Department of Craniofacial Development, Guys Campus, Guys Tower, Floor 27, King's College London, London SE1 9RT, UK
* Author for correspondence (e-mail: andrea.streit{at}kcl.ac.uk)
Accepted 6 July 2005
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SUMMARY |
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Key words: Chick, Quail, Placode, Lens, Inner ear, Olfactory epithelium, Cranial ganglia
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Introduction |
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Patterning events during gastrula and early neurula stages lead to the
subdivision of the ectoderm into at least four distinct domains: neural plate,
neural crest, PPR and future epidermis. Although in some species the PPR can
be identified as a continuous `primitive placodal thickening' encircling the
anterior neural plate (Platt,
1896; Knouff,
1935
; van Oostrom and
Verwoerd, 1972
; Verwoerd and
van Oostrom, 1979
; Miyake et
al., 1997
), in other organisms the subdivision first becomes
apparent through the expression of molecular markers specific for each of the
four tissues. A number of markers have been identified recently that are
uniquely expressed in the ectoderm surrounding the anterior neural plate (for
reviews, see Baker and Bronner-Fraser,
2001
; Streit,
2004
), reflecting the position of sensory placode precursors as
determined by fate maps (Kozlowski et al.,
1997
; Whitlock and
Westerfield, 2000
; Streit,
2002
; Bhattacharyya et al.,
2004
). Among these are members of the Six, Eya and Dach families
(Mishima and Tomarev, 1998
;
Esteve and Bovolenta, 1999
;
Sahly et al., 1999
;
Pandur and Moody, 2000
;
Streit, 2002
;
McLarren et al., 2003
;
Schlosser and Ahrens, 2004
),
which are known to act as a molecular complex to regulate transcription of
downstream target genes (Chen et al.,
1997
; Ohto et al.,
1999
; Ikeda et al.,
2002
; Li et al.,
2003
; Silver et al.,
2003
). Importantly, this complex controls various aspects of
sensory organ development from the fly to vertebrates (for reviews, see
Kawakami et al., 2000
;
Wawersik and Maas, 2000
;
Hanson, 2001
;
Donner and Maas, 2004
), and in
Xenopus, Six1 has recently been shown to promote generic placodal
fate in the early embryo (Brugmann et al.,
2004
). Thus, the PPR is unique with respect to morphology, cell
fate and gene expression and the expression of the Six/Eya/Dach cassette may
be regarded as crucial step in its induction.
In addition, special properties can be attributed to the PPR that
distinguish it from non-placodal ectoderm. First, unlike the rest of the
ectoderm, cells within the PPR are competent to form any placode until fairly
late developmental stages (Jacobson,
1963b; Baker et al.,
1999
; Groves and
Bronner-Fraser, 2000
). Second, while a number of signalling
molecules and transcription factors have been described that, when
misexpressed, result in the formation of ectopic placodes, they can only do so
close to the location of endogenous placodes (i.e. within the PPR) or when
associated with ectopic neural tissue
(Oliver et al., 1996
;
Altmann et al., 1997
;
Begbie et al., 1999
;
Chow et al., 1999
;
Koster et al., 2000
;
Ladher et al., 2000
;
Vendrell et al., 2000
;
Lagutin et al., 2001
;
Nissen et al., 2003
;
Shimada et al., 2003
;
Solomon et al., 2003
). These
observations suggest that by the time Six, Eya and Dach gene expression
overlaps at the border of the neural plate, PPR cells have received signals
that bias them towards a placode fate and/or confer generic placode character
without imposing specific placode identity.
Although some of the molecular events that control specification of
individual placodes, such as lens and inner ear, have been investigated
extensively (for reviews, see Baker and
Bronner-Fraser, 2001; Chow and
Lang, 2001
; Brown et al.,
2003
; Riley and Phillips,
2003
), we know very little about the signalling mechanisms that
establish the PPR and are therefore responsible for initiating the development
of all sensory placodes. Two recent studies in Xenopus provided
evidence that a balance of BMP and its antagonists is in part responsible for
positioning the PPR (Brugmann et al.,
2004
; Glavic et al.,
2004
). However, modulation of BMP only affects cells close to the
neural plate border and cannot induce a PPR in future epidermis away from its
normal location. Thus, the signals that confer PPR properties to naive cells
away form the endogenous domain are still elusive. Two other important
questions have so far remained unanswered. First, unlike neural crest cells,
placodes are exclusively found in the head - what are the molecular mechanisms
responsible for this restriction? Second, in the head ectoderm, future neural
crest and placode cells arise in close proximity and their precursors are
initially intermingled - how do multipotent ectodermal cells decide between
these fates?
Here, we use Six1, Six4, Eya2 and Dach1 as molecular markers to define the temporal and spatial aspects of PPR induction in relation to neural and neural crest induction. We then identify the head mesoderm as both necessary and sufficient to induce the PPR, while the neural plate seems to play a reinforcing role. Using gain- and loss-of-function experiments, we demonstrate that activation of the FGF pathway, together with WNT and BMP antagonists, imparts PPR character to naive, ectodermal cells. In addition, we show that WNT signalling is required to restrict PPR development to ensure that placode derivatives only form in the head ectoderm next to the neural tube. Finally, we demonstrate that WNT signalling mediates the decision between neural crest and placode fates: activation of the canonical WNT pathway promotes the formation of neural crest cells at the expense of placodes. Together, our data provide the first molecular model for how cranial neural crest and placode induction is integrated during ectodermal patterning and how the induction of sensory placodes is initiated.
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Materials and methods |
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Electroporation
For targeted misexpression of secreted and intracellular factors, primitive
streak stage embryos were electroporated as described before
(McLarren et al., 2003).
Crescent, N-frizzled8, activated ß-catenin and SMAD6 were cloned into
pCAß-IRES-GFP (McLarren et al.,
2003
; Linker and Stern,
2004
), while WNT8C was cloned into pCAß and co-electroporated
with control GFP vector.
Whole-mount in situ hybridisation and immunocytochemistry
In situ hybridisation and immunostaining using the quail-specific antibody
QCPN (Developmental Studies Hybridoma Bank; Department of Pharmacology and
Molecular Sciences, The Johns Hopkins University School of Medicine,
Baltimore, MD 21205; Department of Biological Sciences, University of Iowa,
Iowa City 52242 under contract N01-HD-2-3144 from NICHD) and anti-GFP
antibodies (Molecular Probes, USA) was performed as described
(Streit et al., 1998;
McLarren et al., 2003
). After
processing specimens were vibratome sectioned (25-35 µm).
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Results |
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|
|
Together, these experiments identify the mesoderm underlying the PPR as a
novel signalling centre in the vertebrate head that directs cell fate
decisions in the overlying ectoderm: signals derived from this mesoderm are
necessary for specification of sensory placode precursors and also sufficient
to induce PPR markers in very remote cells that have never been exposed to
neural-inducing factors or to signals from the neural plate. Furthermore, our
results show that the neural plate cooperates with mesoderm-derived signals.
By contrast, juxtaposition of neural plate and epidermis is sufficient to
induce neural crest cells and their derivatives
(Moury and Jacobson, 1990;
Selleck and Bronner-Fraser,
1995
), suggesting that different signalling mechanisms mediate the
decision of multipotent ectodermal progenitor cells to form neural crest and
placode precursors.
|
WNT signalling restricts the placode territory to the head ectoderm next to the neural plate
WNT proteins are good candidates for such inhibitory signals. The mesoderm
lateral and posterior to the PPR expresses high levels of Wnt8c
(Fig.
4A,A',A''), while Wnt6 is found in
trunk ectoderm (Garcia-Castro et al.,
2002; Schubert et al.,
2002
). Electroporation of the soluble WNT antagonist Crescent, but
not GFP alone (Fig. 3A-E;
n=15), into the ectoderm lateral and posterior to the PPR causes an
expansion of Six1 (12/20), Six4 (7/12) and Eya2
(12/22) in both directions (Fig.
3L-O). However, misexpression of Crescent in more distant epiblast
away from the endogenous PPR has no effect (n=33). As attenuation of
WNT signalling can also influence mesoderm specification and is required for
the formation of heart mesoderm (Marvin et
al., 2001
), we tested whether the expansion of PPR markers might
be due to an alteration of mesoderm patterning. We observed no change in the
expression of Nkx2.5, a marker for heart mesoderm that normally
underlies the PPR (Fig. 4B,C;
n=10). Thus, as with inhibition of BMP signalling, attenuation of the
WNT pathway can expand the PPR, but cannot induce it de novo. However, unlike
attenuation of BMP, WNT inhibition can also expand Six4 and
Eya2 expression into trunk ectoderm.
In a complementary approach, we addressed the issue of whether attenuation of WNT signalling is required to generate sensory placode precursors. To activate the canonical WNT pathway, we misexpressed activated ß-catenin or WNT8C and GFP alone (control) in the pre-placodal region. Control embryos occasionally show reduced expression of Six1 (2/10), Six4 (5/20) and Eya2 (3/15). However, when the WNT pathway is activated the expression of all three markers is lost in the electroporated cells (Fig. 3F-I; Six1, 6/10; Six4, 11/15; Eya2, 10/12 show loss). Thus, whereas inhibition of WNT signalling expands the pre-placodal territory, the activation of the canonical pathway suppresses it. We therefore suggest that WNT signals from the lateral and posterior mesoderm and from the trunk ectoderm are critical to restrict sensory placode formation to a narrow band of the head ectoderm and thus ensure that placode derivatives are never found in the trunk.
Activation of the WNT pathway promotes neural crest formation at the expense of placodes
In the head ectoderm, neural crest and placode precursors arise in close
proximity, but segregate over time
(Streit, 2002). Subdivision of
the cranial ectoderm into four distinct domains - neural plate, neural crest,
PPR and future epidermis - is first apparent around neurula stages (stage 5),
when the neural plate has already acquired columnar morphology and expresses
definitive neural markers like Sox2
(Fig. 5F,F'). The
ectoderm immediately adjacent to it expresses the early neural crest marker
Pax7, except in its most anterior aspect
(Fig. 5E,E'), and placode
precursors can be identified by their co-expression of Six1, Six4,
Eya2 and Dach1. Whereas Dach1 is found in the entire
ectoderm, including the neural plate (Fig.
5D,D'), Six1, Six4 and Eya2 transcripts
are confined to a horseshoe-shaped domain surrounding the anterior neural
plate (Fig.
5A-C,A'-C'), which medially overlaps with part of the
Pax7 domain, but never with Sox2. Expression of placode and
crest markers separates at the 3- to 4-somite stage
(Fig. 5G-L,G'-L'): Pax7 becomes restricted to the neural folds
(Fig. 5K,K'), where
Slug is now also detected (Fig.
5L,L'). These changes of expression patterns reflect the
segregation of neural crest and placode fates as the neural folds form
(Streit, 2002
).
|
These results suggest that WNT activity regulates the cell fate choice
between crest and placode precursors. This is confirmed by misexpression of
the WNT antagonists Crescent or N-frizzled 8, which results in the loss of
Pax7 (5/7; Fig. 3P)
and Slug (5/6; Fig.
3Q). However, pre-placodal specific transcripts never expanded
into the crest territory. This may be due to the fact that the neural folds
express high levels of Bmp4 (Liem
et al., 1995; Streit and
Stern, 1999
), while formation of the pre-placodal territory
requires BMP inhibition (this study). Together these results suggest that
segregation of crest and placodal precursors at the border of the neural plate
is mediated by WNT signalling: activation of the WNT pathway expands the crest
territory at the expense of the pre-placodal region.
|
We have previously shown that FGF signalling induces Msx1, Sox3
(Fig. 6E; 4/4) and
Erni (Streit and Stern,
1999; Streit et al.,
2000
). While the expression of Sox3 and Erni is
widespread before gastrulation, all three genes are later co-expressed with
PPR genes at the border of the neural plate. We now find that FGF8-coated, but
not control, heparin beads grafted into the extra-embryonic region can also
induce the expression of the non-neural ectoderm marker Dlx5
(Fig. 6F; 12/16) and the PPR
marker Eya2 (Fig. 6H;
10/16) in the absence of the mesodermal markers Brachyury
(n=5) and Tbx6l (n=6). However, FGF8 cannot elicit
expression of Six1 (n=16) or Six4
(Fig. 6G; n=48). Thus,
although FGF signalling promotes the expression of some genes characteristic
of the neural plate border, it is not sufficient to induce the complete set of
PPR genes.
However, it is possible that FGFs are required upstream and/or in parallel
with WNT and/or BMP inhibition to induce a complete ectopic PPR. We therefore
co-electroporated SMAD6 or Crescent into the extra-embryonic region of
primitive streak stage embryos and grafted FGF8 coated heparin beads next to
the electroporated site. Protein expression from electroporated constructs is
normally first observed after about 4 hours; therefore, cells are initially
exposed to FGF alone, while BMP and WNT antagonists are produced with a delay
of a few hours. After overnight culture, neither SMAD6/FGF8 nor Crescent/FGF8
misexpression results in ectopic induction of Six4 in an isolated
patch of cells away from the endogenous PPR (not shown). However, when all
three factors are combined, Six4 is induced in cells next to the FGF8
bead where SMAD6 and Crescent are co-expressed
(Fig. 6I,J; 12/15). If the FGF8
bead is removed after 4-5 hours and replaced with a bead coated with the FGF
inhibitor SU5402 (Mohammadi et al.,
1997), Six4 induction is still observed
(Fig. 5K,L; 7/8), indicating
that sustained FGF signalling is not required for Six4 induction.
These observations demonstrate that FGF signalling together with inhibition of
both BMP and WNT pathways is sufficient to induce the pre-placodal territory
in naïve ectoderm.
To investigate whether FGF signalling is indeed required for normal expression of PPR markers, head process stage embryos were incubated in the FGF signalling inhibitor SU5402 (50 µM) for 1 hour and then cultured in the presence of the inhibitor until they had reached head fold to early somite stages. No Six4 expression was observed in the PPR, while control embryos pre-incubated in the appropriate amount of DMSO (solvent for SU5402) showed normal levels of expression (not shown). We have shown above that head mesoderm is able to induce PPR markers in cells that normally never contribute to placodes. Is FGF activity in this mesoderm necessary for their induction? Head mesoderm was grafted into the extra-embryonic region together with either control or SU5402-coated beads, and the expression of Six4 was assessed after overnight culture. Whereas in controls Six4 is induced in the overlying epiblast (Fig. 6Q,R; 9/10), its induction is considerably reduced when FGF signalling is inhibited (Fig. 6S,T; 2/10).
|
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Discussion |
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Our results demonstrate that the head mesoderm provides crucial signals
that are necessary and sufficient to confer generic, pre-placode marker
expression to naïve ectodermal cells in the absence of characteristics of
individual placodes. Previous studies have implicated signals from the
mesendoderm in the induction of individual placodes, namely the olfactory,
lens and otic primordia (Zwilling,
1940; Raven and Kloos,
1945
; Yntema,
1950
; Yntema,
1955
; Jacobson,
1963a
; Orts-Llorca and
Jimenez-Collado, 1971
; Henry
and Grainger, 1990
; Gallagher
et al., 1996
). However, owing to the lack of molecular markers,
species differences and different timing of the experiments, its precise role
remained ill defined. Although recent studies clearly demonstrate a role for
mesoderm underlying the otic placode in its induction
(Ladher et al., 2000
;
Wright and Mansour, 2003
),
its importance in imparting generic placode character to the overlying
ectoderm has so far not been recognised. Although our experiments do not
specifically test different subpopulations of head mesoderm for their
PPR-inducing properties, the heart precursors are among the inducing cells.
Fate map and cell movement studies in amniotes, amphibians and teleosts
demonstrate that in the cranial region the heart mesoderm comes to underlie
the PPR precisely at the time when Six and Eya gene
expression becomes confined to the overlying ectoderm
(Rosenquist, 1970
;
Kimmel and Warga, 1988
;
Keller and Tibbetts, 1989
;
Sater and Jacobson, 1989
;
Sater and Jacobson, 1990
;
Warga and Kimmel, 1990
;
Parameswaran and Tam, 1995
;
Tam et al., 1997
;
Redkar et al., 2001
;
Hochgreb et al., 2003
). In
addition, like PPR markers in the ectoderm, the early heart-specific
transcript Nkx2.5 is expressed in a horseshoe-shaped domain in the
mesoderm. By contrast, input from the neural plate seems to play a minor role
in PPR induction. As in Xenopus
(Glavic et al., 2004
;
Ahrens and Schlosser, 2005
), we
find that the neural plate induces Six1 expression, but it fails to
elicit the expression of other markers characteristic for the PPR. Thus, the
formation of the common primordium that generates all sensory placodes in the
vertebrate head is likely to be initiated through signals that emanate from
the head mesoderm, including future heart tissue.
We propose that mesoderm-derived signals are essential to activate placode
specific gene expression downstream of the Six/Eya/Dach cascade. While the
complex of Six and Dach acts as a transcriptional repressor, the recruitment
of Eya into this complex brings in transcriptional co-activators and initiates
transcription of downstream targets. At gastrula stages, low levels of
Six1 and Six4 expression are detected in the neural plate
(Esteve and Bovolenta, 1999)
(A.L. and A.S., unpublished), where Dach1 is strongly expressed, thus
preventing the activation of target genes. At the time when the definitive
neural marker Sox2 becomes strongly upregulated in the neural plate
(stage 4+), Six1 and Six4 expression is lost from
this domain and confined to the PPR (see
Fig. 5). At the same time, the
onset of Eya2 is observed in the PPR, allowing the activation of
downstream genes. Thus, the crucial step in the initiation of placode
induction may be regulated by the appearance of Eya2 under the influence of
mesodermal signals.
Making the difference between cranial neural crest and placode precursors
Like placodes, neural crest cells contribute to the cranial sensory nervous
system. Both arise at the border of the neural plate and their precursors are
initially mixed. Over time, however, these two cell fates segregate
(Streit, 2002). What are the
cellular and molecular mechanisms that control this cell fate decision? Unlike
the PPR, interaction between the neural plate and future epidermis is
sufficient to induce neural crest cells, including some of their derivatives
(Moury and Jacobson, 1990
;
Dickinson et al., 1995
;
Selleck and Bronner-Fraser,
1995
; Mancilla and Mayor,
1996
; Mayor et al.,
1997
). In addition, signals from gastrula stage dorsolateral
mesoderm have been implicated (Raven and
Kloos, 1945
; Mancilla and
Mayor, 1996
; Bonstein et al.,
1998
; Marchant et al.,
1998
; Monsoro-Burq et al.,
2003
). We find that at neurula stages neither cranial
(PPR-inducing) nor trunk mesoderm is able to induce neural crest markers in
competent ectoderm, whereas trunk paraxial mesoderm from slightly later stages
can (A.S., unpublished). Thus, the signals that induce definitive PPR and
neural crest character are secreted by different tissues at different times in
development.
Multiple signalling pathways have been implicated in the induction of
neural crest cells (for reviews, see Aybar
et al., 2002; Knecht and
Bronner-Fraser, 2002
). At gastrula stages, the neural crest domain
is thought to be positioned in the ectoderm by intermediate levels of BMP
activity, while subsequently FGF, WNT and RA are required to generate
definitive neural crest (Mayor et al.,
1997
; Chang and
Hemmati-Brivanlou, 1998
;
LaBonne and Bronner-Fraser,
1998
; Garcia-Castro et al.,
2002
; Villanueva et al.,
2002
; Monsoro-Burq et al.,
2003
). One view holds that FGFs, WNT proteins and RA act as
posteriorising agents that impart posterior, i.e. neural crest, properties
onto cells with `anterior neural plate border' character (for reviews, see
Aybar et al., 2002
;
Knecht and Bronner-Fraser,
2002
). However, cranial neural crest cells are generated
immediately adjacent to sensory placodes and are therefore unlikely to be
subjected to posteriorising signals. Furthermore, we show that in the head,
WNT signalling plays an important role in mediolateral patterning of the
ectoderm without affecting the position of regional neural markers
(Fgf3 and Krox20): activation of the canonical WNT pathway
suppresses the formation of sensory placodes while expanding the crest
territory. We propose that cells at the border of the anterior neural plate
initially have the potential to become both crest and placode, reflected by
the fact that their precursors are interspersed
(Streit, 2002
). As the neural
folds form, Wnt expression is initiated in the folds concomitant with
the onset of Slug. Cells that receive WNT signals develop along the
neural crest cell lineage, while those that are protected from WNT become
placodes (Fig. 7).
Interestingly, even in the absence of WNT activity, placode specific gene
expression never expands into the neural folds, suggesting that they contain
additional inhibitory signals. Indeed, the neural folds express high levels of
Bmp4 and Bmp7 transcripts
(Liem et al., 1995;
Streit and Stern, 1999
) and
show elevated levels of BMP activity, as determined by the presence of
phosphorylated SMAD1 (Faure et al.,
2002
; Linker and Stern,
2004
). By contrast, BMP activity in the placode territory is low
(Faure et al., 2002
). In
agreement with these observations, the generation of neural crest cells
requires some level of BMP activity (Liem
et al., 1995
; Sasai and De
Robertis, 1997
; Wilson et
al., 1997
; Nguyen et al.,
1998
; Aybar and Mayor,
2002
; Tribulo et al.,
2003
; Glavic et al.,
2004
), while placode precursors require its attenuation (this
study).
Thus, the decision of multipotent ectodermal cells to give rise to crest or placode cells is controlled by modulation of local signals that emanate from surrounding tissues. Signals from the neural folds - WNT and BMPs - trigger neural crest development, while signals from the head mesoderm (for which the BMP antagonist DAN and the WNT/BMP antagonist Cerberus are good candidates) protect placode precursors from their inhibitory influence.
Temporal and spatial integration of signalling events to position the placode territory
Several studies in amphibians and fish suggest that in the ectoderm
different fates are allocated through a gradient of BMP activity
(Sasai and De Robertis, 1997;
Wilson et al., 1997
;
Nguyen et al., 1998
;
Aybar and Mayor, 2002
;
Tribulo et al., 2003
;
Brugmann et al., 2004
;
Glavic et al., 2004
). However,
the formation of the otic and olfactory placodes is differentially affected in
zebrafish mutants that show different residual levels of BMP activity
(Nguyen et al., 1998
), making
it unlikely that a BMP gradient alone determines the position where placodes
develop. Our findings reveal that although BMP antagonism plays a role in the
formation of the pre-placodal territory, its induction by the head mesoderm
and neural plate requires the temporal and spatial integration of at least
three signalling pathways and is tightly coordinated with the generation of
other cell types in the cranial ectoderm
(Fig. 7).
|
Simultaneously, the head mesoderm provides both BMP and WNT antagonists,
most likely DAN (Ogita et al.,
2001) and Cerberus (Rodriguez
Esteban et al., 1999
; Chapman
et al., 2002
), to counteract the inhibitory effect of both factors
on the generation of placode precursors
(Fig. 7). Our results show that
attenuation of either the BMP or WNT pathway leads to an expansion of the PPR
into the adjacent ectoderm. However, while the expansion in response to BMP
inhibition is limited to the head ectoderm, WNT antagonism also results in the
expression of PPR specific genes in the trunk. This is in agreement with
recent findings in Xenopus reporting that simultaneous overexpression
of BMP and WNT antagonist expands Six1 expression posteriorly along
the induced secondary axis (Brugmann et
al., 2004
). In the chick, Wnt8c is expressed in trunk
mesoderm and the mesoderm lateral to the heart primordium
(Hume and Dodd, 1993
) (this
study), whereas Wnt6 is found in trunk ectoderm
(Garcia-Castro et al., 2002
;
Schubert et al., 2002
). We
propose that WNT activity from surrounding tissues is essential to restrict
the placode territory to the head ectoderm next to the neural plate and thus
ensure that sensory placodes are confined to the head. To allow placode
formation, WNT antagonists in cooperation with FGF and anti-BMPs from the head
mesoderm protect placode precursors from this inhibitory influence.
![]() |
ACKNOWLEDGMENTS |
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