1 Center for Molecular Neurobiology Hamburg, University of Hamburg, Falkenried
94, D-20251 Hamburg, Germany
2 Instituto de Biología y Genética Molecular, Universidad de
Valladolid y Consejo Superior de Investigaciones Cientificas, Departamento de
Bioquímica, Biología Molecular y Fisiología, Facultad de
Medicina, E-47005 Valladolid, Spain
3 Institute for Animal Developmental and Molecular Biology,
Heinrich-Heine-University, D-40225 Düsseldorf, Germany
4 Institute of Molecular and Cellular Biosciences, University of Tokyo,
Bunkyo-Ku, Tokyo 113, Japan
5 School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG,
UK
Author for correspondence (e-mail:
schimman{at}epos.zmnh.uni-hamburg.de)
Accepted 23 September 2003
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SUMMARY |
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Key words: Fibroblast growth factor, Otic vesicle, Hindbrain, Mouse
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Introduction |
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Owing to their gene expression patterns and various experimental
manipulations, several members of the fibroblast growth factor (FGF) gene
family, including FGF2, FGF3, FGF8, FGF10 and FGF19 have been implicated in
different stages of inner ear formation
(Baker and Bronner-Fraser,
2001; Rinkwitz et al.,
2001
; Noramly and Grainger,
2002
). Among these, FGF3 in particular has been the earliest
candidate postulated to play a role during early inner ear development.
Initially, it was proposed on the basis of its expression pattern in the
developing hindbrain next to the forming inner ear placode and vesicle in
mice, thus consistent with a role in inner ear induction
(Wilkinson et al., 1988
).
Furthermore, this early hindbrain expression pattern is fundamentally
conserved between different vertebrate species including avians
(Mahmood et al., 1995
),
amphibians (Lombardo et al.,
1998a
) and fish (Phillips et
al., 2001
). This idea gained further support by experiments in
which antibodies and antisense oligonucleotides, presumably directed against
FGF3, blocked otic vesicle formation in chicken explants
(Represa et al., 1991
),
although later studies have questioned the conclusions that were drawn from
these experiments (Mahmood et al.,
1995
). Further doubt for a role in otic vesicle formation was
derived from the generation of Fgf3 mutant mice, where a neomycin
resistance (neor) gene was inserted into the coding region
of this gene via homologous recombination in order to prevent its expression
(Mansour et al., 1993
). The
analysis of Fgf3 homozygous mutant mice showed that formation of the
otic vesicle was unaffected, arguing against an early role of FGF3 during
inner ear development. However, defects affecting the morphogenesis and
differentiation of the inner ear were described, such as a loss of the
endolymphatic duct leading to hydrops of the inner ear, a lack of the
posterior semicircular canal and cochlear sensory neurons, and behaviors
characteristic of inner ear defects. Importantly, only 50% of homozygous
mutants were recovered after birth, and only very few of these animals
survived to adulthood. Moreover, the inner ear phenotype described had reduced
penetrance and expressivity. This could be explained by either a non-uniform
genetic background, the existence of parallel signaling pathways, leaky
expression of the mutant allele, or any combination of the above. Therefore,
the consequences of a loss of FGF3 function for mouse inner ear development
may not have been fully explored. Indeed, a role for FGF3 during early inner
ear development has gained further support following its overexpression in
chicken embryos, which leads to the formation of ectopic vesicles expressing
otic marker genes (Vendrell et al.,
2000
). In the same species, FGF3 expression is also induced by
another FGF family member, FGF19, which together with WNT8C and possibly FGF3
itself, act as synergistic signals to induce otic development
(Ladher et al., 2000
). Next to
FGF3, FGF2 and FGF8 have also been shown to induce ectopic otic structures
and/or expression of genes marking otic identity
(Lombardo and Slack, 1998b
;
Adamska et al., 2001
;
Léger and Brand, 2002
).
Several recent studies have reported the requirement for both FGF3 and FGF8
function for proper formation of the otic placode and vesicle in zebrafish,
demonstrating the synergistic role of a combination of different FGF family
members acting in a redundant fashion during this process
(Phillips et al., 2001
;
Léger and Brand, 2002
;
Maroon et al., 2002
;
Liu et al., 2003
). In mice,
FGF3 has been suggested to share redundant functions with FGF10 during tooth
morphogenesis (Kettunen et al.,
2000
). As the expression of FGF3 and FGF10 also partially overlap
during otic morphogenesis, and they have been suggested to play roles in
forming parallel signaling pathways
(Pirvola et al., 2000
),
experiments examining functional relationships between these and other FGF
ligands are required to dissect the complexity of FGF inputs into otic vesicle
formation.
In the present study we address the potential role of FGF3 and other FGF
family members, including FGF2, FGF8 and FGF10 to act as neural signals during
murine inner ear formation. We also generate a new mutant allele for
Fgf3 and find that, unexpectedly, mice that lack the
Fgf3-coding region show no apparent inner ear defects. Ectopic
expression of different FGFs to anterior regions of the developing hindbrain
reveals that FGF10 acts as a potent inducer of ectopic vesicles with otic
character, thereby indicating its capacity to function as a neural signal
during inner ear formation. A role in normal otic vesicle formation is also
supported by its endogenous expression in the hindbrain next to the developing
inner ear placode and vesicle. Finally, by the analysis of double mutant mice,
we confirm that FGF3 and FGF10 act as redundant signals during otic vesicle
formation. A similar analysis of double mutant mice for FGF3 and FGF10 has
been reported recently (Wright and
Mansour, 2003).
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Materials and methods |
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For the generation of transgenic mice expressing FGFs in the hindbrain a
plasmid containing the EphA4 r3/r5 enhancer and a lacZ
reporter gene was used (see Fig.
3A). Murine FGF cDNAs were amplified by PCR and cloned into the
EheI site of the vector. Transgenic mice were generated and
identified by PCR or ß-galactosidase staining, as described previously
(Theil et al., 1998). Ectopic
expression of FGFs was verified by RNA in situ hybridisation. Levels of
transgene expression were estimated by RNA in situ hybridization and
ß-galactosidase staining. Maximal levels of transgene expression were
found to be similar between embryos expressing different transgenes.
|
RNA whole-mount in situ hybridization was essentially performed as
described by Conlon and Rossant (Conlon and
Rossant, 1992) using digoxigenin- and fluorescein-labelled
riboprobes, which were detected by using alkaline phosphatase-coupled
antibodies. For double detection, NBT/BCIP (purple) staining was always
carried out first, and the antibody was stripped in 0.1 M glycine-HCl (pH
2.2). The embryos were then incubated with the other antibody and stained with
INT/BCIP (red). For histological examination, embryos were postfixed in 4%
PFA, embedded in gelatin and sectioned at 30 µm on a vibratome or embedded
in Tissue-Tek (Sakura) and sectioned at 10 µm on a cryostat. For
whole-mount RNA in situ hybridization the following probes were used:
Dlx5 (Acampora et al.,
1999
; Depew et al.,
1999
), Sox9 (Ng et
al., 1997
), Lmx1
(Failli et al., 2002
),
Pax2 (Rinkwitz-Brandt et al.,
1996
), kreisler/Mafb
(Giudicelli et al., 2003
),
lunatic fringe (Morsli et al.,
1998
) and full-length cDNA for Fgf3 (kindly provided by
Clive Dickson). Fgf10 expression analysis was performed using a probe
corresponding to nucleotides 12-547 (kindly provided by Rosanna Dono) and a
full-length cDNA (Invitrogen). As negative controls to confirm specificity and
fidelity of Fgf10 expression,
Fgf10/ mutant embryos were also used.
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Results |
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FGF3 mutant mice are viable and show tail defects, but normal inner
ears
In contrast to Fgf3neo/neo mutants
(Mansour et al., 1993),
Fgf3/ mice lacking the entire coding region
for Fgf3 were found be viable and fertile and showed no abnormal
behavior. The most striking phenotype of
Fgf3/ mutants was their shortened, thickened
and curved tail (Fig. 2A). This
phenotype was first observed at day 11 of embryonic development (E11) and has
also been described in Fgf3neo/neo mice
(Mansour et al., 1993
). To
analyse in more detail any inner ear phenotypes in
Fgf3/ mice, we performed a histological
analysis of developing ears from these mutants from the otic vesicle stage
until adulthood, focusing especially on those structures that had been
described as defective in Fgf3neo/neo mutant mice. At
E10.75 otic vesicles of Fgf3/ mutants
appeared slightly smaller compared with age-matched wild-type littermates
(Fig. 2B,C). However, all of
the inner ears of Fgf3/ mutant animals
examined (n=60) were otherwise found to have an apparently normal
morphology, including presence of the endolymphatic duct, the posterior
semicircular canal and cochlear ganglia
(Fig. 2B-E). Adult homozygous
mutants showed a normal Preyer's reflex and revealed no obvious structural
abnormalities of the cochlea or the vestibular system
(Fig. 2F,G and data not shown).
Therefore, we found no evidences that deletion of the Fgf3-coding
region has consequences on viability or on function of the inner ear.
|
Expression of FGF3 and FGF10 during inner ear formation
Before and during otic placode formation, Fgf3 is detected in the
developing neuroectoderm in a broad domain that extends from the
midbrain-hindbrain boundary down to r6, with the highest expression levels
present in r4, r5 and r6 next to the developing otic placode
(Fig. 4A)
(Mahmood et al., 1996;
McKay et al., 1996
).
Subsequently, during formation of the otic pit and vesicle, Fgf3
transcripts are concentrated in r5 and r6
(Fig. 4B,C)
(Mahmood et al., 1996
;
McKay et al., 1996
). As FGF10
showed a strong and reproducible capacity to induce ectopic otic vesicles
after overexpression in the developing hindbrain, we were interested to
analyse its endogenous expression pattern during formation of the otic placode
and vesicle. Between the 0 somite (s) to 4 s stage, Fgf10 was
expressed in the anterior and ventral mesenchyme
(Fig. 4D-F). From the 5 s stage
onwards, we detected a very dynamic expression in the developing hindbrain
next to the area where the otic placode and vesicle develops
(Fig. 4G-K). To facilitate the
detailed localisation of Fgf10 during early inner ear development in
the developing hindbrain, we performed double in situ hybridisation of
Fgf10 with a probe for the Mafb gene, which is expressed at
the level of r5 and r6 during formation of the hindbrain
(Giudicelli et al., 2003
),
next to where the otic placode and vesicle are formed. Before formation of the
otic placode at the 5 s and 7 s stage Fgf10 was expressed in a domain
largely posterior to the anteriormost extent, but overlapping with posterior
Mafb expression (Fig.
4G,H). After formation of the otic placode at the 10 s and 11 s
stage, this domain extended further posteriorly down the neural tube to the
level of the fifth somite, and anteriorly maintained its overlapping
expression with Mafb in r6 (Fig.
4I). During this developmental timepoint, an additional domain of
Fgf10 expression was detected in the anterior hindbrain. At the 13 s
stage expression of this anterior domain and the posterior neural tube domain
were both being downregulated but Fgf10 expression was still
maintained in r6 and furthermore, now also extended into r5
(Fig. 4J). Some two somites
later (15 s) Fgf10 expression was detected in r5 and the anterior
part of the invaginating otic cup (Fig.
4K). Analysis of sections at these stages showed that
Fgf10 expression was restricted to the neural tissue of the ventral
hindbrain (Fig. 4L-N and data
not shown). Therefore, Fgf10 expression in the developing hindbrain
coincides spatially and temporally with the formation of the murine otic
placode and/or vesicle in the neighboring ectoderm, and also coincides with
some of the endogenous areas of Fgf3 hindbrain expression.
|
|
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Discussion |
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Both FGFR2-IIIb and FGF10 mouse mutants develop smaller otic vesicles and
show defects during further morphogenesis and differentiation
(Ohuchi et al., 2000;
Pirvola et al., 2000
;
Pauley et al., 2003
). However,
as the phenotype of FGFR2-IIIb mutants is more severe than the one observed in
the single FGF10 knockout mice, other FGF ligands are required to control
inner ear development via this receptor isoform. Additionally, the IIIc
isoform of FGFR2 may also be involved during inner ear formation, as well as
the ligands binding this isoform, because hypomorphs affecting all FGFR2
isoforms (Xu et al., 1998
)
show an otic vesicle that is even smaller than the one observed in FGFR2-IIIb
mouse mutants (Pirvola et al.,
2000
). Finally, the severity of the inner ear phenotype observed
in some of the
Fgf3//Fgf10/
double mutants may only be explained by the interaction of FGF3 and FGF10 with
additional FGF receptors next to FGFR2. In this context, it is noteworthy that
FGFR1-IIIb has also been shown to act as a functional receptor for FGF3
(Ornitz et al., 1996
) and
FGF10 (Beer et al., 2000
).
A key question raised by our results is the explanation underlying the
phenotypic differences observed between the
Fgf3/ mutants described in this study and
more severe phenotypes noted in Fgf3neo/neo animals
(Mansour et al., 1993). In the
latter strain, a postnatal loss of homozygous mutants and inner ear phenotypes
had been reported. Fgf3neo/neo mutants show defects during
formation of the endolymphatic duct and the cochlearvestibular ganglion that
are also observed in FGFR2-IIIb mutant mice
(Mansour et al., 1993
;
DeMoerlooze et al., 2000; Pirvola et al.,
2000
). Therefore, the most likely reason for the differences
observed between Fgf3/ and
Fgf3neo/neo mice is that in the latter mutants, the
compensatory mechanisms present in Fgf3/
mutants (see above) are not active. Thus, variations between the genetic
background of these different Fgf3 mutant strains may well underlie
the observed phenotypic differences. However, we have started to backcross
mice carrying the deletion of Fgf3 onto the Bl6 background but have
so far not observed any differences from the phenotypes described in the
present article. Alternatively, the contrast of this phenotype with that
observed in Fgf3neo/neo mutants may be explained by the
presence of the neor gene in the
Fgf3neo/neo locus, which may influence the expression and
function of neighboring genes (Lewandoski,
2001
). This may then lead to the inner ear defects and/or a
reduction of viability of Fgf3neo/neo mutants. To clarify
this issue further we are at present creating mice in which the Fgf3
gene has been replaced by the neor gene.
Consequences of ectopic expression of FGFs in the hindbrain on inner
ear development
Several studies have suggested an important role for FGFs as
hindbrain-derived signals controlling inner ear induction
(Represa et al., 1991;
Phillips et al., 2001
;
Léger and Brand, 2002
;
Maroon et al., 2002
;
Liu et al., 2003
). To address
the capacity of different FGFs to direct the formation of the inner ear, we
used a gain-of-function approach by ectopically expressing FGFs in the
anterior hindbrain. This aim was achieved for FGF2, FGF3 and FGF10 by
expressing them under the control of the Epha4 enhancer that drives
expression in r3 before and during formation of the otic placode and vesicle.
Using this enhancer, we were unable to obtain transgenic mice that ectopically
express FGF8. However, unlike in zebrafish
(Phillips et al., 2001
), FGF8
is not expressed in the hindbrain of mice
(Lin et al., 2002
) and is
therefore unlikely to influence mouse otic development via this tissue.
Nevertheless, FGF8 may still participate in inner ear development because it
is transiently expressed in the otic placode of chicks
(Adamska et al., 2001
) and the
preplacodal ectoderm in mice (Crossley and
Martin, 1995
). Although we obtained transgenic mice ectopically
expressing FGF2, no phenotypic changes could be observed. Moreover, so far we
have found no evidence for localized expression of FGF2 within the hindbrain
near the otic region (Vendrell et al.,
2000
) and in addition, FGF2 mouse mutants show no defects during
inner ear development (Dono et al.,
1998
). Therefore, unlike in Xenopus and chick embryos,
FGF2 does not appear to influence otic development in mice. However, it is
important to note that in the latter cases FGF2 was applied via beads
implanted into the mesenchyme of the embryos, which may explain the different
experimental outcomes. By contrast, we found that ectopic expression of FGF3
and FGF10 in r3 of transgenic embryos resulted in the formation of ectopic
vesicles with otic character. However, the capacity of FGF10 to direct the
development of these vesicles was much stronger than for FGF3. Possibly, this
difference could be explained by an overlap of ectopic FGF10 expression with
endogenous FGF3 expression in r3 (Mahmood
et al., 1995
; McKay et al.,
1996
), which may result in a more potent combined signal to induce
ectopic vesicles in FGF10 transgenic embryos. Vice versa, owing to its
endogenous expression restricted to the posterior part of the hindbrain, an
overlap between FGF10 expression (Fig.
4) and ectopic FGF3 expression in r3 in FGF3 transgenic embryos
does not occur during otic induction and thus may lead to a much weaker single
signal for the formation of ectopic vesicles. To further address the potential
cooperativity between FGF3 and FGF10, we have created double transgenic
embryos containing both misexpression transgenes, but have not obtained an
increased frequency of ectopic vesicle formation compared with single
transgenic embryos (Y.A. and T.S., unpublished). In summary, our results show
that expression of FGF10 (and to a lesser extent FGF3) in the hindbrain is
sufficient to direct the formation of ectopic vesicles expressing otic
markers. Similar results have been obtained in zebrafish, where ectopic otic
vesicles are observed upon anterior expansion of both FGF3 and FGF8 expression
in the hindbrain (Phillips et al.,
2001
). As suggested earlier
(Léger and Brand,
2002
), these results indicate that hindbrain tissue by itself may
contain signals sufficient to direct the formation of the early inner ear.
Control of inner ear formation by FGFs in vertebrates
Both mesoderm and neural tissue contribute to the formation of the inner
ear placode and vesicle. However, at present there is a lack of information
about which molecular signals are necessary or sufficient to execute this
developmental program. Our present results demonstrate that both FGF3 and
FGF10 are necessary for formation of the otic vesicle in mice. Interestingly,
FGF10 expression is observed in the mesoderm and hindbrain during embryonic
development. At the 0 s stage, FGF10 was detected in anterior mesenchyme,
which may correspond to an area where the future otic placode will be formed
in the overlying ectoderm. Therefore, mesenchymal expression of FGF10 has been
suggested to act as an inductive signal for inner ear formation
(Wright and Mansour, 2003).
However, shortly after this stage (4 s) and before the otic placode has
formed, mesenchymal FGF10 expression is observed in a more ventral position
(Fig. 4F), which will give rise
to pharyngeal mesoderm (Kelly et al.,
2001
). Importantly, FGF3 is not detected in the anterior
mesenchyme, but is coexpressed with FGF10 in r5 and r6 of the developing
hindbrain before and during otic placode induction (see
Fig. 4)
(McKay et al., 1996
;
Mahmood et al., 1996
).
Additionally, FGF10, and to a lesser extent FGF3, are sufficient to induce the
formation of ectopic vesicles with otic characteristics, when they are
expressed ectopically in the developing hindbrain (see above). The
co-expression of both genes in the developing murine hindbrain thus suggest
that they may act as redundant neural signals during inner ear formation. A
similar scenario is apparent in the zebrafish, where FGF3 and FGF8 are
coexpressed in r4 and have been shown to control inner ear formation in a
redundant fashion (Phillips et al.,
2001
; Maroon et al.,
2002
; Léger et al., 2002;
Liu et al., 2003
).
Loss of FGF3 and FGF8 expression in the zebrafish leads to a failure to
induce the otic placode or vesicle
(Phillips et al., 2001;
Maroon et al., 2002
;
Léger and Brand, 2002
;
Liu et al., 2003
). In this
context, it was also proposed that FGF3 and FGF8 are responsible for
epithelial organization of placodal cells to form the otic vesicle
(Liu et al., 2003
). In
addition to these morphological observations, a reduction or loss of otic
marker gene expression, including members of the Pax, Dlx and
Sox transcription factor gene families was described
(Phillips et al., 2001
;
Maroon et al., 2002
;
Léger and Brand, 2002
;
Liu et al., 2003
).
Interestingly, a differential dependence of transcription factors on the
expression of FGF3 and FGF8 has been demonstrated
(Liu et al., 2003
).
Specifically, expression of sox9a and pax2.1 the zebrafish
orthologues of mouse Sox9 and Pax2 are severely affected in
zebrafish mutants for both FGF3 and FGF8
(Phillips et al., 2001
;
Maroon et al., 2002
;
Léger and Brand, 2002
;
Liu et al., 2003
). In contrast
to these zebrafish mutants, we consistently observe the presence of small otic
vesicles in
Fgf3//Fgf10/
mouse mutants, showing that the capacity to organise an otic epithelium is
still maintained in these mutants. We have examined expression of Pax2,
Dlx5 and Sox9 in these vesicles and found a severe reduction or
absence of expression in the most affected
Fgf3//Fgf10/
mutants. In a very recent publication, similar results have been reported for
Fgf3neo/neo/Fgf10/
mutant embryos (Wright and Mansour,
2003
). However, in contrast to the latter study in less affected
vesicles of
Fgf3//Fgf10/,
normal patterns of otic marker gene expression could be observed, indicating
that proper inner ear morphogenesis had been initiated. As discussed above,
the inner ear phenotypes observed in Fgf3neo/neo versus
Fgf3/ mutants are also likely to underlie
the subtle differences found between the phenotypes of
Fgf3neo/neo/Fgf10/ and
Fgf3//Fgf10/
animals. The inner ear phenotypes of
Fgf3//Fgf10/
mouse mutants can clearly be considered less severe compared to the zebrafish
mutants lacking FGF3 and FGF8. A further difference between zebrafish and
mouse mutants may be also present in the hindbrain. Whereas the zebrafish
mutants show a loss of hindbrain markers
(Maves et al., 2002
;
Walshe et al., 2002
),
including a complete absence of Mafb expression in r5 and r6, we have
observed an unaltered expression of this gene in the hindbrains of
Fgf3//Fgf10/
mouse mutants (Y.A., V.V. and T.S., unpublished). This indicates that although
the inner ear defects caused by the absence of FGF genes in zebrafish and
mouse are rather similar, there are different consequences on the hindbrain
development in these species. A less severe defect in the hindbrain of
Fgf3//Fgf10/
mice may thus also explain the reduced severity of the otic phenotype.
Alternatively, FGF3 and FGF10 may act in a completely different mode by
directly signaling to and/or within the otic ectoderm.
Conflicting evidence exists on the inhibition of FGF signaling during inner
ear induction by using an inhibitor for FGF receptors. Whereas Léger
and Brand (Léger and Brand,
2002) reported a complete block of inner ear formation and otic
marker genes, Maroon et al. (Maroon et
al., 2002
) still observed the presence of pax8 expression
which is considered as one of the first steps of otic placode induction in
vertebrates. Therefore, the initial steps of inner ear development including
formation of the otic placode may be independent of FGF signaling.
Interestingly, recent results have shown that the zebrafish forkhead-related
transcription factor foxi modulates FGF signaling required for inner
ear formation (Nissen et al.,
2003
). Although its expression is independent of FGF signaling,
foxi interacts with FGF3 and FGF8 by maintaining their expression
(Nissen et al., 2003
).
Furthermore, inner ear formation may involve additional FGF family members. In
chick, FGF4 is expressed in a region which will give rise to r4- r6
(Shamim et al., 1999
;
Shamim and Mason, 1999
) and
thus has been suggested as an additional hindbrain-derived signal because of
its early co-expression with FGF3 (Mahmood
et al., 1995
; Maroon et al.,
2002
). In mice, expression of FGF15, the orthologue of chicken
FGF19, has also been observed in the hindbrain next to the developing inner
ear (McWhirther et al., 1997
).
In chicks, FGF3, FGF4 and FGF19 are all expressed in the mesoderm underlying
the prospective otic territory (Mahmood et
al., 1995
; Shamim and Mason,
1999
; Ladher et al.,
2000
). The participation of the endomesoderm in inner ear
induction has also been suggested by the analysis of zebrafish
one-eyed-pinhead mutants
(Mendonsa and Riley, 1999
;
Phillips et al., 2001
).
However, in a different study of these mutants, it was concluded that otic
induction can largely proceed normally in the absence of cephalic endomesoderm
and that signals from the hindbrain are sufficient for inner ear induction
(Léger and Brand,
2002
).
On the basis of the phenotype observed in Fgf3//Fgf10/ mutants, we suggest that these FGF signals reinforce and/or maintain early inner ear induction and then subsequently participate in patterning of the otic vesicle. The potential involvement of other FGFs in the endomesoderm and hindbrain, and any redundant functions shared with FGF3 or FGF10 will now similarly have to be further addressed during inner ear induction in mice.
![]() |
ACKNOWLEDGMENTS |
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![]() |
Footnotes |
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