1 Department of Biopharmaceutical Sciences, Programs in Human Genetics,
Developmental Biology, Genetics, and Neuroscience, University of California,
San Francisco, CA 94143-0446, USA
2 Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY
10021-6399,USA
* Author for correspondence (e-mail: suguo{at}itsa.ucsf.edu)
Accepted 20 March 2003
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SUMMARY |
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Key words: epibranchial placodes, foxi1, phox2a, Neurogenin, Zebrafish, Visceral sensory neurons
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INTRODUCTION |
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Visceral sensory neurons are derived from such neurogenic placodes, known
as the epibranchial placodes. These neurons constitute the distal ganglia of
cranial sensory nerves and carry out important functions including
transmitting information on heart rate, blood pressure and visceral distension
from the periphery to the central nervous system. Visceral sensory neurons are
composed of the geniculate, petrosal and nodose ganglia, which are developed
in a rostral to caudal sequence. The geniculate ganglion originates from the
first epibranchial placode, associates with the VIIth (facial) cranial nerve,
and primarily innervates taste buds. The petrosal ganglion originates from the
second epibranchial placode, associates with the IXth (glossopharyngeal)
cranial nerve, and innervates taste buds, the heart and other visceral organs.
The nodose ganglion originates from the third epibranchial placode, associates
with the Xth (vagal) cranial nerve, and primarily innervates the heart and
other visceral organs (Baker and
Bronner-Fraser, 2001). Once the connectivity of visceral sensory
neurons is established, their survival and maintenance are dependent upon
GDNF, a neurotrophic factor of the TGFß superfamily
(Buj-Bello et al., 1995
;
Moore et al., 1996
;
Trupp et al., 1995
).
In contrast to the knowledge about their physiological properties and
neurotrophic dependency, the molecular program underlying the specification of
visceral sensory neurons is just beginning to be unraveled. The bHLH
transcription factor Neurogenin 2 (Ngn2), a vertebrate homologue of the
Drosophila proneural gene atonal
(Jan and Jan, 1993), is
expressed in the epibranchial placodes
(Gradwohl et al., 1996
;
Sommer et al., 1996
). Its
expression coincides with the timing when neuronal precursors delaminate from
these placodes, migrate dorsomedially, and aggregate to form the distal
ganglia. ngn2 expression is confined to the undifferentiated neuronal
precursors and absent in the ganglionic anlagen. In contrast to Ngn2, the
paired homeodomain transcription factor Phox2a is turned on in differentiating
visceral sensory neurons (Tiveron et al.,
1996
; Valarche et al.,
1993
). Targeted disruption of ngn2 in mice results in a
transient loss of neuronal fate in geniculate (VIIth) and pertrosal (IXth)
ganglia at early stages, but the development of these ganglia appear to
recover at later stages, possibly due to functional compensation by
ngn1 (Fode et al.,
1998
; Ma et al.,
1998
; Ma et al.,
1999
). Nevertheless, the lack of ngn2 is shown to block
the delamination of neuronal precursors from the placodes and abolish their
pan-neuronal fate in early stage embryos, but, Phox2a activation is not
affected in these embryos (Fode et al.,
1998
). Conversely, inactivation of phox2a in both mice
and zebrafish leads to atrophy of visceral sensory neurons
(Guo et al., 1999a
;
Morin et al., 1997
), but they
are able to undergo general neuronal differentiation, as is evident from their
expression of pan-neuronal genes (Morin et
al., 1997
). These analyses suggest that two distinct subprograms
controlled by ngn and phox2a may operate independently in
determining visceral sensory neuronal identity. The genetic mechanisms that
act upstream of ngns and phox2a in the visceral sensory
lineage are currently unknown.
In this study, we have analyzed a zebrafish mutant named no soul, in which the development of most visceral sensory neurons fails to occur. The positional candidate approach reveals that no soul encodes a winged helix domain-containing protein, belonging to the foxi1 subfamily. Foxi1 expression is detected in the placodal progenitor cells at the neural plate stage, prior to their subdivision into neurogenic placodes and the expression of ngn. Subsequently, its expression is maintained during the period of the birth of visceral sensory neurons. Finally, its expression is extinguished upon the differentiation of visceral sensory neurons. The expression of both ngn and phox2a are defective in the no soul mutant, indicating that in the absence of foxi1 activity, placodal progenitor cells fail to express both neuronal fate and subtype identity of visceral sensory lineage. Shortly thereafter, increased cell death is detected, suggesting that in the absence of their normal developmental program, the placodal progenitor cells undertake an apoptotic pathway. Furthermore, ectopic expression of foxi1 in zebrafish embryos is sufficient to induce ectopic phox2a+ and ngn+ cells. Taken together, our analyses indicate that the winged helix transcription factor No soul/Foxi1 is an important determination factor for epibranchial placodal progenitor cells to acquire both neuronal fate and subtype visceral sensory identity.
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MATERIALS AND METHODS |
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Mapping and cloning
AB/EK female fish carrying the no soul mutation were crossed to
wild-type WIK male fish, and F1 progeny were raised to adulthood.
Genomic DNA was extracted from pools of wild-type sibling and mutant embryos,
and PCR reactions were performed using microsatellite marker primers
(Knapik et al., 1998). The
genetic linkage of no soul to microsatellite markers was established
by detection of differential amplification of wild-type and mutant DNA pools
(Knapik et al., 1998
), and
microsatellite marker Z1400 yielded two recombinants and marker Z13938 yielded
23 recombinants out of 276 individual no soul mutant embryos
tested.
For mutation detection in no soul, primers specific for the
foxi1 cDNA were used to amplify genomic DNA from pools (10) of
the no soul mutant and wild-type sibling embryos. PCR products from
mutant and wild-type sibling embryos (two independent sets) were directly
sequenced by automated cycle sequencers (ABI).
Time lapse confocal analysis
Embryos carrying an islet-GFP (green fluorescent protein)
transgene were anesthetized with 0.01% ethyl-m-aminobenzoate methanesulphonate
(Sigma), and mounted in 3% methyl cellulose. They were viewed and photographed
at different stages using a Bio-Rad confocoal microscope. After viewing, they
were immediately returned to the 28.5°C incubator. The genotype of
photographed embryos was subsequently confirmed by genotyping with tightly
linked polymorphic Z markers.
Whole-mount in situ hybridization and immunostaining
Digoxigenin- or fluorescein-labeled antisense RNA probes were prepared from
linearized templates using RNA labeling reagents (Boehringer Mannheim).
Hybridization and detection with antidigoxigenin or anti-fluorescein
antibodies was done as previously described
(Guo et al., 1999b). For
two-color in situ hybridization, two RNA probes (digoxigenin- or
fluorescein-labeled) were hybridized simultaneously, and developed
sequentially with purple and red substrates (Roche). After staining, embryos
were cleared with glycerol, either whole-mounted or sectioned for viewing.
Immunostaining was performed as previously described
(Guo et al., 1999b
). TUNEL
staining was carried out using the ApopTag kit according to the manufacturer's
instructions.
DNA and RNA injection
Capped sense RNA was synthesized by in vitro transcription from linearized
pCS2 plasmids. DNA plasmids or in vitro transcribed RNA for either
foxi1 or lacZ were microinjected at the 1- to 8-cell stage.
At appropriate stages, they were fixed with 4% paraformaldehyde and processed
for staining. Morpholino antisense oligonucleotide specific for foxi1 was
provided by A. Fritz, the sequence is: 5'-TAATCC-
GCTCTCCCTCCAGAAACAT-3'. Gene Tools, LLC standard control oligo was used.
Oligos were injected at a concentration of 2-5 µg/µl.
Protein structure modeling
A comparative model of the winged helix domain was constructed by MODELLER
(Sali and Blundell, 1993),
relying on its high (41-62%) sequence identities to the template structures of
genesis (Marsden et al.,
1997
), FREAC-11 (van Dongen et
al., 2000
), and AFX (Weigelt
et al., 2000
) determined by NMR spectroscopy. The native and
mutant 7-residue segments (57-63) were modeled de novo in the context of the
rest of the comparative model (Fiser et
al., 2000
).
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RESULTS |
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no soul encodes a winged helix domain-containing protein of
the Foxi1 subfamily
To identify the gene that is disrupted by the no soul mutation, we
genetically mapped the mutation to linkage group (LG) 12, between polymorphic
microsatellite markers Z1400 and Z13938. Primers for both markers amplified
two distinct fragments using genomic DNA prepared from both parents and
wild-type sibling embryos, while amplified only one of two fragments in DNA
from no soul mutant embryos, indicating genetic linkage (data not
shown). A winged helix domain-containing gene of the Foxi1 subfamily, which
was identified in an expression cDNA screen
(Kudoh et al., 2001), has been
located at this interval by radiation hybrid mapping, and found to be
essential for otic development (Solomon et
al., 2003
). Given the otic phenotypes we observed in the no
soul mutant and the closeness in genetic distance between no
soul and foxi1, we sought to determine if foxi1 is
disrupted in the no soul mutant. We cloned and sequenced
foxi1 from the no soul mutant embryos, as well as from their
wild-type siblings. This analysis revealed that the no soul mutant
carries a single substitution from serine to proline at amino acid 194 (Fig.
2A,C).
This substitution was never found in wild-type siblings or in foxi1
from other species (Fig. 2C).
Furthermore, serine-194 is an absolutely conserved residue in helix H3, the
recognition helix of the winged helix DNA binding domain
(Gajiwala and Burley, 2000
).
Secondary structure prediction and comparative protein structure modeling
(Sali and Blundell, 1993
;
Fiser et al., 2000
) indicated
that the change of the serine-194 to the helix-breaking proline residue
shortens the critical recognition helix of the winged helix domain, which in
turn is likely to destroy its ability to bind to DNA
(Fig. 2B). It is probable that
approximately one half of the crucial residues in the H3 recognition helix are
not able to interact with DNA: the number of atomic contacts at less than 4.5
angstroms between the ab initio-modeled 7-residue segment and DNA in the
no soul mutant is less than half of that in the wild type. In
summary, both the experimental evidence and theoretical considerations provide
strong evidence that the no soul mutation disrupts
foxi1.
|
Expression of no soul/foxi1
Embryological experiments have mapped the origin of cranial placodes to the
border of neural plate and future epidermis
(Baker and Bronner-Fraser,
2001). At the tailbud stage (
10 hpf), foxi1
expression is found in bilaterally symmetric domains at the boundary of
lateral neural plate/epidermis (Fig.
3A), suggesting that it is expressed in lateral cranial placodal
progenitor cells. As the neural tube forms, the foxi1-expressing
domains become elongated and by 24 hpf, the expression of foxi1 is
somewhat reduced but still detectable (Fig.
3D). By 36 hpf, its expression is still present lateral to the
neural tube (Fig. 3G). Cross
sectioning showed foxi1 expression in the ectodermal layer. Weak
expression was also detected in a few internal cells, which most likely
represent delaminating neuronal precursors
(Fig. 3G'). By 48 hpf,
foxi1 expression domain has moved ventrolaterally, and appears to be
in the pharyngeal arch primordia (Fig.
3M). Cross sectioning detected foxi1 expression again in
the ectodermal layer (Fig.
3M'). Thus, the expression pattern of foxi1 is
consistent with its role in cranial sensory neuron and pharyngeal arch
development.
|
Epibranchial placodal progenitor cells fail to initiate ngn
and phox2a expression and subsequently disappear in the no
soul mutant
To further look into the relationship between foxi1, ngn and
phox2a, we examined their expression in the no soul mutant.
Since foxi1 expression precedes that of both ngn and
phox2a foxi1 may be required to initiate their expression in the
visceral sensory neuronal lineage. Alternatively, foxi1 may be
required to maintain the integrity of progenitor cells, that is, in the
absence of foxi1 activity, the progenitor cells disappear or are
transformed to other cell types, thus, precluding their expression of
ngn and phox2a and subsequent acquisition of visceral
sensory neuronal identity. To look into these possibilities, we compared the
state of progenitor cells and their expression of ngn and
phox2a. Since the mutated no soul/foxi1 gene still gave rise
to stable transcript, we used the foxi1 RNA to mark the presence of
progenitor cells. At 24 hpf, the foxi1-expressing progenitor cells
are present in the no soul mutant
(Fig. 4B). In fact, they
appeared to express foxi1 at a higher level compared to their
wild-type siblings, suggesting that foxi1 negatively regulates its
own expression (Fig. 4A-D).
While the progenitor cells are still present in the no soul mutant at
this stage, we detected no ngn or phox2a expression in the
epibranchial placodes (Fig.
4E-H). Double in situ hybridization with foxi1 and
ngn or foxi1 and phox2a further confirmed that
while foxi1-expressing progenitor cells are still present, they fail
to initiate the expression of ngn and phox2a
(Fig. 4I-L). Consistent with
the lack of ngn and phox2a expression, sectioning analysis
of foxi1 and phox2a double-labeled embryos revealed that
foxi1-expressing epibranchial placode progenitor cells fail to
delaminate and subsequently fail to express phox2a
(Fig. 4M-P). Taken together,
this analysis suggests that in the absence of foxi1 activity,
visceral sensory progenitor cells fail to initiate the expression of
ngn and phox2a. In addition, the ngn expression in
lateral line placodes was also absent in the no soul mutant
(Fig. 4F), suggesting that
foxi1 is also required to regulate the development of these
placodes.
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DISCUSSION |
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Whereas factors like olig2
(Mizuguchi et al., 2001;
Novitch et al., 2001
;
Zhou et al., 2001
),
Mash1 and phox2b (Pattyn
et al., 1999
) have been identified that coordinate pan-neuronal
fate and subtype identity of motor neurons and autonomic ganglia respectively,
molecules that carry out such function in the cranial sensory neuronal lineage
have not been identified. Our study suggests that foxi1 is one such
factor. In the absence of foxi1 activity, while
foxi1-expressing progenitor cells are still present in the no
soul mutant, they express neither ngn nor phox2a. Thus,
foxi1 is required to coordinate ngn-mediated pan neuronal
fate and phox2a-mediated subtype identity in placodal progenitor
cells. Since foxi1 encodes a putative transcription regulator, a
simple mechanism would be that foxi1 could directly activate the
transcription of ngn and phox2a. The fact that the
foxi1-expressing domain is much broader than that of ngn and
phox2a suggests that foxi1 needs to cooperate with yet
unidentified factors to turn on the expression of ngn and
phox2a. Bmp7 from the pharyngeal endoderm has been shown to be an
inducing factor for epibranchial placodes
(Begbie et al., 1999
). It will
be important in the future to determine if foxi1 is regulated by Bmp7
in zebrafish.
It is worth noting that in the absence of foxi1 activity, placodal
progenitor cells apparently undergo apoptosis. This observation suggests that
foxi1 is involved in suppressing the apoptotic pathway in these
progenitor cells. Since not all foxi1-expressing cells undergo
apoptosis in the no soul mutant, it appears unlikely that
foxi1 directly represses pro-apoptotic genes. Rather, apoptosis may
be an alternative pathway when the normal developmental program is not
initiated. Whereas it is not well understood how progenitor cells choose to
differentiate or undergo apoptosis in vertebrates, it has been reported that
progenitor cells can either undergo autonomic neurogenesis or apoptosis in
culture in response to different concentrations of TGFß
(Hagedorn et al., 2000),
suggesting that progenitor cells can adopt distinct fates in response to
different extrinsic signals.
Foxi1 as a forkhead related winged helix domain-containing
transcription factor
Winged helix domain (also known as the forkhead domain) was originally
found in the Drosophila forkhead gene and the rat hepatocyte
nuclear factor 3 (HNF-3), which function in determining terminal
structures in the Drosophila embryo
(Weigel et al., 1989), and in
controlling gene expression in the liver in mice
(Lai et al., 1990
),
respectively. Subsequently more than 100 winged helix domain-containing genes
have been identified in species ranging from yeast to human, which serve such
diverse functions as early patterning, differentiation and survival (refer to
http://www.biology.pomona.edu/fox.html).
X-ray and solution NMR structures of a number of winged helix proteins have
been determined. These studies identify the H3 recognition helix as the most
important DNA-binding portion of a winged helix
(Gajiwala and Burley, 2000
).
Mutations in this region completely abolish DNA binding
(Clevidence et al., 1993
).
Here we show that the no soul mutation lies in the H3 helix, changing
a conserved serine to proline. Our comparative modeling analysis strongly
suggests that the no soul mutation would disrupt DNA binding and thus
the regulation of downstream target genes. Furthermore, the morpholino
experiment phenocopied the no soul mutant phenotype. Taken together,
we believe that the no soul mutation probably represents a severe to
complete loss of function allele of foxi1.
Based on the similarity within the winged helix domain, the winged helix
domain-containing proteins are further classified into more than 15
subfamilies. Relatively little is known about the expression pattern and
function of the foxi1 subfamily. Our study with no soul
demonstrates that foxi1 is required for the development of zebrafish
epibranchial placode-derived visceral sensory neurons. The expression of
Xenopus foxi1c has been recently reported
(Pohl et al., 2002). Similar
to our findings, the Xenopus Foxi1c is initially expressed in an
epidermal ring around the neural field, and subsequently, is exclusively
localized to placodal precursor cells. The targeted disruption of a probable
homologue, Fkh10 (Foxi1), in mice leads to defects in inner
ear development (Hulander et al.,
1998
). Otic defects were also observed in the no soul
mutant (our unpublished observation). Furthermore, otic defects were well
characterized in the hearsay mutation, which is another allele of
foxi1 (Solomon et al.,
2003
). It will be interesting to determine whether Fkh10
or a related forkhead gene is required for the development of visceral sensory
neurons in mice.
Differential effects of no soul on subgroups of visceral
sensory neurons
Visceral sensory neurons include the geniculate, petrosal and nodose
ganglia, which have distinct but also overlapping connectivity patterns. Fate
mapping experiments show that they all derive from the epibranchial placodes
(Baker and Bronner-Fraser,
2001). However, in the no soul mutant, we saw a
differential effect on these neurons: whereas the geniculate and petrosal
neurons fail to develop, the nodose ganglia are partially spared.
Interestingly, nodose ganglia were also less affected in mice with targeted
disruption of ngn 2 (Fode et al.,
1998
) and phox2a
(Morin et al., 1997
). These
analyses suggest that although the three distal ganglia share a developmental
origin, different mechanisms may operate in their determination.
Interestingly, we observed that unlike geniculate and petrosal ganglia, which
express phox2a prior to phox2b, nodose ganglion initiates
phox2b expression prior to that of phox2a. Therefore, it is
possible that the commitment and differentiation of at least subsets of nodose
ganglion is under the control of yet unidentified regulatory hierarchies.
Alternatively, other neural progenitor populations are able to compensate for
the loss of epibranchial placode-derived nodose progenitor cells. For example,
compensation from cardiac neural crest cells has been previously reported in
animals whose nodose precursors have been ablated
(Harrison et al., 1995
).
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ACKNOWLEDGMENTS |
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