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First published online 16 April 2008
doi: 10.1242/dev.017954
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Division of Biology 139-74, California Institute of Technology, Pasadena, CA 91125, USA.
* Author for correspondence (e-mail: mbronner{at}caltech.edu)
Accepted 20 March 2008
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SUMMARY |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
Conclusion
REFERENCES |
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Key words: PDGF, Induction, Neurogenesis, Trigeminal placode, Chicken
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INTRODUCTION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
Conclusion
REFERENCES |
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). Despite their important role in peripheral
nervous system development, the tissue interactions and molecular signaling
events leading to placode specification and differentiation remain a
mystery.
Growth factors appear to be crucial for specification of particular placode
fate. The otic placode, for example, is induced by interactions with hindbrain
and/or surrounding tissues (reviewed by
Groves, 2005). Similarly,
epibranchial placode neurons can be induced by tissue interactions with
pharyngeal endoderm (Begbie et al.,
1999), though this may represent promotion of neurogenesis rather
than initial induction. At least three families of growth factor have been
implicated in specification of various placode fates. BMP signaling is
required for lens and olfactory placode induction
(Sjodal et al., 2007); for
epibranchial placodes, BMP7 and FGFs appear to mediate the effects of the
pharyngeal endoderm (Begbie et al.,
1999) and the mesenchyme, respectively
(Nechiporuk et al., 2007;
Sun et al., 2007); similarly,
FGFs and WNTs are involved in otic placode induction (reviewed by
Barald and Kelley, 2004).
The trigeminal placode gives rise to ganglia that provide sensory
innervation to much of the face. These cells differentiate early and solely
give rise to sensory neurons. Because it generates a single cell fate, the
trigeminal placode provides an excellent model for studying the processes
underlying placode induction and acquisition of neuronal traits. Unlike some
other placodes (e.g. lens and otic) that are morphologically distinct from
neighboring ectoderm, trigeminal placode cells cannot be distinguished from
surrounding tissue. Cell marking techniques suggest that the ectoderm
overlying the presumptive midbrain and rostral hindbrain is fated to
contribute to the trigeminal ganglion (Webb and Noden, 1983;
Xu et al., 2008). Furthermore,
the transcription factor Pax3 and the tetraspanin CD151 serve as molecular
markers of the ophthalmic trigeminal placode
(Stark et al., 1997;
Baker et al., 1999;
McCabe et al., 2004). Like
otic and epibranchial placodes, the trigeminal placode appears to be induced
by tissue interactions. One or several factors derived from the dorsal neural
tube (Stark et al., 1997;
Baker et al., 1999) can mediate
this inductive interaction. However, the molecular nature of the signals
involved has yet to be elucidated. The maxillomandibular placode is
molecularly distinct from the ophthalmic placode and may arise via separate
and as yet unknown interactions. For simplicity, we will refer to the
ophthalmic trigeminal placode throughout the paper as the opV trigeminal
placode.
Platelet derived growth factors (PGDFs) were originally isolated in a
search for serum factors that promote proliferation of arterial smooth muscle
cells (Ross et al., 1977).
Subsequently, they were shown to function in migration, proliferation,
survival, deposition of extracellular matrix and tissue remodeling factors in
many cell types (reviewed by Hoch and
Soriano, 2003). The ligands PDGFA, PDGFB, PDGFC and PDGFD are
secreted as disulfide bound homo- or heterodimers. Upon binding, the ligands
induce receptor dimerization, phosphorylation and activation of signal
transduction cascades. PDGF receptors form both homo- and heterodimers when
activated, each with different affinities towards the four PDGF ligands
(reviewed by Reigstad et al.,
2005). PDGFRββ homodimers can be activated by ligand
homodimers of PDGFBB and PDGFDD, whereas PDGFR
β heterodimers can
be activated by PDGFAB, PDGFBB, PDGFCC and PDGFR by the ligands
PDGFAA, PDGFAB and PDGFCC (reviewed by
Hoch and Soriano, 2003).
Here we examine the molecular nature underlying opV trigeminal placode formation, and present evidence that PDGF signaling is required for induction. The PDGFD ligand and its receptor PDGFRβ are expressed at the right time and place to play a role in placode development. Furthermore, both in vitro and in ovo inhibition experiments demonstrate that PDGF signaling is required for expression of Pax3. Blocking initial induction reduces later neurogenesis of the ophthalmic lobes of the trigeminal ganglia. Conversely, exogenous PDGFD causes an increase in the number of Pax3+ cells and the overall size of the opV trigeminal placode domain, as well as increasing the number of neurons in the condensing ganglia. These experiments demonstrate that PDGF signaling is essential for ophthalmic trigeminal placode induction.
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MATERIALS AND METHODS |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
Conclusion
REFERENCES |
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). Tissue was added after the bottom layer of collagen
solidified. After positioning ectodermal explants on dorsal neural tubes, a
top layer of collagen was added, allowed to set for 10 minutes at 38°C
with 5% CO2, and F12/N2 was added for 18 hours at 38°C with 5%
CO2. Conjugates were cultured with vehicle (DMSO), 10 nM or 100 nM
PDGF Receptor Tyrosine Kinase Inhibitor III (PIII) (Calbiochem). For
immunohistochemistry, explants were fixed overnight in 4% paraformaldehyde at
4°C. PIII has a half-maximal inhibitory concentration (IC50) of
IC50=50-80 nM for PDGFR and PDGFRβ
(Matsuno et al., 2002a;
Matsuno et al., 2002b).
Pharmacological studies have shown that PIII is selective for PDGFR and
PDGFRβ, and can block other signaling pathways only at very high
concentrations, greatly exceeding those used here (Flt3 IC50=230
nM; EGFR, FGFR, Src, PKA and PKC IC50> 30 mM)
(Matsuno et al., 2002a;
Matsuno et al., 2002b).
Embryo injections
Using a fine glass needle, 
1 nl of 1, 2.5, or 5 µm PIII or 250
ng/µl PDGFD (R&D Systems) or control (DMSO or BSA, respectively) was
injected just under the ectoderm adjacent to the midbrain on the right side of
st. 8-10 chick embryos. Embryos were fixed overnight in 4% paraformaldehyde at
4°C for immunohistochemistry and in situ hybridization.
Immunohistochemistry
Embryos were cryoprotected, embedded in gelatin and cryosectioned at 10
µm as previously described (Sechrist et
al., 1995). Gelatin was removed from sections by incubating at
42°C for 10 minutes and rinsed in PBS. Sections were blocked at room
temperature for 1 hour using 10% donkey serum, 0.1% Triton and 0.1% BSA in
PBS. Primary antibodies in blocking solution were incubated overnight at
4°C at the following concentrations: mouse Pax3 (Developmental hybridoma
bank), 1:50; mouse QCPN (Developmental hybridoma bank), 1:10; rabbit 145kDa
Neurofilament (Chemicon), 1:500; mouse HuC/D (Molecular Probes), 1:250; mouse
Phospho-histone H3 (Upstate Biotech), 1:2000. Samples were then rinsed three
times in PBS for at least 15 minutes. Secondary antibodies in 0.1% Triton,
0.1% BSA in PBS were incubated for 1 hour at room temperature. Secondary
antibodies (goat anti-mouse IgG or IgG2a Alexa 488, goat anti-mouse IgG2a
Alexa 568, goat anti-mouse IgG1 or IgG2b Alexa 594, goat anti-rabbit Alexa
594) were used at 1:2000-4000 (Molecular Probes) and washed as above. Sections
were counterstained with 1 µg/ml DAPI (Sigma) in PBS for 10 minutes, and
rinsed three times in PBS for 5 minutes and coverslipped using Permafluor
(Beckman Coulter).
Embryos were immunostained with Pax3, Hu
(Wakamatsu and Weston, 1997;
Okano and Darnell, 1997) and
Neurofilament-M [NF (Shaw and Weber,
1982)], and counter-stained with DAPI. Hu and NF were visualized
using the same fluorophore to facilitate identification of neurons.
Cell death and proliferation
TUNEL labeling was performed using the In Situ Cell Death kit (Roche) with
modifications from the manufacturer's directions. Samples were subsequently
immunostained with the proliferation marker Phospho-histone H3. Cryosectioned
slides were next rinsed three times in PBST (PBS + 0.5% TritonX-100) for 10
minutes each, permeabilized for 10 minutes with 0.5% TritonX-100, 0.1% sodium
citrate in PBS and rinsed twice in PBST. In the dark, the reaction mix was
diluted 1:40 with TUNEL buffer. Slides were incubated with 100 µl for 3
hours at 37°C in a humidified chamber, rinsed three times in PBST for 10
minutes, and immunostained for Phospho-histone H3.
In situ hybridization
Embryos were fixed overnight in 4% paraformaldehyde (pH 9.5)
(Basyuk et al., 2000).
Antisense digoxigenin-labeled RNA probes were made according to manufacturer's
directions (Roche). Whole-mount in situ hybridization was performed as
described (Kee and Bronner-Fraser,
2001) using NBT/BCIP (Roche) for color detection. Whole-mount
pictures were taken using a Zeiss Stemi SVII microscope with an Olympus DP10
digital camera.
Cell counting
Explants were sectioned, immunostained and photographed using a Zeiss
Axioskop2 Plus. Pax3+/QCPN+ ectodermal cells were counted using Photoshop
(Adobe) in the individual color channels using DAPI to verify total cell
number. Because of the variation of the size and plane of sectioning explants,
as many sections as possible (at least six) were counted per explant to reduce
variability. Pax3+/QCPN+ cells were expressed as a percentage of total cell
number. All values were normalized to the percentage of Pax3+/QCPN+ cells of
total cell number for controls. ANOVA with the Bonferonni multiple comparisons
post-hoc test was performed between control and treated groups.
For inhibitor injection, PDGFD injection and dnPDGFRβ electroporation experiments analyzed at early stages, embryos were stained with Pax3 and DAPI. For injection experiments, all Pax3+ cells on the right injected side of the embryo in the ectoderm of the midbrain were counted (at least six sections). Total cell number in the ectoderm was assessed using DAPI. Pax3+ cells were expressed as a percentage of total cell number and normalized to controls. For electroporation experiments, Pax3/GFP+ cells were counted. To evaluate transfection efficiency, all GFP+ cells were expressed as a percentage of total cell number using DAPI. Student's unpaired t-test was performed between control and treated groups with error bars indicating s.e.m.
Stage 13-15 embryos were stained with Pax3 (green), DAPI (blue), NF (red) and Hu (red), with the latter two visualized with the same fluorophore (Alexa 594). All Pax3/Hu/NF+ cells on the right injected side were counted (at least 10 sections). Average number of cells per section was normalized to controls. ANOVA with the Bonferonni multiple comparisons post-hoc test was performed between control and multiple treated groups. For single treatment experiments, Student's unpaired t-test was performed.
Electroporation of dominant-negative PDGFRβ
The dnPDGFRβ construct was made by cloning the murine PDGFRβ
lacking the kinase and autophosphorylation sites
(Ueno et al., 1991), which was
then subcloned into the pCIG expression construct
(Megason and McMahon, 2002)
that drives expression through the chicken β-actin promoter and CMV
enhancer. GFP is driven from an IRES sequence downstream of the coding
sequence allowing detection of transfected cells. Embryos were electroporated
at st. 4-6 to ensure expression of constructs by st. 8. Embryos were cultured
ventral side down on filter rings in albumen by the modified New method. DNA
(2 µg/ml) was injected between the epiblast and the vitelline membrane.
Platinum electrodes were placed vertically over the embryo and electroporated
with five pulses of 7 V for 50 mseconds with 100 msecond intervals as
previously described (Shiau et al.,
2008). Embryos were then cultured in 1 ml of albumen at 38°C
for 18 hours until st. 10-11.
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RESULTS |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
Conclusion
REFERENCES |
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) appear to be responsible for induction. Here, we
explore the role of PDGF ligands and receptors during this process.
Identification of PDGF receptors in the forming opV trigeminal placode
As a first step to identify potential signals involved in induction, we
performed RT-PCR on presumptive opV trigeminal placode ectoderm to look for
transcripts that encode receptors for secreted factors as candidate inducers.
To this end, ectoderm adjacent to the presumptive midbrain region of 3-4
somite stage (ss) (st. 8) chicken embryos was dissected and harvested for
mRNA. Primers were designed to specifically recognize PDGFR and
PDGFRβ. Both were expressed in ectoderm derived from 3-4 ss (st. 8)
embryos (McCabe et al., 2007).
In addition, receptors for members of the fibroblast growth factor family,
insulin-like growth factors, sonic hedgehog, the transforming growth factor
β super family, and WNTs were all expressed in patterns consistent with a
role in opV trigeminal placode formation
(McCabe et al., 2007).
Because RT-PCR lacks spatial information, we next performed in situ
hybridization with specific probes for both PDGF receptors. Whole-mount in
situs revealed that PDGFRβ is expressed in presumptive midbrain-level
ectoderm at st. 8, prior to the time of placode induction
(Fig. 1E,F); ectodermal
expression continues through st. 10 by which time induction has begun
(Fig. 1G,H). Interestingly,
PDGFRβ is also expressed in the tips of st. 8 neural folds, which may
contribute to presumptive placode, but also neural crest and neural tube
(Bronner-Fraser and Fraser,
1988). PDGFRβ expression has expanded to include the entire
ectoderm by st. 10, when the majority of opV trigeminal placode cells have
been induced. PDGFR is present in the mesenchyme at presumptive
midbrain-level at st. 8 (Fig.
1A,B), although ectodermal staining is very faint. At st. 10,
PDGFR is present on migrating neural crest at the level of the midbrain
(Fig. 1C,D). As previously
shown (Stark et al., 1997;
Baker et al., 1999), Pax3 is
expressed by future ingressing placodal cells by st. 10
(Fig. 1K,L) and PDGFRβ is
expressed both on Pax3+ as well as Pax3-ectodermal cells. Early migrating
neural crest cells express only low levels of Pax3 at st. 10
(Fig. 1L).
We next assayed PDGF ligands in the neural tube. Both PDGFA and PDGFD are
expressed in the neural folds, consistent with a possible role for PDGF
signaling in opV trigeminal placode induction
(Stark et al., 1997). Notably,
PDGFD is expressed in the st. 8 neural folds
(Fig. 2K,L) and st. 10 neural
tube in the midbrain as well as the trunk
(Fig. 2M,N,O). Faint expression
of PDGFD can be detected in the adjacent ectoderm at st. 8. Importantly, PDGFD
is expressed at all axial levels in the neural tube
(Fig. 2N,N'',O),
consistent with the finding that both cranial and trunk neural tube at st.
10-11 are able to induce competent ectoderm to become opV trigeminal placode
(Baker et al., 1999). PDGFD
signal is also detected in migrating neural crest at st. 10
(Fig. 2N,N'), but is
absent from ectoderm (Fig.
2N'). PDGFA is expressed in the caudal st. 8 neural folds,
just below the presumptive midbrain, making it a less likely candidate
(Fig. 2A,B). At st.10, PDGFA is
strongly expressed in the midbrain and trunk-level ectoderm itself, but not
the neural tube (Fig. 2C,D,E).
PDGFC, however, is expressed in the presumptive midbrain-level ectoderm at st.
8 (Fig. 2F,G) and maintained at
st. 10 (Fig. 2H,I) in a similar
pattern to Pax3. In the trunk, PDGFC is also found in the somites and mesoderm
(Fig. 2H,J). Owing to the high
levels of PDGFRβ expression in the ectoderm, the most likely signaling
scenario is that PDGFD through PDGFRββ; however, PDGFA may be
signaling through PDGFRβ heterodimers at low levels.
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;
McCabe et al., 2004). As
cranial and trunk neural tubes are virtually interchangeable in this assay, we
used trunk for ease of dissection. Both placodal ectoderm and dorsal neural
tube express Pax3. To identify ectodermal Pax3 expression specifically, we
used interspecific recombinants to juxtapose quail ectoderm with chick neural
tube, such that ectodermally derived Pax3+ cells also expressed quail specific
QCPN (Fig. 3A). After 18 hours,
Pax3 is abundantly expressed in the quail ectoderm
(Fig. 3C), whereas 3-4 ss (st.
8) ectoderm cultured alone does not express Pax3 (data not shown)
(McCabe et al., 2004).
To test the necessity of PDGF ligand/receptor interactions, we blocked all
PDGF signaling with an inhibitor, the receptor tyrosine kinase inhibitor III
(PIII), that blocks with a half maximal inhibitory concentration
(IC50) of 50-80 nM for PDGFR and PDGFRβ
(Matsuno et al., 2002a;
Matsuno et al., 2002b). In our
experiments, we find that IC50<10nM, which is significantly
lower than previously published studies. Pharmacological studies have shown
that PIII is selective for PDGFR and PDGFRβ, and can only block
other signaling pathways at very high concentrations, greatly exceeding those
used in the present study (Flt3 IC50=230 nM; EGFR, FGFR, Src, PKA
and PKC IC50>30 mM) (Matsuno
et al., 2002a; Matsuno et al.,
2002b). In addition, we have previously shown that EGFR is not
present in presumptive opV trigeminal placode
(McCabe et al., 2007).
At 18 hours, PIII concentrations of 10 and 100 nM dramatically decreased the number of Pax3+/QCPN+ cells compared with DMSO controls (Fig. 3F,J,N). PIII reduced the number of Pax3+ cells by 58% at 10 nM (n=15 explants) and by 84% at 100 nM (n=11 explants) compared with controls (n=15 explants) (Fig. 3B) with no change in cell viability (Fig. 3E,I,M). The results show that there is a dose-dependent reduction in the numbers of Pax3+ cells after treatment with the PIII inhibitor and suggest a potent role for PDGF signaling in opV trigeminal placode induction in vitro.
PDGF signaling is necessary for Pax3 and CD151 opV trigeminal placode induction in vivo
We next examined the effects on opV trigeminal placode formation of
blocking PDGF signaling in the developing embryo. To this end, we injected a
small volume (1 nl) of 1, 2.5 and 5 µm of PIII into the mesenchyme in
the presumptive midbrain-level at st. 8. As a control, an equivalent
concentration of the vehicle DMSO was injected in an identical manner. Because
the inhibitor is small and may cross the midline, we compared the injected
side of experimental embryos to stage-matched control-injected embryos.
Transverse sections through these embryos revealed a marked reduction of the
numbers of Pax3+ cells (Fig.
4B) compared with stage-matched controls
(Fig. 4A), with no significant
difference in the total number of DAPI+ cells
(Fig. 4C,D;
Fig. 5D). A 1 µm PIII
solution (n=6) resulted in a 71% reduction Pax3+ cells compared with
control embryos (n=7) (Fig.
5A). Similarly, 2.5 and 5 µm solutions of PIII resulted in a
67% and 84% reduction (n=8, n=6), respectively. The results
demonstrate that PDGF signaling is necessary for opV trigeminal placode
induction in vivo.
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Because Pax3 is an early placode marker, we next asked whether PDGF
signaling was necessary for expression of a later placode marker. For this
purpose, we injected 2.5 µm PIII or vehicle control into the st. 8 cranial
mesenchyme adjacent to the midbrain and assessed the effects by in situ
hybridization on CD151, a member of the tetraspanin superfamily of proteins
that was upregulated in response to opV trigeminal placode induction
(McCabe et al., 2004). It is
strongly expressed by opV trigeminal placode cells at st. 10
(McCabe et al., 2004) and thus
initiates later than the onset of Pax3 expression. Similar to Pax3, we
observed a marked reduction in the expression of CD151 on the PIII-injected
side relative to the uninjected side of experimental embryos
(Fig. 6D-F; n=9),
whereas control embryos were unaffected
(Fig. 6A,B,C;
n=5).
Because pharmacological inhibitors may have specificity problems, we
verified the requirement for PDGF signaling in opV trigeminal placode
formation using an alternative approach. To this end, we generated a
dominant-negative (dn) PDGF receptor β that was truncated and thus bound
the ligand but failed to signal. This construct has been shown to inhibit
PDGFRββ homodimers, as well as PDGFRβ heterodimers
(Ueno et al., 1991;
Ueno et al., 1993). The
dnPDGFRβ construct was made as previously described
(Ueno et al., 1991) and
subcloned into a vector with a chicken specific β-actin promoter [pCIG
(Megason and McMahon, 2002)].
Using New Culture to culture whole embryos on paper rings, st. 4-6 embryos
were electroporated as described by Shiau et al.
(Shiau et al., 2008) with
either an empty control pCIG or dnPDGFRβ-pCIG vector and allowed to
develop until st. 10-11. Embryos were sectioned and the number of Pax3+/GFP
cells were counted in the midbrain. Similar to the PDGFR inhibitor
experiments, the dnPDGRβ construct resulted in a greater than 50%
reduction in the number of Pax3+ transfected cells compared with controls
(Fig. 7E-G; n=4
embryos each). There was no significant difference in the transfection
efficiency between empty vector pCIG and dnPDGFRβ
(Fig. 7H; P>0.3).
These results confirm that PDGF signaling is necessary for opV trigeminal
placode induction.
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).
The results show that the PDGFR inhibitor PIII blocks neurogenesis in ovo.
In control embryos, abundant Pax3/Hu/NF+ cells are present in the condensing
ganglion (Fig. 8A-C). By
contrast, injection of 2.5 µm PIII causes a marked reduction in the number
of Pax3+ neurons (Fig. 8D-F).
PIII (1 and 2.5 µm) caused a statistically significant reduction in
neurogenesis by 70% of control (control n=6; 1 µm PIII
n=3; 2.5 µm PIII n=5)
(Fig. 9A). Therefore, PDGF
signaling is necessary for neurogenesis as well as for induction.
Our results are consistent with either a dual role for PDGF signaling, an early role in induction as well as later in neurogenesis, or a single early role with later effects on neurogenesis occurring secondarily as a consequence of those on induction. To test the role of PDGF signaling after specification has begun, embryos were injected with vehicle or 2.5 µm PIII at st. 10, by which time the majority of opV trigeminal placode cells have been specified, and allowed to develop to st. 13/14. To examine effects on neurogenesis, we counted Pax3-, Hu- and NF-expressing cells but found no significant change in the number of Pax3+, Hu/NF+ and Pax3/Hu/NF+ cells within the condensing opV trigeminal ganglion in PIII-treated embryos (Fig. 9B; n=6 embryos each, P>0.05). These results suggest that, once the opV trigeminal placode cells have been specified, they continue to generate neurons in the absence of PDGFR signaling.
PDGFD increases the number of Pax3 expressing cells and size of the opV trigeminal placode
Because inhibition of PDGFR signaling results in fewer opV trigeminal
placode cells, increasing PDGFR signaling might be expected to increase the
number of placode cells. To test this, we microinjected 250 ng/µl solution
of PDGFD into the mesenchyme in the presumptive midbrain-level at st. 8 and
assessed the effects of the placode at st. 11. As a control, an equivalent
concentration of the vehicle BSA was injected in an identical manner. We found
that 250ng/µl of PDGFD resulted in an increase in both the number of the
Pax3+ cells at midbrain-levels by 32%
(Fig. 10K; P=0.0032,
n=8 control, n=10 PDGF), as well as the overall size of the
placode (Fig. 10A,B). The
white lines in Fig. 10A-D
demarcate the ventral boundaries of the placodes in transverse section. To
address whether this occurred by alterations in cell number and/or cell
density, we counted the total number of cells in the ectoderm between the
midline of the injected side to the last Pax3 cell within the section (see
white line, Fig. 10A,B). In
the presence of exogenous PDGFD, the placode spread laterally into more
ventral ectoderm. The number of Pax3+ cells increased by 29%
(P=0.0014) compared with control, with no change in the density,
suggesting that the increase was mediated by an increase in the total number
of placode cells, rather than total cell number. When comparing total cell
number, we found no significant difference between control and PDGFD-injected
embryos (P>0.3). Interestingly, PDGFAA, PDGFAB, PDGFBB, PDGFCC or
PDGFDD alone was not sufficient to induce 3-4 ss (st. 8) presumptive opV
trigeminal ectoderm in vitro, nor could beads when placed in permissive
epiblast in vivo induce ectopic opV trigeminal placode cells (data not shown),
indicating that other factors in addition to PDGF may be necessary for opV
trigeminal placode induction.
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DISCUSSION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
Conclusion
REFERENCES |
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; Baker et al.,
1999). Here, we show that PDGF has the correct spatiotemporal
pattern to fill this role and is necessary for induction of the opV trigeminal
placode, as assessed by Pax3 and CD151 expression. This provides the first
experimental evidence of a molecular inducer of the ophthalmic trigeminal
placode.
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).
After this stage, placode cells fail to change fate even when transplanted to
another placode-forming region (Baker et
al., 1999). By st. 10, the ligand PDGFD is expressed in the neural
tube at all axial levels. In vitro data have shown that the inducer for the
opV trigeminal placode is present along the entire neuraxis at st. 10-12
(Baker et al., 1999),
consistent with the PDGFD expression pattern. As PDGFC is expressed in the
adjacent mesenchyme and PDGFD is present at low levels in the ectoderm, it is
possible that there are multiple sources of PDGF ligands not solely arising
from the neural folds. Expression studies in the zebrafish and mouse have
reported PDGFR in the opV trigeminal placodes and later in the ganglia
(Liu et al., 2002a;
Zhang et al., 1998;
Andrae et al., 2001), with the
ligand PDGFA expressed in the adjacent neural tube
(Liu et al., 2002b). This may
reflect paralog switches between species. Expression of another ligand, PDGFC,
has been reported in olfactory and otic placode in the mouse
(Ding et al., 2000). PDGFB
does not appear to be expressed in mouse placodes, and no information has yet
appeared for PDGFD.
PDGF signaling is necessary for opV trigeminal placode induction
Induction of the opV trigeminal placode upregulates expression of the
transcription factor Pax3 concomitant with specification of opV trigeminal
placode cells (Baker et al.,
1999). Pax3+ cells in the forming opV trigeminal ganglia can first
be detected at st. 9+ and are abundant by st. 10. We show that inhibition of
PDGF receptor function in vitro abrogates Pax3 expression in a dose-dependent
manner. In vivo studies further show that blocking PDGF signaling effects not
only Pax3 expression but also a later placodal marker, CD151, as well as the
formation of placode-derived neurons. This effect is not due to changes in
either cell proliferation or death; rather, these cells continue to express an
ectodermal marker, Pax6 (data not shown), suggesting that they may remain in
an undifferentiated state. These results show that PDGF signaling is essential
for induction and subsequent differentiation of the opV trigeminal
placode.
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). Extensive genetic studies in mouse have revealed
many roles for PDGF ligands and their receptors during embryonic development
in mouse (reviewed by Betsholtz,
2004). The Patch mutant, which has a large deletion that includes
the PDGFR gene (Morrison-Graham et
al., 1992; Orr-Urtreger et
al., 1992; Schatteman et al.,
1992) exhibits disruption of non-neuronal neural crest cells.
However, no gross abnormalities in the opV trigeminal ganglion were noted,
possibly because the placodal component is often overlooked or ignored.
Indeed, further inspection of the images presented by Morrison-Graham et al.
(Morrison-Graham et al., 1992)
suggests that the trigeminal ganglia look smaller, thus raising the issue of
the role of PDGFR in the mouse. In the PDGFR null, neurofilament
expression was analyzed for neural crest derivatives only
(Soriano, 1997). Other
PDGFR-null alleles were not analyzed for perturbations of the
trigeminal ganglia (Klinghoffer et al.,
2002; Hamilton et al.,
2003). PDGFRβ mouse nulls die at or shortly before birth with
defects in the blood and kidney glomerulus
(Soriano, 1994) and have yet
to be analyzed for defects in cranial ganglia. Thus, it is not known whether
PDGF signaling is necessary for trigeminal placode induction in the mouse and
in the chicken.
OpV trigeminal placode induction
Placodal induction probably occurs via two separable steps. The first
occurs when ectodermal cells gain general competency to become presumptive
placode cells in a `pre-placodal domain' (reviewed by
Streit, 2004;
Bailey and Streit, 2006;
Schlosser, 2006), which
expresses a unique combination of Six, Eya and Dach gene family members
shortly after neural plate formation
(Streit, 2002;
McLarren et al., 2003;
Bhattacharyya et al., 2004;
Kozlowski et al., 2005;
Litsiou et al., 2005).
Fate-mapping experiments have shown that placodal progenitors cells are
interspersed throughout the pre-placodal domain
(Kozlowski et al., 1997;
Whitlock and Westerfield,
2000; Streit,
2002; Bhattacharyya et al.,
2004). Eventually, these cells separate into distinct,
identifiable areas along the neural tube
(D'Amico-Martel and Noden,
1983; Couly and Le Douarin,
1985; Couly and Le Douarin,
1987; Noden, 1993;
Xu et al., 2008). The first
step in opV trigeminal placode induction probably occurs during formation of
this domain; this is followed by specific induction of the placode towards an
opV trigeminal fate in a manner requiring PDGF signaling
(Fig. 11).
Recent studies suggest that all cells within the pre-placodal domain may
initially be specified as lens. Subsequently, lens fate is repressed in
non-lens placodal regions, followed by induction of alternative placode fates
(Bailey et al., 2006). For
olfactory placode, FGF from the anterior neural ridge as well as an
unidentified inhibitory factor from neural crest cells is required for
suppression of lens fate and the subsequent induction of olfactory placode.
However, FGF alone is not sufficient to restrict lens fate
(Bailey et al., 2006).
Similarly for the otic placode, cells must first acquire general competency in
the pre-placodal domain, then later are able to respond to FGF signaling to be
specified as otic placode (Martin and
Groves, 2006). For both otic and olfactory placodes, FGF signaling
is not sufficient to induce all markers, indicating that additional factors
are required. Sjodal et al. (Sjodal et
al., 2007) found that at st. 4, BMP signaling is necessary for
both olfactory and lens placodal precursors. This indicates that placode
induction is likely to be a multifactorial process. Here, we show that the
second step in opV trigeminal induction requires PDGF signaling. Addition of
exogenous PDGFD in ovo results in more opV trigeminal placode cells and
placode-derived neurons, suggesting that PDGF ligand is a limiting factor in
opV trigeminal placode induction in vivo. However, PDGFs do not appear to be
sufficient for opV trigeminal placode induction. PDGFAA, PDGFAB, PDGFBB,
PDGFCC or PDGFDD alone is not sufficient to induce 3-4 ss (st. 8) presumptive
opV trigeminal ectoderm in vitro (data not shown). Nor can beads coated with
either PDGFAB, BB, CC or DD when placed in permissive epiblast at st. 4-6
generate ectopic opV trigeminal placode cells (data not shown). Therefore, we
speculate that factors in addition to PDGFD may be required for opV trigeminal
placode induction, similar to olfactory and otic placode induction.
Placode induction and neurogenesis
The epibranchial and otic placodes exhibit morphological characteristics
long before neurogenesis occurs, making it possible to separate factors
involved in induction versus neurogenesis; e.g. the chick epibranchial placode
is distinguishable as a thickening at st. 10
(Groves and Bronner-Fraser,
2000; Abu-Elmagd et al.,
2001), prior to expression of neuronal markers at st. 16
(Begbie et al., 1999). By
contrast, olfactory and opV trigeminal placodes express neuronal markers
shortly after induction. The thickened olfactory ectoderm is obvious by st. 14
(Street, 1937), and the
neuronal marker, Hu, is observed concomitant with delamination
(Fornaro and Geuna, 2001).
Unlike olfactory placode, the opV trigeminal is not readily morphologically
identifiable; rather small groups of cells begin expressing Pax3 and soon
thereafter, express neurofilaments and commence delamination.
It is difficult to separate opV trigeminal placode induction from
neurogenesis. In the chick opV trigeminal placode, neuronal specification
temporally correlates with Pax3 expression in vitro and in vivo
(Baker and Bronner-Fraser,
2000). Accordingly, we find that PDGF signaling is necessary both
for Pax3 expression and subsequent neurogenesis. When the PDGFR inhibitor is
injected in ovo, Pax3 induction was dramatically reduced after 9-12 hours and
the number NF/Hu+ neurons was also significantly reduced after 24 hours. Thus,
if opV trigeminal placode cells fail to express Pax3, they do not form
neurons. Our data show that specification, as detected by Pax3, cannot be
separated from neurogenesis in the opV trigeminal ganglia. If we block PDGFR
signaling at st. 10 rather than st. 8, we see no significant change in number
of neurons. Therefore, absence of PDGF signaling during the inductive period
results in the loss of specified opV trigeminal placode cells and consequent
loss of opV trigeminal placode-derived neurons.
In contrast to the opV trigeminal placode, epibranchial placodes appear to
undergo additional steps between induction and neurogenesis. In explant
culture, pharyngeal endoderm or BMP7 can induce neurons from cranial
non-neuronal ectoderm (Begbie et al.,
1999). Neither pharyngeal endoderm nor BMP7 was able to generate
neurons from trunk ectoderm (Begbie et
al., 1999), although trunk ectoderm transplanted into the
presumptive epibranchial placodes did generate epibranchial neurons
(Vogel and Davies, 1993). The
differences between these two studies are probably due to timing differences.
The ectoderm used by Begbie et al. (Begbie
et al., 1999) has the thickened morphology of placodal ectoderm
(Groves and Bronner-Fraser,
2000; Abu-Elmagd et al.,
2001), and is known to express a presumptive epibranchial marker,
Sox3 (Abu-Elmagd et al., 2001).
As neuronal markers were used to identify cells as epibranchial, these results
suggest that BMP7 is required for neurogenesis and accounts for the effects
mediated by pharyngeal endoderm; however, whether a similar situation exists
for initial induction is unknown and signals in addition to BMP7 may be
required for epibranchial placode formation in chick. The studies of Sun et
al. (Sun et al., 2007) argue
that FGFs are also involved, and Nechiporuk et al.
(Nechiporuk et al., 2007)
provide new evidence supporting the hypothesis that mesenchyme is a source of
inducing signals. Support for this idea comes from studies in zebrafish
mutants that lack endoderm (Nechiporuk et
al., 2005) and suggest that at least two inductive signals are at
work: one that is endoderm-independent as Foxi1 epibranchial placode
precursors form in the absence of pharyngeal endoderm; and a second
endoderm-dependent process required for neuronal differentiation.
PDGF transcriptional targets
Many transcription factors have been implicated in the formation of
placodes (reviewed by Schlosser,
2006). Several of these, including GATA and Hairy-related
transcription factors, play a role in PDGF-mediated processes in vascular
smooth muscle cells, megakaryocytes and hepatocellular carcinomas. For
example, GATA2 is upregulated during the PDGF-mediated epithelial to
mesenchymal transition during hepatocytic cancer
(Gotzmann et al., 2006). In
megakaryocytic cells lines where PDGF promotes proliferation, Chui et al.
(Chui et al., 2003) found that
PDGF upregulates GATA1 protein over 2.5 times in 2 hours. In addition, PDGF
downregulates Hairy-related transcription factors in vascular smooth muscle
cells (Wang et al., 2002;
Sakata et al., 2004). GATA
transcription factors have been found in the pre-placodal region in
Xenopus embryos (Kelley et al.,
1994; Walmsely et al., 1994;
Read et al., 1998) and
Hairy-related genes in the differentiating trigeminal placode
(Turner and Weintraub, 1994;
Deblandre et al., 1999;
Koyano-Nakagawa et al., 2000;
Davis et al., 2001;
Tsuji et al., 2003).
In order to find direct transcriptional targets of PDGF, Chen et al.
(Chen et al., 2004) used a
gene-trap screen to identify genes that are regulated by PDGF. When comparing
the outputs of the PDGF transcriptional targets screen
(Chen et al., 2004) and a
screen looking for genes upregulated by trigeminal placode induction
(McCabe et al., 2004), three
genes were found in common: calmodulin 2, kinesin family member 4A and 60S
ribosomal protein L12. In addition, two families of transcription factors that
have been implicated in placodes were found in the enhancer trap screen, Msx1
and Foxi1, both of which are expressed in the pre-placodal domain and
differentiating trigeminal placode in Xenopus
(Lef et al., 1994;
Maeda et al., 1997;
Suzuki et al., 1997;
Feledy et al., 1999;
Pohl et al., 2002;
Schlosser and Ahrens, 2004),
although the function of these genes in PDGF induction of the opV trigeminal
placode has yet to be determined. The shared expression of direct PDGF targets
and genes downstream of placode induction is particularly intriguing in light
of the present data showing that PDGF signaling is required in the induction
process.
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Conclusion |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
Conclusion
REFERENCES |
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
Conclusion
REFERENCES |
|---|
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