future enamel knot
(Kratochwil et al., 2002
). In
addition, it has been suggested that interactions between epithelial expressed
Wnt7 and Shh determine the position of tooth initiation
(Sarkar et al., 2000
). We have
found that Wnt4 maintained mesenchymal expression of Msx1
transcription factor, which is essential for tooth morphogenesis
(Satokata and Maas, 1994
) in
the early jaw mesenchyme, whereas Tgfß1, the expression of which
correlates with tooth morphogenesis, stimulated the proliferation of the
dental mesenchymal cells. Thus, besides regulating Sema3a, Wnt4 and
Tgfß1 appear to be involved in the regulation of tooth formation. We
propose that they may act as signals that mediate epithelial-mesenchymal
interactions and coordinate trigeminal axon growth and patterning with tooth
formation (Fig. 8).
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ACKNOWLEDGMENTS |
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