1 Department of Biological Structure, University of Washington, Box 357420,
Seattle, WA 98195, USA
2 Department of Biology, Emory University, Rollins Research Center, 1510 Clifton
Road, Atlanta GA 30322, USA
3 Centre for Regenerative Medicine and Developmental Biology Program, Department
of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK
Author for correspondence (e-mail:
ishephe{at}emory.edu)
Accepted 8 October 2003
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SUMMARY |
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Key words: Zebrafish, GFR1, GFR
2, Ret, GDNF, Enteric nervous system, Morpholino oligonucleotides
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Introduction |
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A key regulatory factor for ENS development is glial cell line-derived
neurotrophic factor (GDNF), a potent trophic factor for many different types
of CNS and PNS neurons (Arenas et al.,
1995; Ebendal et al.,
1995
; Henderson et al.,
1994
; Mount et al.,
1995
; Trupp et al.,
1995
). GDNF is the founding member of a subgroup of the TGFß
superfamily, of which there are four members: GDNF, neurturin
(Kotzbauer et al., 1996
),
persepehin (Milbrandt et al.,
1998
) and artemin (Baloh et
al., 1998b
). The biological activities of the GDNF family ligands
are mediated through a multicomponent receptor complex that consists of a
GPI-linked ligand binding component, the GDNF family receptor
(GFR
) subunit and a common transmembrane signaling component, the
tyrosine kinase Ret (Jing et al.,
1996
; Treanor et al.,
1996
). There are four GFR
subunits; each preferentially
binds to a different GDNF family member
(Baloh et al., 1998a
;
Baloh et al., 1997
;
Baloh et al., 1998b
;
Buj-Bello et al., 1997
;
Jing et al., 1996
;
Jing et al., 1997
;
Klein et al., 1997
;
Masure et al., 2000
;
Naveilhan et al., 1998
;
Thompson et al., 1998
;
Trupp et al., 1998
;
Worby et al., 1998
). GDNF
preferentially binds to GFR
1 (Jing
et al., 1996
; Treanor et al.,
1996
) but can also bind to and mediate signaling in vitro through
GFR
2, the
subunit that preferentially binds to neurturin
(Baloh et al., 1997
;
Creedon et al., 1997
;
Sanicola et al., 1997
).
The role of GDNF in ENS development has been studied extensively in vitro
and in vivo. In cell culture, GDNF has been shown to promote survival,
proliferation, differentiation and neurite out growth of enteric precursors
(Chalazonitis et al., 1998;
Hearn et al., 1998
;
Heuckeroth et al., 1998
;
Taraviras et al., 1999
;
Worley et al., 2000
). More
recently in vitro studies have shown that GDNF can act as a chemoattractant
for mouse enteric neural crest precursors
(Young et al., 2001
). The
crucial role of GDNF in ENS development has been conclusively demonstrated by
mouse in vivo studies. Mice deficient in GDNF or its receptor components die
prior to birth and exhibit an absence of enteric neurons in the gut distal to
the stomach, as well as agenesis of the metanephric kidney
(Cacalano et al., 1998
;
Enomoto et al., 1998
;
Moore et al., 1996
;
Pichel et al., 1996
;
Sanchez et al., 1996
;
Schuchardt et al., 1994
). The
role of GDNF in ENS development has been conserved evolutionarily. We
previously showed that blocking zebrafish GDNF function through injection of
antisense morpholino oligonucleotides disrupted ENS neuronal differentiation
(Shepherd et al., 2001
).
To determine the crucial steps of zebrafish ENS development regulated by GDNF and its receptors, we have isolated full-length clones of two Gfra1 genes and a gfra2 ortholog. We have examined the temporal and spatial expression, along with the expression of gdnf and ret, within the developing zebrafish ENS, and have blocked their function using antisense morpholino oligonucleotides. We find that gfra1a and gfra1b, as well as ret, are expressed very early in the development of ENS precursors, and that interfering with their function blocks migration into the gut and subsequent proliferative expansion. However, precursors are initially specified, as identified by expression of phox2b, and are still present at the anterior end of the gut in morpholino-injected embryos after migration has substantially progressed in controls. Although gfra2 is expressed later in ENS development in only a small subset of ENS neurons, introduction of mRNA for this gene is able to functionally compensate for loss of gfra1.
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Materials and methods |
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PCR conditions used were 1 cycle of 94°C for 3 minutes; 39 cycles of 94°C for 1 minute, 60°C for 1minute and 72°C for 1.5 minutes; and 1 cycle of 94°C for 1 minute, 60°C for 1 minute, 72°C for 5 minutes.
Using probes generated to the previously published partial cDNAs for
zebrafish gfra1a and gfra1b we screened a colony
macroarrayed cDNA library filter set (RZPD library ICRFp524) that was
generated from cDNAs isolated from late somitogenesis (18-24 hpf) whole
zebrafish embryos (Clark et al.,
2001
). We identified a single clone that on sequencing was shown
to be a zebrafish gfra2 ortholog.
Sequence data has been submitted to GenBank (Accession Numbers AY436320, AY436321 and AY436322).
Whole-mount in situ hybridization
Embryos were collected and processed for whole-mount in situ hybridization
as previously described (Thisse et al.,
1993). Digoxigenin-labeled riboprobes were synthesized from
templates linearized with NotI using Sp6 RNA polymerase for
gfra1a, gfra1b and gfr
2 and using T7 RNA
polymerase for ret. Other digoxigenin-labeled riboprobes used in this
study were synthesized from templates linearized and transcribed as follows:
tyrosine hydroxylase (th), HindIII and T7;
crestin, SacI and T7; phox2b, NotI and T7; and islet2,
EcoRI and T7.
Immunocytochemistry
Embryos were processed for immunocytochemistry as previously described
(Raible and Kruse, 2000). The
pattern of primary motoneuron axon projection was revealed with anti-Znp1
(University of Oregon) (Melancon et al.,
1997
; Trevarrow et al.,
1990
). Posterior lateral axon projection was revealed by
anti-acetylated tubulin (Sigma) (Raible
and Kruse, 2000
). The pronephric kidney was revealed by
6F
immunoreactivity (Developmental Studies Hybridoma Bank)
(Drummond et al., 1998
;
Takeyasu et al., 1988
).
Differentiated enteric neurons and cranial ganglia neurons were revealed with
the anti-Hu mAb 16A11 (Molecular Probes) that labels differentiated neurons
(Marusich et al., 1994
). All
mAbs were visualized using an Alexa Fluor 568 anti-mouse IgG antibody
(Molecular Probes).
mRNA injection
gfra1a, gfra1b and gfra2 mRNAs were synthesized using the
mMessage mMachine kit (Ambion) and injected at a concentration of 50 ng/µl.
The mRNAs were co-injected with GFP mRNA, also at a concentration of
50 ng/µl, to assess expression. Approximately 1 nl of diluted mRNA was
injected into one- to two-cell embryos using a gas-driven microinjection
apparatus (Model MMPI-2; Applied Scientific Instrumentation) through a
micropipette.
gfra1a, gfra1b and ret antisense oligo injections
The antisense oligonucleotides used were 25-mer morpholino oligos (Gene
Tools LLC) with the following the base composition: gfra1a
morpholino, 5'-CGCTTTTATCCGTGGTAAGTTCGCT-3'; gfra1b
morpholino 5'-TCATCGTCGCTTTATTCAGATCCAT-3'; ret
morpholino 5'-GTCAATCATAAGTGTTAATGTCACAA-3'.
The oligos were resuspended in sterile filtered water and diluted to
working concentrations in a range between 1-5 µg/µl. Approximately 1 nl
of diluted morpholino was injected into one- to two-cell embryos using a
gas-driven microinjection apparatus. In morpholino rescue experiments
gfra1a or gfra1b morpholinos, at a concentration 1-5
µg/µl, were co-injected with modified gfra1a mRNA made from a
plasmid encoding the modified gfra1a containing the following
sequence modifications to gfra1a:
5'-ACCGACAAGTCTGCAatg-TTTATCGCCGCG-3'
(underlined bases were modified lower case is the translational start site);
or gfra1b mRNA or gfr2 mRNA, at a
concentration of 50 ng/µl, into one- to two-cell stage embryos.
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Results |
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At all concentrations and in all combinations tested, gfra1a and
gfra1b morpholino-injected embryos were morphologically
indistinguishable from control embryos. In addition, no defects were observed
in: the pattern of CaP/VaP primary motoneuron (PMN) differentiation, as
determined by islet2 expression; the pattern of PMN axon projection,
as determined by ZNP-1 immunoreactivity; the pattern of expression
tyrosine hydroxylase in the midbrain; the projection pattern of the
posterior lateral line ganglion cell axons in the lateral line, as determined
by acetylated-tubulin immunoreactivity; the development of the pronephric
kidney, as determined by 6F immunoreactivity; and the pattern of
cranial ganglia differentiation, as determined by Hu immunoreactivity (data
not shown). These structures were also unaffected after injection of
ret morpholino oligonucleotide (data not shown).
By contrast, interfering with GDNF receptor components had strong effects on ENS development. In control embryos, enteric neurons are distributed all along the complete length of the gut (Fig. 5A). Injection of the gfra1a morpholino alone resulted in a reduction in the total number of enteric neurons at 96 hpf, with the loss of neurons particularly apparent at the distal end (Fig. 5B). Injection of the gfra1b morpholino had no effect on the total number of enteric neurons (Fig. 5C); however, co-injection of both gfra1a and gfra1b morpholinos resulted in their nearly total elimination (Fig. 5D). A similar loss of enteric neurons was seen after injection of a ret morpholino oligonucleotide (Fig. 5F). By contrast, there was no statistically significant loss of neurons after injection of gfra2 morpholinos, either alone (Fig. 5E) or additional effects in combination with gfra1 morpholinos (data not shown).
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Discussion |
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Zebrafish enteric precursors can still reach the anterior gut in embryos
when GDNF receptor components have been blocked by morpholino injection, but
cannot migrate posteriorly or expand in number and instead remain in the same
position. These results suggest that GDNF is not involved in the initial
specification of ENS precursors, because they are still able to express
phox2b when Gfra or ret expression is blocked.
Alternatively, Gfra or ret morpholinos might block later
differentiation of ENS neurons after precursor migration; however, we do not
see crestin-positive cells in the distal part of the intestine after
morpholino injection, suggesting that this is not the case. Our results are
consistent with in vitro studies suggesting that GDNF acts as a
chemoattractant for ENS neural crest precursors in their migration along the
intestine (Natarajan et al.,
2002; Young et al.,
2001
). These studies demonstrated that GDNF and Ret are involved
in promoting the directed migration of enteric neural crest precursors along
the gut but not in directing the neural crest's initial migration from the
post-otic region of the hindbrain to the anterior end of the gut. Our results
are also consistent with a role for GDNF in controlling enteric precursor
proliferation (Gianino et al.,
2003
) because we do not see an increased number of enteric neurons
at the anterior end of the intestine.
Despite extensive analysis, we have not detected any changes in apoptotic
cell death by TUNEL analysis (Shepherd et
al., 2001). These results contrast with studies of mice that
harbor a null mutation in ret in which there is an increase in the
number of apoptotic cells at the anterior end of the gut as compared with
wild-type siblings (Taraviras et al.,
1999
), but are consistent with recent findings that GDNF does not
affect ENS cell death (Gianino et al.,
2003
). However, injection of morpholino oligonucleotides are best
considered to cause only a partial loss of function, and thus lack of
apoptosis observed in our system might result from residual GDNF
signaling.
Blocking GDNF receptor function had no other effects besides altering
enteric neuron development. Similarly, overexpression of Gfra mRNA had no
effect. These results extend our previous observations that depletion of GDNF
only affected the ENS (Shepherd et al.,
2001). One possibility is that eliminating Gfra or gdnf
function could be compensated for by other GFR
subunits or by other
GDNF ligands such as neurturin. However, injection of ret morpholinos
also only affected the ENS, making this scenario less likely as Ret is the
common signaling component for these other ligands and receptors. Deficits are
not observed in every expression domain after inactivation of receptors and
ligand in mouse. Although GDNF was originally isolated as a neurotrophic
factor (Lin et al., 1993
),
mice deficient in GDNF and its receptor components exhibit comparatively minor
deficits in the majority of the central and peripheral nervous system
excluding the ENS (Cacalano et al.,
1998
; Enomoto et al.,
1998
; Moore et al.,
1996
; Pichel et al.,
1996
; Sanchez et al.,
1996
).
We propose that there are two predominant GDNF-dependent precursor
populations within the migrating ENS precursors in zebrafish. One population
of ENS precursors expresses gfra1a and ret, while the second
expresses both gfra1a and gfra1b as well as ret. As
we have been unable to carry out successful double label in situ hybridization
experiments with probes for both zebrafish Gfra1 genes, we cannot formally
prove this hypothesis. It is also possible that there is a third population of
precursors that do not express either Gfra1 subunit but express another Gfra
subunit and ret. In embryos injected with both gfra1
morpholinos there is always a small percentage (3-5%) of remaining enteric
neurons, while in embryos injected with ret morpholinos there is
consistently closer to 1% of cells remaining. Although this putative Gfra
subunit might be gfra2, injecting morpholinos against all three
identified zebrafish Gfra subunits still did not bring the number of neurons
down to levels observed after ret morpholino injection (I.T.S.,
unpublished). However, some caution is needed in the interpretation of
phenotypes as morpholinos may not completely eliminate gene function and small
differences among the morpholino injection experiments may instead reflect
differences in efficacy. The small number of enteric neurons remaining after
ret morpholino injection may represent a population of cells that
differentiate independently of ret function, as reported in the
ret knock-out mouse (Durbec et
al., 1996).
Our finding that zebrafish gfra2 is expressed in a small subset of
ENS precursors, and occurs later in development than that of gfra1
expression, is consistent with expression patterns previously described for
gfra2 in mouse (Baloh et al.,
1997; Golden et al.,
1999
; Widenfalk et al.,
1997
). In mice, gfra2 has been shown to be required for
the development of cholinergic neurons in the duodenum
(Rossi et al., 1999
). In
addition our finding that gfra2 expression occurs later in
development than that of gfra1 expression is consistent with that
described for gfra2 in mouse
(Gianino et al., 2003
). It
will be interesting in the future to determine whether the small subset of
cells expressing gfra2 in zebrafish corresponds to a cholinergic
population of enteric neurons.
Phenotypic rescue by co-injection of mRNAs along with morpholino
oligonucleotides suggests that there is functional redundancy among
gfra1a, gfra1b and gfra2. These results are consistent with
previously described experiments in vitro demonstrating that GDNF can bind to
gfra2 and signal through Ret when gfra1 is not present
(Baloh et al., 1997;
Creedon et al., 1997
;
Sanicola et al., 1997
). If our
interpretation is correct, this study would be the first to show that
gfra2 can functionally replace gfra1 in vivo. However, we
cannot determine if we have changed the cell fates of the ENS precursors by
rescuing them with gfra2 mRNA, so that they differentiate as another
type of enteric neuron. The development of markers that recognize different
subsets of neurons in zebrafish will help clarify this issue. It is also
possible that the rescue we observe by overexpression of gfra2 is not
due GDNF signaling through this receptor but may be instead due to endogenous
neurturin present in the intestine that signals through the overexpressed
GFR
2 receptor. Isolation of zebrafish neurturin orthologs(s) and
identifying patterns of expression during embryogenesis will help resolve this
issue.
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ACKNOWLEDGMENTS |
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Footnotes |
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