Laboratory for Vertebrate Axis Formation, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan
* Author for correspondence (e-mail: hibi{at}cdb.riken.jp)
Accepted 13 January 2005
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SUMMARY |
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Key words: Neurogenesis, hairy, enhancer-of-split, Proneural gene, Proneuronal domain
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Introduction |
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As proposed in Drosophila
(Campos-Ortega, 1993),
proneural genes play an important role in neurogenesis. neurog1 is
required for the formation of RB neurons
(Cornell and Eisen, 2002
), and
olig2 is required for the formation of primary motoneurons
(Park et al., 2002
). Within
the proneuronal domains, a subset of cells is selected to become neurons. This
selection is controlled by the Notch-mediated lateral inhibition mechanism
(Appel and Chitnis, 2002
). In
the context of lateral inhibition, cells that express proneural genes, such as
neurog1, at high levels become neurons and simultaneously express the
Notch ligands Delta or Serrate, which activate Notch signaling in neighboring
cells (Appel and Eisen, 1998
;
Chitnis and Kintner, 1996
;
Haddon et al., 1998
;
Ma et al., 1996
). These
neighboring cells express Hairy and Enhancer of Split-related (Her)
transcriptional repressors that inhibit neurogenesis
(Takke et al., 1999
). Although
the mechanism that restricts the number of cells differentiating into neurons
within the proneuronal domains is relatively clear, the mechanism that
represses neurogenesis in the inter-proneuronal domains is largely
unknown.
In Drosophila, Hairy functions differently from Enhancer of Split
[E(spl)], which functions downstream of Notch signaling, in the context of
sensory organ development (Orenic et al.,
1993; Skeath and Carroll,
1991
). hairy is expressed in four longitudinal stripes in
the Drosophila pupal legs, located between stripes expressing the
proneural gene acheate. In the absence of hairy function,
acheate expression expands into the inter-stripe regions that
normally express hairy, fusing the acheate stripes and
resulting in the disorganization of sensory organ bristles
(Orenic et al., 1993
),
indicating that Hairy suppresses the neurogenesis in the inter-stripe region
in the Drosophila leg. hairy expression is controlled by
positional cues, and it is proposed to function as a prepattern gene that
links positional information to the spatial regulation of neurogenesis
(Kwon et al., 2004
;
Orenic et al., 1993
;
Skeath and Carroll, 1991
) A
similar role has been proposed for the Her/Hes-family genes in
vertebrates. Xenopus ESR6e, which is expressed in the superficial
layer of the ectoderm, is involved in protecting the ectodermal layer cells
from becoming neurons (Chalmers et al.,
2002
), and mouse Hes1 represses neurogenesis in the olfactory
placode independent of lateral inhibition
(Cau et al., 2000
). Her5
represses neurogenesis independently of Notch signaling in the
midbrain-hindbrain boundary (MHB) in zebrafish
(Geling et al., 2004
). These
reports suggest that Her/Hes-mediated prepattern mechanisms are involved in
the spatial regulation of neurogenesis in vertebrates.
Bmp activity has been shown to provide positional information for the
posterior primary neurons (Barth et al.,
1999; Nguyen et al.,
2000
). In embryos with mild defects in Bmp signaling, the RB
neurons are absent, and the primary interneuron domains are expanded and
located ventrally. In embryos with severe defects in Bmp signaling, both the
RB neurons and primary interneurons are absent. These studies suggest that the
position and width of the proneuronal and the inter-proneuronal domains are
regulated directly or indirectly by Bmp signaling. It has been reported that
the Xenopus Zic-related gene Zic2 is expressed in the
inter-proneuronal domains and is involved in patterning the proneuronal and
inter-proneuronal domains (Brewster et
al., 1998
). However, none of the zic-related genes
displays a similar expression pattern in zebrafish
(Grinblat and Sive, 2001
) or
any other vertebrate species. There should be other genes that are controlled
by positional information, in which Bmp signaling is involved, and that
spatially control neurogenesis along the dorsoventral axis in the zebrafish
posterior neuroectoderm.
We report that zebrafish her3 and her9, which are expressed in the inter-proneuronal domains, repress the expression of proneural genes in the inter-proneuronal domains and thereby control the formation of the inter-proneuronal domains. her3 and her9 expression is not regulated by Notch signaling, but rather is controlled by positional information, in which Bmp signaling is involved. The data indicate that her3 and her9 function as prepattern genes, which spatially control neurogenesis through a mechanism similar to that involving hairy in Drosophila.
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Materials and methods |
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Plasmids and transcription detection
Expression plasmids for Myc-tagged Her9 (Her9MT), Her9VP16, Her9EnR and
Her3MT were constructed in pCS2+ as previously published
(Bae et al., 2003). Expression
plasmids for the activated form of zebrafish Notch5 (zN5ICD), the antimorphic
form of Xenopus Delta-1 (xDlustu) and ß-galactosidase
have also been published (Bae et al.,
2003
). The RNA for Her9MT, Her9VP16, Her9EnR, Her3MT, zN5ICD or
xDlustu was co-injected with 50 pg of ß-galactosidase RNA into
one blastomere of two- to four-cell stage zebrafish embryos. The embryos were
fixed and stained with X-gal and antisense riboprobes, as reported previously
(Bae et al., 2003
). To
visualize the in situ hybridization, BM purple AP substrate was used as the
substrate for alkaline phosphatase. The neurod4
(Wang et al., 2003
),
her2 (NM_131089), her4
(Takke et al., 1999
),
her12 (NM_205619), her3
(Hans et al., 2004
) and
hes5 (Raya et al.,
2003
) probes were amplified by PCR. pnx
(Bae et al., 2003
),
her9 (Leve et al.,
2001
), olig2 (Park et
al., 2002
), neurog1
(Kim et al., 1997
),
islet1 (Bae et al.,
2003
), deltaA (Haddon
et al., 1998
) and elavl3
(Kim et al., 1996
) were
detected as described previously.
DAPT treatment
Embryos were incubated with 100 µM DAPT from 60% epiboly until the
one-somite stage.
Antisense morpholino oligonucleotides
Morpholino oligonucleotides (MOs) were generated by Gene Tools.
neurog1-MO and olig2-MO have been previously published
(Cornell and Eisen, 2002;
Park et al., 2002
). The other
MOs used here were: her9ATG-MO,
5'-CTCCATATTATCGGCTGGCATGATC-3'; her9SD- MO,
5'-GTGATTTTTACCTTTCTATGCTCGC-3'; her9_5mis-MO (the
lower-case letters indicate mispaired sequences in the control morpholino),
5'-CTCtATATgcTCGGCTGatATGATC-3'; her3-MO1,
5'-CTGTTGGATGCTGTAGCCATTGTCC-3'; and her3-MO2,
5'-TGCAGCCATTGTCCTTAAATGCTCA-3' [the same sequence as published
(Hans et al., 2004
)]. We also
used the standard MO, 5'-CCTCTTACCTCAGTTACAATTTATA-3'. We used two
distinct MOs for her3 (her3-MO1 and her3-MO2) and
her9 (her9ATG-MO and her9SD-MO), and obtained
essentially the same results from them. Neither the her9_5mis control
MO nor the standard MO elicited significant abnormalities in neurogenesis at
the doses used.
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Results |
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Expression of her3 and her9 is independent of Notch signaling
Many Her genes are known to be targets of Notch signaling in various
zebrafish tissues (Henry et al.,
2002; Itoh et al.,
2003
; Oates and Ho,
2002
; Pasini et al.,
2004
; Raya et al.,
2003
; Takke and Campos-Ortega,
1999
; Takke et al.,
1999
). We therefore examined the regulation of her3 and
her9 by the Notch signal. mind bomb (mib) embryos
have a mutation in the gene encoding a ubiquitin ligase for Delta and display
a strong reduction in Notch signaling
(Itoh et al., 2003
). We also
used a chemical compound, DAPT, which is a
-secretase inhibitor that
inhibits Notch signaling by preventing the generation of NotchICD
(Geling et al., 2002
), and
RNAs for an activated form of Notch5 (zN5ICD)
(Bae et al., 2003
) or an
antimorphic form of Xenopus Delta (xDlstu), which inhibits
Notch signaling (Chitnis et al.,
1995
). In the mib mutant embryos and embryos treated with
DAPT, hes5 expression was strongly reduced or abolished, and the
neurod4 expression became homogenous within the proneuronal domains
(Fig. 3E,H,I,L). This is a
typical expression pattern seen in Notch-defective embryos
(Appel et al., 2001
;
Itoh et al., 2003
) and is
consistent with hes5 being a target of Notch signaling
(Raya et al., 2003
). By
contrast, the expression of her3 and her9 was not
significantly affected at the early segmentation stage in these
Notch-defective embryos (Fig.
3F,G,J,K). Expression of zN5ICD strongly induced the ectopic
expression of hes5 and abolished the neurod4 expression
(Fig. 3M,P). By contrast,
expression of xDlstu suppressed the hes5 expression and
induced a homogenous expression of neurod4 within the proneuronal
domains (Fig. 3Q,T). However,
neither zN5ICD nor xDlstu affected the her9 expression
(Fig. 3O,S). The her3
expression was suppressed by zN5ICD, as reported
(Hans et al., 2004
), but was
not affected by xDlstu (Fig.
3N,R). These data indicate that neither the her3 nor the
her9 expression requires Notch signaling at the early segmentation
stage. The expression of her3 and her9 was partly dependent
on Notch signaling at later stages (data not shown).
|
|
Her9 functions as a transcriptional repressor to inhibit neurogenesis
To reveal the functions of her3 and her9, we injected the
her3-MO and/or her9-MO into wild-type or mib mutant
embryos. We used two different MOs for each of Her genes and obtained
essentially the same results (see Materials and methods). We show the data
from the her9ATG-MO and her3-MO1 in Figs
5 and
6. In the
her9-MO-injected embryos, neurod4 was detected in the
inter-proneuronal domains between the RB neurons and primary interneurons,
whereas neurod4 was not expressed in this region in the control
embryos at the early segmentation stage
(Fig. 5A,B,E,F). In the
her9-MO-injected wild or mib mutant embryos, the
neurod4-expressing intermediate and lateral domains were fused and
became homogenous (Fig.
5C,D,G,H) (94%, n=129 for
Fig. 5C,G; and 96%,
n=45 for Fig. 5D,H),
indicating that her9 is required for the suppression of
neurod4 expression in the inter-proneuronal domains between the RB
neurons and the primary interneurons. her9 is not required for
restricting the number of neurod4-expressing cells within the
proneuronal domains. In the her9-MO-injected embryos, the fourth
ventricle in the hindbrain became smaller and the domain containing the
atoh1-expressing neural precursors in the subventricular area was
reduced at the pharyngula stage (88%, n=67 at 30 hours post
fertilization, hpf), compared with the control embryos. The data suggest that
Her9 is involved in the generation or maintenance of neural progenitor cells
in the hindbrain, which are located in the ventricular zone of the fourth
ventricle. As reported previously, injection of the her3-MO induced
ectopic neurog1 expression only in rhombomeres 2 and 4
(Hans et al., 2004) (86%,
n=52 for Fig. 5M,N).
These data suggest redundant roles for Her3 and Her9 in the inter-proneuronal
domains that are located between the primary motoneurons and interneurons, and
in the position posterior to rhombomere 4.
|
|
|
As the ectopic expression of neurog1, deltaA, neurod4 and
elavl3 was detected in the position of the inter-proneuronal domains
of the her3/her9-MO-injected embryos, it is possible that some
population of differentiated cells was increased or ectopically generated in
the position of the inter-proneuronal domains. We examined the expression of
islet1 and tlx3a, which are expressed in the primary
motoneurons and RB neurons, and in the RB neurons, respectively
(Andermann and Weinberg, 2001;
Inoue et al., 1994
;
Langenau et al., 2002
), in the
her3/her9-MO-injected embryos. The islet1 and tlx3a
expression was not affected in the her3/her9 morphant embryos
[Fig. 6R (100%, n=55),
Fig. 6T (100%, n=63)].
Furthermore, there was no prominent change in the expression of the
interneuron markers, lim1 (Nguyen
et al., 2000
), hlx1/2
(Fjose et al., 1994
;
Seo et al., 1999
),
eng1b (Higashijima et al.,
2004
), evx1 (Thaeron
et al., 2000
), vsx1/2
(Passini et al., 1997
),
sax2 (Bae et al., 2004
)
and pax2.1 (Mikkola et al.,
1992
) at the early and late segmentation stages, or at the
pharyngula stage (data not shown). These data suggest that, although ectopic
neurogenesis took place in cells located in the inter-proneuronal domains of
the her3/her9 morphant embryos, they did not undergo differentiation
to specific neuronal cell-types at the early segmentation stage or they
differentiated into neurons that are not recognized by the genetic
markers.
In the her3/her9-MO-injected embryos, neurog1, deltaA, neuroD4 and elavl3 still displayed spotty expression patterns, suggesting that the cells expressing these genes in the inter-proneuronal domains were still subjected to lateral inhibition. Consistent with this, in the her3/her9-MO-injected mib embryos, all of these genes were expressed ubiquitously and homogenously within the neural plate, except in the midline region [Fig. 6D (100%, n=31), Fig. 6H (96%, n=22), Fig. 6L (100%, n=26), Fig. 6P (100%, n=27)], further indicating that Her3/Her9 and Notch signaling play different roles in neurogenesis. Notch signaling functions in lateral inhibition to restrict the numbers of neuronal cells in the proneuronal domains. Her3 and Her9 function as prepattern genes that spatially repress neurogenesis and thereby generate the inter-proneuronal domains.
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Discussion |
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It has previously been reported that her3 is negatively regulated
by Notch signaling (Hans et al.,
2004). We also observed the repression of her3 expression
by the expression of NotchICD or the misexpression of Neurog1. As the
misexpression of neurog1 upregulates the hes5 expression
(Fig. 4C), the suppression of
her3 is likely to be mediated through Delta-Notch signaling. However,
the expression of her3 was not affected in mib mutant,
DAPT-treated or antimorphic Delta-expressing embryos, indicating that Notch
signaling is not required for the endogenous expression of her3. The
situation is similar to that of the expression of her5, which is
proposed to function as a prepattern gene (described below) in the zebrafish
mid-hindbrain boundary. her5 expression is repressed by NotchICD
expression but is not affected in Notch-defective embryos
(Geling et al., 2004
). It is
possible that NotchICD activates a gene cascade(s) that is not activated under
physiological conditions, and renders the neuroectoderm incompetent to express
her3. In any case, the striped expression of her3 and
her9 does not require Notch signaling.
her2, her4, her12 and hes5 are expressed in the
proneuronal domains, where the proneuronal genes and pnx are also
expressed (Fig. 1). The
expression of these Her genes is absent or strongly reduced in Notch-defective
embryos (Fig. 3, data not
shown), indicating that they are strictly regulated by Notch signaling. This
is in contrast to the homogenous expression of neurog1, neurod4 and
deltaA in the Notch-defective embryos
(Fig. 6). As the proneural gene
neurogenin activates the delta expression and subsequently
activates Notch signaling in the neighboring cells
(Takke et al., 1999), the
cells expressing these Her genes are different from those expressing the
proneural genes within the proneuronal domains, although their expression may
overlap transiently during the lateral inhibition. All of these data indicate
that the regulation of her3 and her9, and that of the other
Her genes, is different: the latter are controlled by Notch signaling and the
former by positional information.
her3 and her9 function as prepattern genes
In Drosophila, hairy and enhancer of split have different
roles in neurogenesis. E(spl) functions downstream of Notch signaling
and is involved in the lateral inhibition mechanism, whereas hairy
does not function downstream of Notch signaling, but rather as a prepattern
gene that acts in the interface between positional information and
neurogenesis (Davis and Turner,
2001; Fisher and Caudy,
1998
). hairy shows a periodic longitudinal expression
pattern in the Drosophila leg and determines the position of sensory
organs by repressing the proneural gene acheate
(Orenic et al., 1993
;
Skeath and Carroll, 1991
).
Although the structure of the zebrafish neural plate is very different from
that of the Drosophila leg, the role of Her3 and Her9 in the
zebrafish neural plate is similar to that of Hairy in the Drosophila
leg. We propose that Her3 and Her9 function as prepattern genes and control
the position of the proneuronal and inter-proneuronal domains through a
conserved mechanism, by which Hairy also controls the position of sensory
organs in the Drosophila leg. Among the Her genes in vertebrates,
only a few are reported to function in a similar way. Mouse Hes1 is
expressed in the olfactory placodal domains independent of Mash1 activity,
thus Hes1 expression is suggested to be Notch signal independent
(Cau et al., 2000
). Combined
disruption of Hes1 and the Hes5 gene, whose expression is
dependent on Mash1 and thus possibly controlled by Notch signaling, leads to a
strong upregulation of neurog1 expression in the olfactory epithelium
(Cau et al., 2000
). The
situation is similar to the effect of the combined inhibition of Her3/Her9 and
Notch signaling in the zebrafish posterior neuroectoderm
(Fig. 6). Zebrafish
her5 and him, which are expressed in the MHB, function to
repress neurogenesis in the MHB (Geling et
al., 2004
; Ninkovic et al.,
2005
). Although the mechanism that induces the expression of
her5 and him is not clear, the maintenance of her5
and him1 in the MHB involves Pax2.1, Eng2/3 and Fgf8, which provide
positional information in the MHB (Geling
et al., 2003
; Geling et al.,
2004
; Ninkovic et al.,
2005
). In this sense, the function of her3 and
her9 is similar to that of her5 and him. Mouse
Hes1 and zebrafish her5 function downstream of positional
information related to the anteroposterior (AP) axis and control neurogenesis
in the specific position of the AP axis, whereas her3 and
her9 function as prepattern genes that control neurogenesis in the
context of the dorsoventral (DV) axis in the neuroectoderm. Intriguingly, the
inhibition of Her5 and Him function leads to ectopic neurog1
expression in the MHB, while leaving a neurog1-negative domain in the
lateral region of MHB (Ninkovic et al.,
2005
). her3 is expressed in the lateral region of the MHB
(Fig. 1)
(Hans et al., 2004
). It is
possible that her3 contributes to the repression of proneural genes
in the lateral region of the MHB. her3, her5 and him might
redundantly function in this region, as the inhibition of Her3 function did
not lead to ectopic neurog1 expression in the MHB
(Fig. 5). All of these data
support the role of a subset of Her genes in the prepatterning that functions
downstream of the positional information linked to the DV and AP axes.
We found a difference in the activity of Her3 and Her9 by misexpression studies (Fig. 5). Cells expressing exogenous her3 contributed to the proneuronal domains and repressed the expression of neurod4 in the proneuronal domains. When cells that expressed exogenous her9 were located in the proneuronal domains, neurod4 expression was repressed. However, the majority of exogenous her9-expressing cells was located in the inter-proneuronal domains and did not contribute to the proneuronal domains. These data suggest that Her9 may play an additional role other than the repression of neurogenesis (which it shares with Her3). Her9 may confer on the cell its ability to be localized to the inter-proneuronal domains. Her9 may be involved in the regulation of genes that encode cell-adhesion molecules, or repulsive or attractant molecules. This Her9-mediated activity to localize cells to the inter-proneuronal domains is attributable to the clear separation of the proneuronal and the inter-proneuronal domains.
In amniotes, there is no discernible primary neuron. However, some
Hes/Her genes show a spatially restricted expression pattern in the
spinal cord during a specific developmental period
(Hatakeyama et al., 2004;
Wu et al., 2003
), and these
Hes/Her genes may function in the spatial regulation of neurogenesis
similar to her3 and her9. As observed for mouse
Hes1 in the olfactory placode
(Cau et al., 2000
), a specific
Her/Hes gene may be regulated by the positional information early and
controlled by Notch signaling later. Consistent with this idea, the expression
of her3 and her9 also becomes dependent on Notch signaling
at the later stages (data not shown). Notch-mediated Her9 function may be
involved in later processes of neurogenesis, such as the reduction of
atoh1-expressing neural precursor cells in the hindbrain region
(Fig. 5L).
Role of the inter-proneuronal domains in neurogenesis
Although neurog1, deltaA, neurod4 and elavl3 were
ectopically expressed in the inter-proneuronal domains in the
her3/her9 morphant embryos, we did not detect ectopic/aberrant
expression of the genes that are expressed in primary motoneurons
(islet1 and islet2), primary interneurons (lim1),
RB neurons (islet1, islet2, tlx3a) or of other interneuronal markers
(hlx1/2, eng1b, evx1, vsx1/2, sax2 and pax2.1)
(Fig. 5, data not shown). There
are two possible explanations for this result. First, the cells ectopically
expressing neurog1, deltaA, neurod4 and elavl3 may not
undergo differentiation to specific types of neurons at the early segmentation
stage. Alternatively, these cells may become neurons that are not detected by
the markers we used, or neurons that do not normally exist. The motor-, inter-
and sensory-neuronal markers used in this study correspond to the chick and
mouse genetic markers that cover the most of the neuronal types along the DV
axis, in particular, mid-ventral interneurons, in the spinal cord. Therefore,
it is more likely that these cells do not differentiate into specific types of
neurons until the physiological timing of the differentiation. These data
suggest that Her3 and Her9 are not involved in the specification of neurons.
We also noticed that glial populations, which were marked by Gfap, Blbp (brain
lipid-binding protein) and MBP, were not prominently affected in the
her3/her9 morphant embryos, whereas they were strongly reduced in the
mib mutant embryos (data not shown). These data support the idea that
Her3 and Her9 do not function in the specification of glia versus neurons.
Considering these observations together, Her3 and Her9 are involved in the
delay of the neuronal differentiation, and the inter-proneuronal domains,
which require the function of Her3 and Her9, provide the field that maintains
undifferentiated neural cells.
It is not yet clear what types of neurons and glia are generated from the
inter-proneuronal domains. In Notch-defective embryos, the numbers of primary
neurons are increased and the secondary neurons are strongly reduced
(Appel et al., 2001). This is
consistent with the finding that Notch-defective embryos show increased
elavl3-expressing neuronal cells and a strong reduction of
elavl3-negative cells within the proneuronal domains
(Itoh et al., 2003
)
(Fig. 6). Thus, it is
conceivable that both the primary and the secondary neurons are generated from
the proneuronal domains, and the inter-proneuronal domains give rise to only
the non-neuronal populations - glia. However, inhibition of the
inter-proneuronal domains by her3/her9-MO did not strongly affect the
glial population in the spinal cord (data not shown). Therefore, it is more
likely that the inter-proneuronal domains generate the secondary neurons after
the expression of her3 and/or her9 is reduced or terminated
at later periods. Notch signaling could function in the inter-proneuronal
domains in the absence of Her3 and Her9 function
(Fig. 6). Therefore, Notch
signaling may function in the specification of glia versus neurons in the
inter-proneuronal domains at the later stages. Precise fate mapping of cells
in the inter-proneuronal domains will be required to clarify the fates of the
cells in the inter-proneuronal domains.
In summary, her3 and her9 function as prepattern genes, the expression of which is controlled by positional information linked to the dorsoventral polarity of the posterior neuroectoderm, and their expression spatially controls neuronal differentiation at the beginning of neurogenesis. The Her-mediated prepattern mechanism contributes to the establishment of the central nervous system through the spatially coordinated regulation of neurogenesis.
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ACKNOWLEDGMENTS |
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