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First published online 29 March 2006
doi: 10.1242/dev.02326
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1 Max-Planck Institute for Biophysical Chemistry, Dept of Molecular Cell
Biology, am Fassberg, 37077 Göttingen, Germany.
2 Hubrecht Laboratory, Netherlands Institute for Developmental Biology,
Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
3 Ceinge Biotecnologie Avanzate and SEMM European School of Molecular
Medicine-Naples site, Via Comunale Margherita 482, 80145 Naples, Italy.
4 MRC Centre for Developmental Neurobiology, New Hunt's House, 4th Floor, King's
College London, Guy's Campus, London Bridge, London SE1 1UL, UK.
5 Institute of Genetics and Biophysics `A. Buzzati-Traverso', CNR, Via P.
Castellino 111, 80131 Naples.
6 Clininal Neurophysiology, University of Göttingen, Robert-Koch-strasse
40, 37075 Göttingen, Germany.
Author for correspondence (e-mail:
amansou{at}gwdg.de)
Accepted 13 March 2006
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Sp8 (mBtd), Isthmic organizer, Midbrain, AP patterning, Mouse
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Wurst and Bally-Cuif,
2001; Raible and Brand,
2004). However, each factor is induced independently of the
others. Fgf8 is the only factor known so far that is able to mimic IsO
activity, i.e. exhibiting midbrain and cerebellum inducing properties
(Crossley et al., 1996). Gain-
and loss-of-function experiments revealed a complex combinatorial genetic
network that acts to maintain a functional IsO
(Simeone et al., 2002;
Wurst and Bally-Cuif, 2001;
Raible and Brand, 2004;
Wurst et al., 1994;
McMahon and Bradley, 1990;
Wassarman et al., 1997;
Urbanek et al., 1997;
Reifers et al., 1998;
Schwarz et al., 1999;
Hirata et al., 2001). Thus, in
the anteroposterior (AP) axis, Otx2 and Gbx2 control,
through reciprocal repression, the proper positioning of the IsO and the
establishment of a sharp Fgf8 expression domain at the MHB
(Acampora et al., 1997;
Wassarman et al., 1997;
Rhinn et al., 1999;
Millet et al., 1999;
Broccoli et al., 1999;
Li and Joyner, 2001;
Martinez-Barbera et al.,
2001). However, only in the absence of Pax2, is
Fgf8 expression not detected in the IsO of C3H/He mouse embryos
(Ye et al., 2001).
Interestingly, an Otx2-dependent repressive mechanism is also
required for the proper positioning of sonic hedgehog (Shh)
expression in the ventral midbrain; hence, specifying neuronal progenitors
along the dorsoventral (DV) axis (Puelles
et al., 2003).
The murine ortholog of the Drosophila buttonhead gene, Sp8
(previously known as mBtd), is a zinc-finger transcription factor
belonging to the Sp family and shares with Fgf8 several
domains of expression that have organizer function, including limb and tail
bud, anterior neural ridge and MHB (Wimmer
et al., 1993; Treichel et al.,
2003; Bell et al.,
2003). In addition, Sp8 mRNA is also detected in the
forebrain, midbrain and spinal cord (Fig.
1A-C; data not shown). In the DV axis, Sp8 is expressed
in the basal plate of the spinal cord and in the ventral midbrain
(Fig. 1D; data not shown).
However, Sp8 is not found in the floor plate. At the MHB,
Sp8 is found along the whole neural tube.
(Fig. 1A-C; data not shown). As
reported previously, Sp8-deficient mice suffer from multiple defects
(Treichel et al., 2003;
Bell et al., 2003). In this
study, we have focused on the role of Sp8 in the establishment of the
IsO and the development of the midbrain. Strikingly, the lack of Sp8
activity resulted in a posterior shift of the IsO and ectopic patches of
Fgf8-, Otx2- and/or Wnt1-expressing cells were
found in the ventral part of the rostral hindbrain. As a consequence, midbrain
dopaminergic neurons were detected posterior to the IsO of mouse
Sp8-/-embryos. Moreover, Sp8 was also required to
control cell proliferation in the developing mid- and hindbrain. Our findings
suggest that Sp8 is a new transcription factor required for normal
development of the MHB boundary region.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). All knockout animals were of mixed CD1X129Sv genetic
background. Genotyping was performed by PCR.
In situ hybridization and immunohistochemistry
Embryos were prepared at the appropriate time points and subjected to in
situ hybridization or immunohistochemistry. Whole-mount in situ hybridization
was performed as previously reported
(Treichel et al., 2003). In
situ hybridization on consecutive sections (18 µm) using
digoxigenin-labeled probes was performed according to Moorman et al.
(Moorman et al., 2001).
Immunohistochemistry was carried out according to manufacturer's
recommendation. Antibodies were anti-serotonin (5-hydroxytryptamine) from
Sigma, and TH, Tuj1 and nestin from Chemicon.
BrdU labeling and TUNEL assay
For BrdU labeling, pregnant females of E10.5 and E11.5 were sacrificed 30
and 60 minutes after intraperitoneal injections of BrdU solution (100 µg/g
body weight). Apoptosis was detected according to TUNEL method and performed
following manufacturer's recommendation (Chemicon).
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In
the present analysis, we included only embryos with closed mid- and hindbrain.
Histological examination of sagittal sections of E10.5 to E12.5 embryos
revealed that, in Sp8 mutant embryos, a remarkable overgrowth of the
hind- and the midbrain occurred. This is more pronounced in the ventral part
of the neuroepithelium (Fig.
1F-H). From 12 analyzed embryos at E17.5 only three were found to
develop a cerebellum-like structure. In most embryos at this stage of
development, although the neural tube appeared closed, owing to disturbed
tissue growth, in histological sections specific structures of the mid- and
hindbrain were difficult to identify and were not further analyzed. Therefore,
our analysis will be limited to embryos up to E12.5 of gestation.
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; Wurst and
Bally-Cuif, 2001; Raible and
Brand, 2004). In the absence of Sp8 activity, this
expression boundary was shifted posteriorly, as revealed by whole-mount in
situ hybridization at E8.5, and using Krox20 transcripts to label rhombomere 3
and 5 (Wilkinson et al.,
1989a) (Fig. 2). At
E9.5, this malformation is still evident
(Fig. 3; see Fig.S1 in the
supplementary material) and the expression of genes transcribed at the MHB,
such as Wnt1, Fgf8, En1 and Pax2
(Simeone et al., 2002;
Wurst and Bally-Cuif, 2001;
Raible and Brand, 2004) is
enlarged (Fig. 3, see Fig. S1,
S2 in the supplementary material). At E10.5 the expression boundary where
Otx2 posterior border and Gbx2 anterior border abut seems
normal, as shown on adjacent sagittal sections
(Fig. 4E,G and 4F,H). However,
ectopic patches of Otx2-, Wnt1- and/or Fgf8-expressing cells
are present in the ventral part of the rostral hindbrain at least until E11.5,
as shown on adjacent sagittal sections of E10.5 embryos
(Fig. 4A-D and 4G,H; data not
shown). This patchy expression is barely detectable at E9.5 but clearly
evident at E9.7 (data not shown; see Fig. S2 in the supplementary material).
Furthermore, it appears that the expression territory of Fgf8 is more
dramatically affected and is more widespread. It is expanded in the dorsal
part of the rostral hindbrain as well, and some Fgf8-expressing cell
patches appear to localize in the most posterior midbrain
(Fig. 4, arrowhead). In
addition, in the absence of Sp8 the expression of Fgf8 is
upregulated. This is also true for Wnt1 that exhibits an increased,
patchy and more widespread expression in the ventral midbrain as well
(Fig. 4). It also appears that
most of the ectopic cell patches in the rostral hindbrain express
Fgf8, thus probably overlapping with Wnt1 and/or
Otx2. By contrast, Wnt1- and Otx2-expressing cells
are less abundant and may not always overlap. Finally, rhombomere (r)
patterning is not perturbed in the absence of Sp8, as revealed by the
presence of Krox20 (r3, 5) and hoxa2 (r2, 3, 5)
(Wilkinson et al., 1989a;
Wilkinson et al., 1989b)
(Fig. 2 and data not
shown).
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) and ventral midbrain (dopaminergic neurons)
(Smidt et al., 2004),
respectively. Interestingly, the expression of Pitx3 is found
expanded into the ventral domain of the rostral hindbrain
(Fig. 4J,K, arrowhead).
Although the expression domain of ephrin A5 in the dorsal midbrain of E11.5
and E12.5 embryos is normal, it is up regulated in the ventral portion of the
midbrain, as shown on sagittal sections at E11.5
(Fig. 4M,O, arrows). This led
us to speculate that Sp8 function may only be required in the ventral part of
the neural tube.
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),
Otx12/Otx12
(Acampora et al., 1997) and
Gbx2-/-/Otx12/Otx12
(Martinez-Barbera et al.,
2001) embryos. It is obvious that Sp8 is not
downregulated in embryos lacking Gbx2, Otx2 or both proteins. In fact,
Sp8 is strongly expressed in Gbx2-/- embryos in
the presumptive rostral hindbrain committed to be transformed in an expanded
posterior midbrain (Wassarman et al.,
1997) (Fig.
5B,F,I). In Otx12/Otx12, the
rostral tip of the CNS should correspond to an isthmus-like structure. In this
mutant, Sp8 is detected along all the CNS
(Fig. 5C and G). Finally, in
Gbx2-/-/Otx12/Otx12 mutants,
Sp8 mRNA is found along all the anterior neural plate
(Fig. 5D). Indeed, in this
mutant this territory fails to activate forebrain or midbrain specific
markers, while it shows ubiquitous expression of all the genes transcribed at
the MHB (Martinez-Barbera et al.,
2001; Li and Joyner,
2001). This suggests that in this mutant, which lacks both Gbx2
and Otx2, the rostral neural plate develops as an expanded MHB. Accordingly,
Sp8 is expressed along the entire neural plate. These data indicate
that Sp8 activation is independent of Otx2 and/or
Gbx2 expression, while these genes have a role in restricting the
expression of Sp8 at the MHB region. Whether, this effect is direct
or indirect remains to be elucidated. Taken together, it appears that Sp8 is required for the proper positioning of the MHB and to restrict the expression of gene functions defining the molecular code of this region.
Sp8-deficient embryos display an expansion of the neural tube in the midbrain and in the rostral hindbrain
Histological analysis of the Sp8 mutant embryos revealed a
remarkable increase in the size of the ventral midbrain and rostral hindbrain.
In fact, this leads to a highly reduced aqueduct space
(Fig. 6B,D,F,H,K,M). To explore
the molecular mechanism underlying such a defect, we used several markers,
including Shh, Nkx6.1, Nkx2.2, Wnt5a, Wnt1, Foxa2, Otx1, Otx2, Grg4, Pax6,
Ngn2, Gata2, Phox2a and Pax3, and compared their expression
pattern in wild-type and mutant embryos at E10.5 and E11.5
(Fig. 6 and data not shown). In
the midbrain of Sp8 mutant embryos, the expression of these markers
reflected the overgrowth of the radial neuroepithelium
(Fig. 6), but did not revealed
obvious patterning defects. However, tissue expansion may be a consequence of
cell proliferation and/or survival defects. To distinguish between these
possibilities, BrdU-labeling and TUNEL assay were performed in mutant and
control embryos at E10.5 and E11.5. Although the cell survival does not seem
to be affected, BrdU labeling revealed a higher number of proliferating cells
in the mid- and hindbrain neuroepithelium of mutant embryos when compared with
wild type (Fig. 7A-D). This
suggests that in the absence of Sp8 the control of cell proliferation
is disturbed.
Ectopic midbrain dopaminergic neurons in the rostral hindbrain of Sp8-deficient embryos
To investigate whether the observed neural tube defects in the mid- and
hindbrain could result in perturbations of neuronal differentiation, we
examined the expression of the neuronal markers nestin and ß-III-tubulin
(Tuj1). The results shown in Fig.
8 indicate that, in contrast to control embryos, in the midbrain
of E11.5 Sp8 mutant embryos, nestin-positive cells, present as cell
patches outside of the ventricular zone, still express nestin but are devoid
of Tuj1 signal (Fig. 8D arrow).
This indicates that these cells might correspond to neuronal progenitors that
are not fully differentiated and could suggest that cell differentiation is at
least delayed in the absence of Sp8.
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), in this
brain area of mutant embryos (Fig.
4J,K). Accordingly, the tyrosine hydroxylase protein (TH),
detected by immunohistochemistry on sagittal sections at E11.5, E12.5 and
E17.5, was also found at ectopic sites in the rostral hindbrain of
Sp8-/-embryos (Fig.
9C, arrowheads; Fig.
9H, arrowhead; Fig.
9L, arrowhead; Fig.
9P, arrowhead). We then asked whether serotonergic neurons,
normally positioned directly posterior to the MHB
(Hynes and Rosenthal, 1999;
Ye et al., 1998), were
affected by the lack of Sp8. As shown in
Fig. 9 on the same embryo
sections together with dopaminergic neurons, serotonergic neurons were not
detected at E11.5 (Fig. 9C,D).
However, at E12.5 and E17.5, serotonergic neurons were found
(Fig. 9G, see arrows in
Fig. 9H,O,P) although the
number of 5HT-positive cells is reduced in the area where some ectopic
dopaminergic neurons emerge (Fig.
9H, arrowhead; see arrowheads in
Fig. 9L,P). This suggests that
the development of serotonergic neurons is at least delayed in Sp8
mutant embryos.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Sp8 plays a crucial role in positioning of the IsO
Embryological as well as gain- and loss-of-function studies have
established that there is a signaling center (IsO) at the MHB that is required
for the patterning of the midbrain and cerebellum
(Simeone et al., 2002;
Wurst and Bally-Cuif, 2001;
Raible and Brand, 2004). The
reciprocal repression of the homeobox genes Otx2 and Gbx2 is
responsible for the positioning of the IsO along the AP axis
(Wassarman et al., 1997;
Rhinn et al., 1999;
Millet et al., 1999;
Broccoli et al., 1999;
Li and Joyner, 2001;
Martinez-Barbera et al.,
2001). The boundary of Otx2/Gbx2 expression
plays also a crucial role in defining restricted and juxtaposed expression
areas of two secreted factors, Fgf8 and Wnt1, at the MHB
(Simeone et al., 2002;
Wurst and Bally-Cuif, 2001;
Raible and Brand, 2004;
Wassarman et al., 1997;
Li and Joyner, 2001;
Martinez-Barbera et al., 2001;
Li et al., 2002;
Li et al., 2005). In the
absence of Gbx2 or both Otx2 and Gbx2, the
expression domains of these secreted factors exhibit an overlapping
disorganized pattern. Sp8 loss of function provokes an altered
positioning of the IsO, which can already be detected at E8.5. This
malformation becomes less pronounced after E10.5. Thus, an
Sp8-independent mechanism might be responsible for this process at
later stages of gestation. Interestingly, the analysis of Gbx2
conditional knockout mutant in r1 uncovered a Gbx2-independent
pathway to repress Otx2 after E9
(Li et al., 2002).
Otx2 and Gbx2 were found to be responsible for the proper
positioning of the IsO along the AP axis
(Martinez-Barbera et al.,
2001; Li and Joyner,
2001; Wurst and Bally-Cuif,
2001). Our findings clearly demonstrate that Sp8
activation is independent of Otx2 and/or Gbx2 expression,
although these genes are necessary for restricting the expression of
Sp8 at the MHB. Whether this effect is direct or indirect remains to
be assessed.
The presence of ectopic patches of cells expressing Fgf8 in the ventral and in the dorsal part, but Otx2, and/or Wnt1 in the ventral part of the rostral hindbrain of Sp8 mutant embryos indicates that its role may be restricted to the ventral neuroepithelium, where it might be required to refine cell identity by repressing the expression of Otx2, Wnt1 and Fgf8. This suggests that Sp8 may contribute to sharpen the molecular code of MHB region on the rostral side of the hindbrain.
By contrast, in Gbx2 conditional mutant, where Gbx2
function in r1 was abolished after E8.5, ectopic patches of cells expressing
Fgf8, Otx2 and/or Wnt1 were described to reside in the
dorsal part (alar plate) of r1 (Li et al.,
2002). Altogether, this may indicate that there may be two
separate pathways operating to maintain a normal expression of these genes in
the dorsal and ventral part of the neural tube.
Sp8 may restrict the Fgf8 expression domain at the MHB
The perturbed and overlapping expression domains of Fgf8 and
Wnt1 in Sp8 knockout embryos are consistent with a role for
Sp8 in mediating the segregation of these territories. The
establishment of a juxtaposed Wnt1 and Fgf8 expression areas
at the mes-met border is required for normal function of the IsO
(Wassarman et al., 1997;
Li and Joyner, 2001;
Martinez-Barbera et al., 2001;
Li et al., 2002).
Otx2 and Gbx2 were shown to promote stable expression and to
define the precise positioning of Fgf8 at the MHB
(Wassarman et al., 1997;
Li and Joyner, 2001;
Martinez-Barbera et al., 2001;
Li et al., 2002;
Li et al., 2005). In the
absence of Otx2 and Gbx2, the expression of Sp8 is similar to that
reported for Fgf8 and other genes transcribed at the MHB
(Martinez-Barbera et al.,
2001; Li and Joyner,
2001). By contrast, in Sp8-deficient embryos no
downregulation of the expression of molecular determinant genes of the MHB was
observed over time, as reported in embryos lacking one of these factors
(Simeone et al., 2002;
Wurst and Bally-Cuif, 2001;
Raible and Brand, 2004;
Chi et al., 2003). Sp8 (Sp8)
and Sp9 were reported to positively regulate Fgf8 expression in the limb of
mouse and chick as well as pectoral fin of zebrafish
(Treichel et al., 2003;
Bell et al., 2003;
Kawakami et al., 2004). Given
the highly GC-rich content of the putative promoter region of Fgf8, which
contains Sp1-binding sites, Sp8 was suspected, together with Sp9, to directly
interact with Fgf8 (Kawakami et
al., 2004). Therefore, one attractive interpretation of the
disturbed Fgf8, Wnt1 and Otx2 expression would be the
requirement of Sp8 to sustain a normal Fgf8 expression at
the MHB. This is in agreement with the more remarkable perturbation and spread
of the Fgf8 expression domain observed in the absence of
Sp8, when compared to Wnt1 and Otx2. Our findings
therefore led us to propose that Sp8 is necessary to restrict the
expression of Fgf8 at the MHB. A disturbed Fgf8 expression
was reported to be accompanied with Otx2 and Wnt1 perturbed
expression at the MHB (Wassarman et al.,
1997; Li et al.,
2002). In the limb of Sp8-/-embryos,
Fgf8 transcripts are properly activated but they gradually disappear
during subsequent development, resulting in severe truncations of the
appendages (Treichel et al.,
2003; Bell et al.,
2003; Kawakami et al.,
2004). At the MHB, however, Fgf8 expression is
upregulated and expanded, suggesting a negative regulation of Fgf8 by
Sp8 in this region. Whether Sp8 is directly involved in this
process remains to be assessed.
Sp8 may control cell proliferation in the midbrain and rostral hindbrain
In the mutant midbrain, the expression domain of Wnt1 was
increased and ectopic patches were detected in the ventral part. Wnt1
has been already demonstrated to play a crucial role in midbrain patterning
(McMahon and Bradley, 1990;
Thomas and Capecchi, 1990).
The lack of Wnt1 activity in mice results in the complete loss of
mid- and hindbrain territories (McMahon
and Bradley, 1990; Thomas and
Capecchi, 1990). Interestingly, this factor may also act on cell
proliferation, as evidenced in embryos carrying a knock in of Wnt1 in
the En1 locus (Panhuysen et al.,
2004). In fact, the overgrowth provoked in the rostral hindbrain
by the absence of Sp8 is reminiscent of similar malformations
described in these embryos (Panhuysen et
al., 2004). Thus, it is conceivable that the perturbed and
increased Wnt1 expression could be responsible for the overgrowth
observed in the mid- and hindbrain. Therefore, Sp8 may act as a
negative regulator of Wnt1. However, in the rostral hindbrain the
normally very restricted expression territory of Fgf8 was highly
enlarged, in the absence of Sp8. Therefore, the cell proliferation
defect detected in this rostral hindbrain may be rather related to
Fgf8 that to Wnt1 expression. It was demonstrated that Fgf8
mimics isthmic organizer activity, inducing midbrain and cerebellum, and
controlling anterior hindbrain development
(Simeone et al., 2002;
Wurst and Bally-Cuif, 2001;
Raible and Brand, 2004;
Crossley et al., 1996;
Martinez et al., 1999;
Irving and Mason, 2000).
Furthermore, at the MHB and in other tissues, Fgf8 has been shown to
act on cell survival and/or proliferation
(Chi et al., 2003;
Lee et al., 1997; Trump et
al., 1999; Sun et al., 2002;
Boulet et al., 2004).
Accordingly, this is consistent with an enhanced or even uncontrolled growth
and correlates with the high incidence of exencephaly at the level of the mid-
and hindbrain of Sp8-deficient embryos. Whether the upregulation of
ephrin A5 in the ventral midbrain is responsible for cell proliferation,
tissue segregation or other not yet identified defects is not clear at this
stage. Finally, it can be assumed that the deregulated expression of Fgf8,
Otx2 and Wnt1 in Sp8-deficient embryos is responsible
for the appearance of cells with mesencephalic cell fate in the rostral
hindbrain. Indeed it is well accepted that the expression of Wnt1 and
Otx2 are indicative for a midbrain territory
(Puelles et al., 2004). Fgf8
and Shh were shown to confer dopaminergic neuron identity
(Hynes and Rosenthal, 1999;
Ye et al., 1998). Moreover, it
has been very recently shown that ectopic expression of Wnt1 in the
ventral region of the rostral hindbrain is sufficient to activate in the same
cells Otx2 and convert serotonergic precursors to a dopaminergic fate
(Prakash et al., 2006). Thus,
the induction and differentiation of dopaminergic neurons in the hindbrain of
Sp8 mutant embryos might probably be related to both over expression
of Fgf8 and ectopic activation of Wnt1 and
Otx2.
Finally, the zebrafish Sp/btd homolog Bts1 has been implicated in the
regulation of Pax2 expression (Tallafuss
et al., 2001). Whether Sp8 is involved in this process remains to
be assessed. In summary, our study provides evidence that Sp8 is involved in
positioning of the IsO. This factor is required to maintain a normal
expression of Fgf8, Otx2 and Wnt1 at the MHB. Our findings are consistent with
a role for Sp8 in sharpening the MHB expression code by restricting the
expression of Fgf8, Otx2 and Wnt1 in this area. We further demonstrate that
Sp8 controls cell proliferation in the midbrain and rostral hindbrain. Our
findings sustain the notion that tissue patterning and cell proliferation
and/or survival are tightly co-regulated.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/133/9/1779/DC1
* Member of the DFG Center for Molecular Physiology of the Brain (CMPB) 
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