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Developmentally regulated expression of Shh and Ihh in the developing mouse cranial baseComparison with Sox9 expression.

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Developmentally Regulated
Expression of Shh and Ihh in the
Developing Mouse Cranial Base:
Comparison With Sox9 Expression
Section of Anatomy and Cell Biology, Department of Biomedicine, University of
Bergen, Bergen, Norway
The cranial base, located between the cranial vault and the facial bones, plays an
important role in integrated craniofacial development and growth. Transgenic Shh and
Sox9-deficient mice show similar defects in cranial base patterning. Therefore, in order to
examine potential interactions of Shh, Ihh, another member of the Hh family, and Sox9
during cranial base development and growth, we investigated their cellular mRNA expression domains in the embryonic (E) and early postnatal (PN) cranial base from E10 to PN5
using sectional radioactive 35-S in situ hybridization. Of the Hhs, Shh was observed in the
foregut epithelium and the notochord, while Sox9 showed broad expression in the loose
mesenchyme of the cranial base area during E10 –E11. Subsequently, from E12 onward, all
genes were observed in the developing cranial base, and after birth the genes were prominently colocalized in the prehypertrophic chondrocytes of the synchondroses. Collectively,
these data suggest that Hh-Sox9 auto- and paracrine signaling interactions may provide a
critical mechanism for regulating the patterning of the cranial base as well as for its
development and growth. © 2005 Wiley-Liss, Inc.
Key words: signaling; skeletogenesis; endochondral bone; embryonic
The cranial base is a bony structure located between the
cranial vault and the facial bones. It is mainly a midline
structure, composed of basioccipital, sphenoid, ethmoid,
and frontal bones (Vilmann, 1969, 1971). Cranial base is
an important growth site of the head and plays a central
role in integrated craniofacial development and growth.
The anterior cranial base rostral to the sella turcica develops from the neural crest-derived ectomesenchymal
cells, whereas the posterior cranial base derives from the
paraxial mesoderm (Couly et al., 1993). Unlike the other
craniofacial bones, which are predominantly formed by
intramembranous ossification, the cranial base is formed
by endochondral ossification, in which the mesenchymal
cells condense and subsequently form the cartilage model
of the cranial base. The cartilage is replaced by bone
except in the synchondroses, which are well-organized
cartilage structures similar to long bone growth plates
connecting the individual bones (Baume, 1968). The enlarging brain influences the growth of the cranial base
during early stages. However, synchondroses continue to
grow after cessation of brain growth (Kantomaa et al.,
1991; Hilloowala et al., 1998). Thus, the formation of the
cranial base is controlled by genetic and epigenetic factors.
In many human syndromes, such as Down syndrome,
Turner syndrome, cleidocranial dysplasia, craniosynostosis syndromes, Seckel syndrome, and Williams syndrome,
the cranial base is affected (Jensen, 1985; Kreiborg et al.,
1993, 1999; Kjaer et al., 2001; Quintanilla et al., 2002;
Lomholt et al., 2003; Axelsson et al., 2005).
While the molecular mechanisms orchestrating axial
and appendicular bone formation and growth have begun
to be elucidated in great detail, less is known about the
Grant sponsor: the Norwegian Cancer Society; Grant sponsor:
the L. Meltzer’s Foundation; Grant sponsor: the University of
Bergen; Grant sponsor: the Research Council of Norway; Grant
sponsor: Helse-Vest and Sparebanken 1 Vest, Bergen, Norway.
*Correspondence to: Päivi Kettunenm, Section of Anatomy and
Cell Biology, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. Fax: 47-55-58-63-60.
Received 9 March 2005; Accepted 1 July 2005
DOI 10.1002/ar.a.20231
Published online 6 September 2005 in Wiley InterScience
molecules regulating that of the cranial base. Genetic and
experimental evidence indicate that some critical signaling pathways are shared among endochondral skeleton
(Opperman, 2000; Karsenty and Wagner, 2002). Bone
morphogenetic proteins (Bmp), fibroblast growth factors
(Fgf), hedgehog (Hh), and Drosophila Wingless (Wnt) families, which are involved in general embryonic development, also regulate skeletal development (Opperman,
2000; Karsenty and Wagner, 2002; Ornitz and Marie,
2002; Ornitz, 2005). Inactivation or overactivation of Fgf
signaling leads to cranial base anomalies (Eswarakumar
et al., 2002, 2004; Rice et al., 2003). Bmp signaling has
been shown to be able to regulate synchondrosis growth in
an in vitro system (Shum et al., 2003).
The hedgehog signaling family consists of three members, Sonic hedgehog (Shh), Indian hedgehog (Ihh), and
Desert hedgehog (Dhh). Shh and Ihh play an important
role in endochondral bone formation. Transgenic mice
lacking Shh function suffer from severe defects in bone
formation, such as absence of spinal column and defects in
limb bones, and cyclopia (Chiang et al., 1996). In humans,
mutations in SHH give rise to holoprosencephaly, a failure of cleavage of the prosencephalon with a deficit in
midline facial development (Belloni et al., 1996; Roessler
et al., 1996). Ihh null mutant mice, on the other hand,
display markedly reduced chondrocyte proliferation, maturation of chondrocytes at inappropriate positions, and a
failure of osteoblast development in endochondral bones
(St-Jacques et al., 1999).
Previous research has provided evidence that Shh mediates its effects on bone development by inducing Sox9
expression, a key transcription factor essential for chondrogenesis and subsequent endochondral ossification (Bi
et al., 1999; Healy et al., 1999; Akiyama et al., 2002; Zeng
et al., 2002; Cheung and Briscoe, 2003; Mori-Akiyama et
al., 2003; Tavella et al., 2004). In humans, mutations in
SOX9 result in campomelic dysplasia (CD), a skeletal
dysplasia syndrome characterized by sex reversal and
skeletal malformations of endochondral bones, such as
bowing of the limbs and cranial defects (Foster et al., 1994;
Wagner et al., 1994). In mouse, targeted inactivation of
Sox9 in the neural crest cells resulted in defective presphenoid and basisphenoid bone formation, demonstrating
its essential role for cranial base development (MoriAkiyama et al., 2003).
The expression domains of Shh, Ihh, and Sox9 at successive stages of embryonic and postnatal development
and growth of the cranial base are not known. Therefore,
in order to investigate potential interactions between Hh
signaling and Sox9 during cranial base development and
growth, we studied their mRNA expression domains by
radioactive in situ hybridization from mouse midsagittal
tissue sections from before the visible onset of cranial base
development at embryonic day 10 (E10) until the development of functional synchondrosis at 9 days postnatally
Preparation of Tissues
All procedures involving animals were approved by the
Animal Welfare Committee of the University of Bergen.
Mice (NMRI) embryos between E10 and E18, as well as
newborn (NB) and PN3, PN5, and PN9 mice were dissected in phosphate-buffered saline (PBS) and fixed in 4%
paraformaldehyde (PFA) overnight at 4°C. The mice were
killed by cervical dislocation and the embryos by decapitation. Mice embryos over E15 were decalcified with 12.5%
EDTA-2.5% PFA in PBS. They were then embedded in
paraffin. Sagittal sections were cut from the midline area.
Construction of Probes and In Situ
Plasmids containing fragments of Ihh and Sox9 cDNAs
were generated by RT-PCR from total RNA isolated from
E18 mouse lower jaws and E13 mouse heads, respectively,
and subcloned into pGEM-T Easy Vector (Promega, Madison, WI): a 405 bp Ihh fragment spanning the region
between 1679 and 2083 in accession number NM 010544,
and a 586 bp Sox9 fragment spanning the region between
748 and 1333 in accession number AF21878. The following
primer oligonucleotides were used: Ihh F 5⬘-CTCTAACCACTGCCCTCCTG-3⬘ and R 5⬘-GGGAATCTAGCAGCATCGAC-3⬘, and Sox9 F 5⬘-GTTGATCTGAAGCGAGAGGG-3⬘ and R 5⬘-TCTGATGGTCAGCGTAGTCG3⬘. Shh cDNA was a kind gift from Dr. Andrew McMahon
(Harvard University, Cambridge, MA).
In situ hybridization on sections was performed as described previously (Luukko et al., 1996). Briefly, 35 SUTP-labeled Shh, Ihh, and Sox9 antisense and sense
cRNA probes were generated by in vitro transcription.
After the hybridization procedure, the slides were dipped
in NTB-2 emulsion (Eastman Kodak) for autoradiography.
After 3 weeks’ exposure at 4°C, the slides were developed
and fixed, counterstained with hematoxylin, and
mounted. Images were taken with a Spot Insight digital
camera (Diagnostic Instruments, Sterling Heights, MI)
mounted on a Zeiss Axioskop2 microscope (Carl Zeiss
Jena, Jena, Germany). The bright-field and dark-field images of each section were digitized separately and the
grains from dark fields were selected, colored red, and
copied onto the bright-field image using Adobe Photoshop
7.0 software (Adobe Systems, San Jose, CA). No specific
signal was detected in sections hybridized with the control
sense probes (not shown).
Expression of Shh During Cranial Base
As the cranial base is largely a midline structure, we
used serial midsagittal sections to analyze mRNA expression of Shh, Ihh, and Sox9 in the developing basioccipital
and basisphenoid bones and in the spheno-occipital synchondrosis.
At E10, before the histological initiation of cranial base
development, Shh was prominently expressed in the notochord (shown for E12; 1C) and in the dorsal midline area
of the foregut epithelium (Fig. 1A). At E11 and E12, Shh
expression continued in the foregut epithelium (Fig. 1B
and C), and at E12 transcripts also appeared in the basioccipital chondroblasts (Fig. 1C). No specific expression
was observed in the later developing anterior cranial base
mesenchyme area at this stage. At E13, Shh transcripts
were seen in the immature chondrocytes of the developing
basioccipital and basisphenoid bones (Fig. 2A). One day
later, Shh was observed in the differentiating chondrocytes, and by E16 expression was confined mainly to the
prehypertrophic chondrocytes, but some expression was
also seen in hypertrophic chondrocytes of the developing
spheno-occipital and intersphenoid synchondroses (Fig.
Fig. 1. Comparison of Shh and Sox9 mRNA expression in the developing cranial base at E10 –E12 analyzed by radioactive in situ hybridization on midsagittal sections. Red coloring, which indicates hybridization signal, is superimposed onto the hematoxylin-stained histology
image. Shh transcripts are seen in the foregut epithelium in the dorsal
midline area between E10 and E12 (A–C). At E12, Shh is seen in the
chondroblasts of the posterior part of the future basioccipital bone and
in the notochord (C). Sox9 shows broad expression in the loose mesenchyme at E10 (D), which subsequently, during E11 and E12, becomes
restricted to the mesenchymal condensates of the future cranial base
bones (E and F). b, brain; ba1, first branchial arch; bo, basioccipital
cartilage; m, mesenchymal cell condensate; n, notochord; pi, pituitary
gland; r, Rathke’s pouch; to, tongue. Scale bars ⫽ 400 ␮m in A (applies
to E10 stages) and B (applies to E11 and E12).
Fig. 2. Comparison of Shh and Sox9 mRNA
expression in E13 (A and G), E14 (B and H), and
E16 (C and I) developing cranial base, as well as in
NB (D and J), PN5 (E and K), and PN9 (F and L)
spheno-occipital synchondrosis analyzed by radioactive in situ hybridization on midsagittal sections. Red coloring, which indicates hybridization
signal, is superimposed onto the hematoxylinstained histology image. A: Shh is observed in the
immature chondrocytes of the developing basioccipital and basisphenoid bones at E13. B: At E14,
Shh expression is seen in the differentiating chondrocytes. C–F: At E16 and postnatal stages, Shh
expression is evident in the prehypertrophic chondrocytes. Some expression is also seen in the
hypertrophic chondrocytes of the developing
spheno-occipital and intersphenoid synchondroses. G: Sox9 is seen in the cartilage model of the
cranial base at E13. H–L: During subsequent development and cranial base ossification between
E14 and PN9, Sox9 expression gradually becomes
restricted to the resting, proliferating, and prehypertrophic chondrocytes of the synchondroses. b,
brain; bo, basioccipital cartilage; bs, basisphenoid
cartilage; e, erosive zone; h, hypertrophic chondrocytes; is, intersphenoid syndchondrosis; pi, pituitary gland; pr, proliferating chondrocytes; pre,
prehypertrophic chondrocytes; rc, resting chondrocytes; so, spheno-occipital synchondrosis; t,
trabecular bone; to, tongue. Scale bars ⫽ 400 ␮m
in A (applies to E13–E16) and D (applies to postnatal stages).
2B–F). The Shh expression in the synchondroses continued to the last studied PN9 stage as shown for sphenooccipital synchondrosis (Fig. 2E and F). The expression of
Shh in the hypertrophic cells correlates with the Shh
expression in the growth plate of the chicken long bone
(Wu et al., 2002).
Expression of Sox9 in Developing Cranial Base
In contrast to Shh, Sox9 showed broad expression in the
loose head mesenchyme at E10 (Fig. 1D). At E11, Sox9
expression had become restricted to the mesenchymal condensates of the developing basioccipital and basisphenoid
bones. At the anterior part of the developing cranial base,
the expression largely continued throughout the loose
mesenchyme (Fig. 1E). At E12, Sox9 transcripts were
restricted to the cartilage templates of the cranial base
bones (Fig. 1F). From E14 onward, Sox9 expression was
gradually downregulated from the chondrocytes as they
became hypertrophic (Fig. 2H–L). The expression became
restricted to the synchondroses with high expression in
the prehypertrophic chondrocytes. In addition, some early
hypertrophic chondrocytes showed Sox9.
Expression of Ihh in Cranial Base
Ihh, which is expressed in the developing endochondral
bones, is an essential regulator of their formation (StJacques et al., 1999; Karp et al., 2000; Long et al., 2001,
2004; Minina et al., 2001, 2002; Jeong et al., 2004), but
characterization of its cellular expression in the cranial
base has been limited to E15 stage (Iwasaki et al., 1997).
We therefore analyzed cellular expression domains of Ihh
mRNAs during E10 –PN5. In agreement with a previous
RT-PCR result (Kronmiller and Nguyen, 1996), we did not
observe Ihh expression in the developing cranial base area
or adjacent tissues during E10 –E11 (Fig. 3A and B). A
prominent Ihh expression in the cartilage model of the
developing basioccipital cartilage was detected at E12
(Fig. 3C). Subsequently, at E13 and E14, the expression
was also observed in basisphenoid cartilage (Fig. 3D and
data not shown). By E16, transcripts were confined to the
differentiating chondrocytes of the future spheno-occipital, intersphenoid, and sphenoethmoidal synchondroses
(Fig. 3E). After birth, Ihh expression in the synchondroses
was evident in the prehypertrophic chondrocytes and was
also observed in some early hypertrophic chondrocytes.
This expression pattern continued in the later postnatal
stages (Fig. 3F and G). It is interesting to note that Ihh
was also observed in the developing intramembranous
mandibular and maxillary bones at E13 and E14, as
shown for E13 (Fig. 3H).
In mouse, the histological initiation of cranial base formation is visible when the mesenchyme condensation of
the posterior part of the future basioccipital cartilage appears at E11. The synchondrosis growth centers are functional and express all the cell types typical for them during postnatal ages in murine (Baume, 1968, and this
study). Therefore, our study, spanning from E10 to PN9
covers all the critical stages of cranial base development
such as patterning, chondrogenesis and osteogenesis, and
growth by synchondrosis. Hh signaling and Sox9 have
been shown to be essential for proper cranial base formation (Bi et al., 1999; Hu and Helms, 1999; Akiyama et al.,
2002; Jeong et al., 2004), but the cellular localization of
Shh, as well as Ihh and therefore the exact roles of Hh
signaling during cranial base development, has remained
unknown. We found that Shh, Ihh, and Sox9 showed developmentally regulated expression patterns in sites that
suggest potential regulatory interactions for them at different stages of the cranial base formation.
Possible Interactions Between Shh and Sox9
During Patterning of Cranial Base
The condensation process of mesenchymal cells started
at the sites of future basioccipital bone at about E11 and
proceeded rostrally. In line with earlier reports (Chiang et
al., 1996; Zeng et al., 2002), we observed Shh in the notochord at E10 –E12. However, we also found that Shh was
specifically expressed in the dorsal midline of the foregut
epithelium. In contrast, Sox9 showed prominent expression in the adjacent loose mesenchyme throughout the
presumptive cranial base area. Later at E12, Shh was also
expressed in the cartilage model of basioccipial bone while
Sox9 continued to show broader expression.
Sox9 regulates the site and shape of the skeletal condensation (Bi et al., 1999). Earlier studies have shown
that paracrine Shh signaling from the notochord and floor
plate induces Sox9 in sclerotome, which is subsequently
maintained by Bmp signaling (Zeng et al., 2002). Targeted
inactivation of the common hedgehog receptor Smoothened in mouse has demonstrated that Hh signaling is not
necessary for cranial neural crest cell generation and migration but is essential for later developmental steps of
cranial patterning, including proper patterning and formation of the cranial base (Jeong et al., 2004). The observed defects in the cranial base of the Smoothened mutant mice correlate remarkably with the defects in
Sox9⫺/⫺ mice, both of which show defective/absence of
presphenoid and basisphenoid bones (Mori-Akiyama et
al., 2003; Jeong et al., 2004). Based on these experimental
results and our gene localization data, we suggest a model
where local paracrine Shh signaling from the foregut epithelium and the notochord controls Sox9 in forming mesenchyme condensations. Later autocrine Shh signaling
regulates Sox9 in the cartilage model. Therefore, we propose that Shh-Sox9 signaling interaction is a critical
mechanism in regulating the patterning and formation of
the cranial base. Our detailed analysis also showed that
Ihh mRNAs were absent from the developing cranial base
during the early stages of cranial base patterning and
formation. Thus, the functions of Shh at these earliest
stages appear not to be redundant with Ihh, as also supported by the fact that Ihh null mutant mice show normal
early patterning of the head skeleton (St-Jacques et al.,
1999). Furthermore, because Dhh is not reported in the
developing skeleton or head and no defects have been
observed in the head in the mutant mice, the function of
Hh signaling in the earliest stages of cranial base development may be solely mediated by Shh (Bitgood and McMahon, 1995; Bitgood et al., 1996).
Possible Roles of Shh Signaling During
Chondrocyte Life Cycle
During subsequent development, the mesenchymal cells
in the future cranial base condensations differentiate into
chondroblasts, which proliferate, differentiate, and become hypertrophic. We observed that at E12 and E13 Shh
Fig. 3. Expression of Ihh mRNA in E10 –E13 and E16 cranial base as
well as in newborn and 5-day postnatal spheno-occipital synchondrosis
analyzed by radioactive in situ hybridization on midsagittal sections. Red
coloring, which indicates hybridization signal, is superimposed onto the
hematoxylin-stained histology image. A and B: No Ihh expression is
seen in the future site of the cranial base or adjacent tissues at E10 and
E11. C: At E12, Ihh transcripts are seen in the chondroblasts of the
posterior part of the future basioccipital bone. D: At E13, Ihh expression
are observed in the chondrocytes of the developing basioccipital and
basisphenoid bones. E: At E16, transcripts are seen in the prehypertrophic and in some early hypertrophic chondrocytes. F and G: In newborn
and 5-day postnatal spheno-occipital synchondrosis, Ihh is expressed in
the prehypertrophic and in some hypertrophic chondrocytes. H: Ihh
transcripts are present in the developing mandibular bone (arrow), which
forms through intramembranous ossification. b, brain; ba1, first
branchial arch; bo, basioccipital cartilage; bs, basisphenoid cartilage; is,
intersphenoid synchondrosis; m, mandibular bone; mc, Meckel’s cartilage; pre, prehypertrophic chondrocytes; h, hypertrophic chondrocytes;
rc, resting chondrocytes; pi, pituitary gland; so, spheno-occipital synchondrosis; t, trabecular bone; to, tongue. Scale bars ⫽ 400 ␮m. Scale
bar in D applies to E13 and E16 stages. Scale bar in F applies to
postnatal stages.
was coexpressed with Sox9 in the cartilage model of the
developing basioccipital bone. Subsequently, similar expression was also observed in the rostral developing cranial bone anlages. Thereafter, Shh expression became restricted to the prehypertrophic chondrocytes, while Sox9
continued in resting, proliferating, and prehypertrophic
chondrocytes. The Shh expression pattern largely correlated with that of Ihh, in particular in the prehypertrophic
chondrocytes. Genetic experiments have shown that both
Sox9 and Ihh are needed for chondrocyte proliferation and
differentiation (St-Jacques et al., 1999; Karp et al., 2000;
Long et al., 2001; Minina et al., 2001, 2002; Akiyama et
al., 2002). Shh and Ihh share the same signaling receptor
in the developing bones (Long et al., 2001; Jeong et al.,
2004), and recently it has been shown that continuous Shh
overexpression in chondrocytes resulted in prominent
Sox9 expression and absence of exoccipital and supraoccipital bones in mice (Tavella et al., 2004). Thus, the
observed overlapping expression domains of Ihh, Shh, and
Sox9 suggest that in addition to Ihh, Shh acts to maintain
Sox9 in the undifferentiated chondrocytes by autocrine
signaling and thereby controls proper chondrocyte proliferation and differentiation and subsequent bone formation.
Possible Function of Hh Signaling and Sox9 in
Synchondroses are bidirectional growth centers, analogous structures to the growth plates of the long bones
(Abad et al., 2002). The proliferation of the cartilage cells
in both sides of the resting zone, which contain stem
cell-like cells, contributes to the postnatal growth and
expansion of the cranial base. Subsequently, the cells become hypertrophic, undergo apoptosis, and are replaced
by the trabecular bone. As cranial base development proceeded, the expression of Shh and Sox9 as well as Ihh was
gradually restricted to the synchondroses. Their expression patterns are virtually similar to that of long bone
growth plates, suggesting the same regulatory functions.
Knowing the essential function of Ihh for cartilage and
bone development (St-Jacques et al., 1999; Karp et al.,
2000; Long et al., 2001, 2004; Minina et al., 2001, 2002)
and that both Shh and Ihh were prominently expressed in
the prehypertrophic chondrocytes, we propose that Shh
may regulate chondrocyte proliferation and differentiation in the synchondrosis and thereby control its development and growth. In support of this, overexpression of
Shh leads to defects in growth plates with cessation of
chondrocyte differentiation at the prehypertrophic stage
(Tavella et al., 2004). Sox9 was broadly expressed in developing synchondrosis, and after birth its expression continued in all chondrocytes except for the late hypertrophic
ones, with the highest expression in the prehypertrophic
chondrocytes. Sox9 function is essential for various stages
of cartilage development. Therefore, it is possible that
Sox9, regulated by auto- and paracrine Shh and Ihh, may
serve important roles in maintaining the organization and
function of cartilaginous synchondroses during cranial
base development and growth. Together, our results provide further evidence that the signaling pathways regulating long bone and cranial base development and growth
by the epiphyseal growth plates and bidirectional synchondrosis, respectively, are shared. However, it is obvious that, like the formation of bones with different size
and shape in general, the formation of the growth plate
and synchondrosis is a result of differential molecular
regulation. The future challenge is to uncover the synchondrosis and growth plate-specific signaling pathways,
which regulate their formation and function.
The authors thank Ms. Kjellfrid Haukanes and Ms.
Helen Olsen for their skilful technical assistance.
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