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First published online September 12, 2006
doi: 10.1242/10.1242/dev.02550
1 Institute for Developmental Biology, University of Cologne, Gyrhofstrasse 17,
50923 Köln, Germany.
2 Institute for Paediatric Endocrinology, Charite University Hospital,
Humboldt-University, Berlin, Germany.
3 University of Massachusetts Medical School, 364 Plantation Street, Worcester,
MA 01605, USA.
4 Max Planck Institute for Molecular Genetics, Berlin, Germany.
Authors for correspondence [e-mail:
heiko.krude{at}charite.de
(mouse);
klaus.rohr{at}uni-koeln.de
(zebrafish)]
Accepted 26 July 2006
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Thyroid, Zebrafish, Mouse, Arteries, Vegf, Scl, Hedgehog
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Dathan et al., 2002). However,
the morphogenetic forces defining the position of organ tissue during the
relocalisation process are unknown.
The disruption of morphogenetic events defining position and shape of
organs can account for congenital malformations and diseases in humans. The
thyroid is particularly prone to morphogenetic variability. Usually present as
a bilobed gland in humans, the thyroid develops as a unilateral gland at a
frequency of one in 2000 individuals
(Maiorana et al., 2003).
Furthermore, the whole or part of the thyroid tends to develop ectopically,
either at positions reminiscent of the relocalisation path or at apparently
unrelated positions, for example embedded into heart tissue close to the
outflow tract (Casanova et al.,
2000). Proper organ function usually depends on normal tissue
localisation with respect to adjacent structures during development.
Therefore, ectopic localisation of the thyroid gland is often associated with
compromised endocrine function, resulting in congenital hypothyroidism
(De Felice and Di Lauro,
2004).
Owing to its accessibility for embryonic manipulation, the zebrafish
thyroid is an excellent model with which to identify structures required for
proper thyroid localisation. As far as investigated, molecules involved in
thyroid development are essentially conserved between zebrafish and mammals
(Elsalini et al., 2003;
Wendl et al., 2002). In
zebrafish, rapid development might explain a slightly different timing in
thyroid differentiation (Elsalini et al.,
2003). More striking differences between species exist with
respect to the final position and shape of the gland. Although in all
vertebrates investigated the primordium relocalises after evagination from the
pharyngeal epithelium, the gland eventually adopts different shapes
(Gorbman and Bern, 1962). In
zebrafish, the initially small globular thyroid grows massively along the
anteroposterior axis in the hypopharyngeal area, expanding into a long strand
of tissue (Alt et al., 2006).
In mouse and humans, the gland adopts its characteristic bilobed shape in
front of the trachea.
In the present study, we investigate how thyroid tissue is positioned during relocalisation. Using zebrafish, we show that ectopic vascular cells are sufficient to mislocate thyroid tissue in a non-cell autonomous manner during growth. Based on this finding and on analysis of zebrafish mutants, we conclude that an adjacent vessel, the ventral aorta, determines thyroid tissue localisation. In the derived circulation of mammals, a vessel homologous to the ventral aorta does not persist. By investigating normal and mutant mouse embryos, we identify the carotid arteries as candidates for vessels that have assumed a comparable role in mammalian thyroid morphogenesis.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) is allelic to the kdr (flk1) lines
described previously (Habeck et al.,
2002) and develops heart oedema owing to compromised circulation
or other specific defects at stages older than 40 hours, so that determination
of mutant phenotypes was possible based on morphology. Homozygous
cloche mutant embryos (clos5)
(Stainier et al., 1995) were
also identified before fixation according to their phenotype at 24 hpf.
Phenotypic details described in this study were always evident in all
homozygous specimens (more than 10 in each experiment).
|
) and
XtJ/XtJ mutant mouse embryos
(Persson et al., 2002) timed
matings of mutants were generated. The homozygous phenotypes are
distinguishable from wild type owing to severe morphological defects, and in
the case of Dsh-XtJ matings we determined the
genotype by PCR from extra-embryonic membranes (primer information available
upon request).
Preparation of specimens
In situ hybridisation on zebrafish was carried out according to standard
procedures, using nk2.1a (Rohr
and Concha, 2000) as molecular marker for the thyroid primordium.
Whole-mount immunohistochemistry with antibodies against thyroid hormone (T4)
or thyroglobulin (TG) in wholemount zebrafish larvae was performed as
described elsewhere (Elsalini and Rohr,
2003).
For histological analysis, paraffin embedded mouse embryos were sectioned and stained with Haematoxylin-Eosin according to standard protocols. Three-dimensional images were reconstructed using every fifth section with the program SURFdriver 4.0, available at http://www.surfdriver.com. For immunohistochemistry on mouse sections, we used a Nkx2.1/Ttf-1 specific antibody generated against rat recombinant antigen (DAKO, Carpenteria, USA). Zebrafish embryos were embedded in Durcupan and sectioned. Diameters of the thyroid were measured using Discus software on a DMRA2 compound microscope (Leica).
Embryonic manipulation
Synthetic mRNA was produced using the message machine kit (Ambion) and
approximately 25 pg scl mRNA and 25 pg lmo2 mRNA were
injected into one cell stage embryos. As a control, we injected synthetic
gfp mRNA at same concentrations. As lineage tracer for grafting
experiments, we injected biotin-dextran (10.000 MW, 5 mg/ml; Invitrogen)
together with synthetic mRNA and detected biotin-labelled donor-derived cells
after in situ hybridisation using the ABC kit (Vector Laboratories). Injection
and grafting experiments were repeated at least twice. At least 50 embryos
were analysed for each mRNA injection experiment.
Morpholino RNA targeted against vegf (vegf-A-3)
(Nasevicius et al., 2000), an
scl splice morpholino (Patterson
et al., 2005), a tnnt2 morpholino
(Sehnert et al., 2002) and an
unspecific control morpholino were purchased (Gene Tools), and dissolved as
recommended by the provider. Morpholinos were always injected into one cell
stage embryos. At least 50 morphants were analysed for each experiment.
Sections were made from five specimens or more in each experiment. All
phenotypes described were consistently found in over 70% of morphants, with
the rest showing milder defects or wild-type appearance.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The close association of thyroid and ventral aorta during
development prompted us to investigate a possible relationship between both
tissues.
Disturbed pharyngeal vessel architecture coincides with thyroid defects in zebrafish mutants
The mechanisms of ventral aorta and branchial artery development are
largely unknown, so we first identified zebrafish embryos with disrupted
pharyngeal vasculogenesis. The transcription factor Scl (also known as Tal1)
is required for haematopoiesis (Gering et
al., 1998; Liao et al.,
1998), and endothelial (Liao
et al., 1998) and dorsal aorta development
(Patterson et al., 2005) in
zebrafish embryos. Correspondingly, Scl is expressed in haematopoietic and
endothelial tissue, as well as in a few cells in the central nervous system
(Jin et al., 2006). The
vascular endothelial growth factor (Vegf) pathway plays crucial roles in
vertebrate haematopoiesis and vasculogenesis
(Ferrara, 2004). In zebrafish,
Kdr (previously known as Flk1) is an endothelial cell specific Vegf receptor
required for vasculogenesis (Covassin et
al., 2006; Habeck et al.,
2002), and vegf and kdr are also expressed in
and around the nascent and growing ventral aorta
(Fig. 1E,F,H-K). As expected
from data regarding trunk vasculogenesis
(Patterson et al., 2005),
reduction of Scl or Vegf (using scl and vegf morpholinos)
(Lawson et al., 2002;
Nasevicius et al., 2000;
Patterson et al., 2005), or
absence of Kdr in kdry17 mutant embryos
(Habeck et al., 2002),
dramatically interferes with pharyngeal vessel formation
(Fig. 2A-D). Analysis of the
endothelial marker tie1 in the three deficiency backgrounds indicates
that here the ventral aorta fails to form properly. Instead, a misshaped
domain of tie1 expression surrounds the outflow tract of the heart,
often expanding laterally, but not along the AP axis, into one pair of
irregular branches. Thus, Scl and the Vegf pathway are required for normal
development and expansion of the ventral aorta along the AP axis.
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To test whether compromised blood circulation evident in all of these
deficiency backgrounds causes indirectly thyroid abnormalities, we targeted
the tnnt2 gene by morpholino knock down. tnnt2 encodes the
thin-filament contractile protein cardiac troponin T, and corresponding
morphants lack heart beat and blood circulation
(Sehnert et al., 2002). In
these morphants, the thyroid is normal at 55 hpf (n=64, data not
shown), showing that specific disruption of circulation does not account for
morphological defects of the thyroid. Thus, it is rather vessel patterning
that appears to be correlated to thyroid morphology. As the ventral aorta is
the only vessel adjacent to the thyroid in wild type, it can be assumed that
this is the artery that guides follicular growth along the midline. However,
the thyroid phenotype in scl morphants could also be due to low level
scl expression in thyroid tissue itself. Furthermore, kdr
and vegf are broadly expressed around vessels
(Fig. 1E,H-K), probably
including thyroid cells, and therefore might act in parallel both in vascular
cells and in thyroid cells. Thus, we asked whether ectopic endothelial cells
are able to change thyroid morphology cell non-autonomously, as this would
prove a direct interaction between vessels and thyroid.
Ectopic endothelial cells can influence thyroid morphology non-cell autonomously
To develop an assay in which cells are forced to adopt endothelial fate, we
used an approach involving Scl and Lmo2, a transcription factor specifically
required for haematopoiesis and angiogenesis
(Yamada et al., 2000;
Yamada et al., 1998).
Co-injection of scl and lmo2 mRNA induces ectopic expression
of the endothelial marker fli1 throughout the head mesenchyme of
zebrafish embryos, indicating that these factors are sufficient to specify
endothelial fate in all head mesenchymal cells
(Gering et al., 2003).
Similarly, coinjection of these mRNAs induces strong kdr expression
in the whole head mesenchyme (Fig.
3A-D). Such injected embryos develop extreme head abnormalities
and die around 24 hpf (data not shown), preventing the analysis of thyroid
development. Instead, we grafted cells from scl+lmo2
co-injected embryos into wild-type hosts in order to create a mosaic of
wild-type and ectopic endothelial cells.
In this transplantation approach, few cells were grafted at late blastula
stage from scl+lmo2 mRNA injected donors into wild-type
hosts (Fig. 3E). We analysed
some embryos at 12-somite stage, when head vasculogenesis is in progress
(Gering et al., 2003), and
ectopic endothelial cells can easily be distinguished from normal sites of
expression. In all embryos investigated, all grafted cells ending up in head
mesenchyme express kdr, and, hence, adopt endothelial fate (12 of 12
sectioned embryos; Fig.
3F,G).
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Three-dimensional analysis of wild-type and mutant mouse embryos suggest an influence of carotid arteries on thyroid morphogenesis
A role of the vascular system in thyroid development has been suspected in
mice based on the close spatial relationship between aortic sac and thyroid
primordium. However, these studies focused on an hypothetical early role of
the aortic sac in induction and evagination of the primordium
(Fagman et al., 2005). To test
whether an instructive role of blood vessels in subsequent steps of thyroid
morphogenesis could be conserved among vertebrates, we analysed
three-dimensional reconstruction of cervical regions of wild-type and mutant
mouse embryos. Thyroid precursor cells firstly occur within the pharyngeal
epithelium in direct contact to the aortic sac
(Fig. 4A), a transient
structure that gives rise to the cardiac outflow tract. Under wild-type
conditions, the primordium first relocates along the AP axis in close contact
to the developing aortic arch (Fig.
4B). Later, the primordium loses its contact to the aortic arch
and bifurcates (Fig. 4C).
During bifurcation the thyroid lobes are again close to vascular structures,
the bilateral pair of carotid arteries. Subsequently, the lobes elongate
following the carotid arteries further cranially
(Fig. 4D). We therefore asked
whether carotid arteries play a similar role in mammalian thyroid morphology
as the ventral aorta does in zebrafish.
Recent work has shown that an abnormal, unilateral single thyroid lobe
develops in Shh-deficient mouse embryos
(Fagman et al., 2004).
Furthermore, Shh deficiency leads to defective cardiac rotation and
atrial dilatation (Tsukui et al.,
1999), suggesting further defects in cervical vessel development.
Three dimensional reconstruction of sections reveals that in the absence of
Shh expression (in Dsh/Dsh mice)
(Niedermaier et al., 2005),
the aortic arch fails to cross the midline and both carotid arteries develop
asymmetrically on one side of the oesophagus
(Fig. 4E-H). Initially, the
thyroid primordium evaginates and relocates along the AP axis in the midline
of Shh-deficient mice as in wild type
(Fig. 4E). However, the
primordium then fails to undergo its symmetric lateralisation and bifurcation.
Instead, after embryonic day 12.5, a single lobe always relocates on the same
side as and in contact with the mislocated carotid arteries (right
n=7, left n=1; Fig.
4F-H, Fig. 5D),
suggesting that the carotid arteries define the symmetric lateral position of
the thyroid gland under wild-type conditions.
Compromised hedgehog signalling affects many aspects of embryonic development, and so it could be that thyroid and vessels are independently affected in Dsh/Dsh mice. However, we did not find detectable expression of Shh or patched (encoding the receptor for Shh) in or around carotid arteries or the thyroid primordium at E12.5, when asymmetry of thyroid and carotid arteries starts to be evident in Dsh/Dsh mice (Fig. 4I-K). Although we cannot exclude low levels of expression, it appears unlikely that Shh is directly involved in thyroid relocalisation at this stage. Instead, it is more likely that Shh deficiency causes vascular problems that indirectly affect thyroid morphology.
Furthermore, we investigated thyroid and carotid artery morphology in a
mutant background where the Dsh/Dsh phenotype is partially restored
to wild-type appearance. Shh and Gli3 are context-dependent
antagonists of each other in mouse limb and neural tube development, so that
in Shh-/- Gli3-/- double mutants, some
aspects of the Shh-/- mutant phenotype are rescued
(Ruiz i Altaba et al., 2003;
te Welscher et al., 2002). We
found that in this double mutant background (Dsh/Dsh
XtJ/XtJ, XtJ is a null allele of
Gli3) (Persson et al.,
2002), the bilateral set of carotid arteries is restored to its
symmetrical appearance and the thyroid regains a midline position with
symmetrical, bilateral cranial lobes (n=3)
(Fig. 5). This parallel
restoration of symmetry further demonstrates the close co-development of both
structures. Owing to a lack of mouse mutants with more specific defects in
carotid artery development, a direct interaction between these vessels and the
thyroid has still to be shown for mice. However, in the light of the zebrafish
data it is likely that in mice vascular and thyroid development are also
functionally linked, and that dependence of thyroid tissue localisation on
co-developing arteries is a conserved mechanism in vertebrates.
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|
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our zebrafish data show that ectopic endothelial cells influence thyroid
morphology in a non-cell autonomous manner. In mice, vessels are involved in
induction of the endoderm-derived pancreas from the primitive gut
(Lammert et al., 2001). A role
of the cardiovascular system in induction of the mouse thyroid has been
suspected (Fagman et al.,
2005), and so ectopic induction could probably also cause lateral
expansion of thyroid tissue in the zebrafish embryos lacking Scl or with
compromised Vegf signalling. However, as reported above, in all deficiency
backgrounds analysed, the thyroid starts to develop from a normally induced
midline primordium. Therefore, an inductive role of vascular structures can be
excluded to be responsible for the thyroid phenotypes observed in our
deficiency backgrounds. Furthermore, in cloche, a zebrafish mutant
lacking all vessel progenitors in head and anterior trunk region
(Liao et al., 1997;
Stainier et al., 1995), the
thyroid primordium is still induced (data not shown). As the myocard forms in
cloche, it is still possible that the heart or some of its precursor
cells are involved in thyroid induction, but an inductive role of vessels can
be excluded.
Cell labelling experiments suggest that the whole strand of thyroid tissue
in zebrafish derives from the small globular primordium that buds off from the
pharyngeal epithelium at around 32 hpf (Alt
et al., 2006), and that no further cells contribute to the thyroid
from outside during its extension along the AP axis. This, and the fact that
in our deficiency backgrounds the thyroid primordium is initially normal,
suggest that in our grafting experiments the lateral expansion of thyroid
tissue adjacent to endothelial cells is generated by misdirected growth. Taken
together, our zebrafish data show that endothelial cells are required for
proper alignment of thyroid tissue along the AP axis during tissue growth.
The grafting experiments show an instructive influence of endothelial cells
on thyroid morphogenesis, but we were not able to discriminate between
different endothelial cell types in this experiment. Under wild-type
conditions, the ventral aorta is the only vessel directly adjacent to the
thyroid in zebrafish, so that it can be assumed that this is the vessel
responsible for interactions with the thyroid. Not only in zebrafish
(Wendl et al., 2002), but also
in other teleosts such as trouts (Raine
and Leatherland, 2000), thyroid tissue remains in close
association with the ventral aorta throughout later development and adulthood.
It will be interesting to find out how such an interaction is mediated.
Extracellular matrix or secreted factors are candidates, but the exact nature
of the interaction between vessels and thyroid tissue remains to be
elucidated.
In both zebrafish and mouse development, two morphogenetic phases are distinguishable in thyroid relocalisation. After induction and evagination, the thyroid primordium adopts a position close to the cardiac outflow tract in zebrafish or to the aortic sac in mice, respectively (Fig. 6). In all deficiency backgrounds investigated, this first phase is not disrupted. Consequently, follicles cluster at a default position around the cardiac outflow tract in the deficient zebrafish larvae, and the primordium initially relocalises correctly in the midline of E11.5 Dsh/Dsh mice. In a second phase of relocalisation that is dependent on ventral aorta or carotid artery development, the thyroid then adopts its species-specific position further cranially. In the complex and derived circulation of mice, the aortic sac is in part homologous to the cardiac outflow tract and probably also to the ventral aorta in zebrafish. Thus, the first phase of thyroid relocalisation from the pharyngeal epithelium to cardiac structures appears to be evolutionary conserved, whereas the second phase seems to be adapted to the presence of different cranial vessels.
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).
Conversely, in some vertebrates such as crocodiles, turtles, and certain
mammals as the echidna (Haynes,
1999; Pischinger,
1937), a single-lobed thyroid is positioned further caudally at
the aortic arch, at the base of the branching carotid arteries
(Fig. 6). Thus, it appears that
the second morphogenetic phase is omitted in these species.
Our data provide a novel starting point to re-investigate and interpret
congenital thyroid defects in humans. Cervical vessel architecture is highly
variable in humans, in particular with respect to the branching mode of the
carotid arteries from the aortic arch that can be classified into few frequent
and many rare variants (Nizankowski et
al., 1975). Based on our data, it is conceivable that some
variants might influence thyroid morphogenesis and account for cases of
unilateral thyroid glands or ectopically positioned thyroid tissue in humans.
Indeed, in clinical studies, congenital defects of the cardiovascular system
have already been associated with congenital thyroid abnormalities
(Casanova et al., 2000;
Olivieri et al., 2002), and
our study is the first to provide a causal link between both structures in
development. Thus, the disruption of signalling pathways linking thyroid and
blood vessel development represents a novel mechanism that is likely to be
relevant for the molecular pathogenesis of congenital thyroid defects in
humans.
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ACKNOWLEDGMENTS |
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Footnotes |
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