|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online 13 September 2006
doi: 10.1242/dev.02585
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Laboratory for Vertebrate Axis Formation, Center for Developmental Biology,
RIKEN, Kobe 650-0047, Japan.
2 Laboratory for Animal Resources and Genetic Engineering, Center for
Developmental Biology, RIKEN, Kobe 650-0047, Japan.
3 Vertebrate Body Plan Group, Center for Developmental Biology, RIKEN, Kobe
650-0047, Japan.
Author for correspondence (e-mail:
hibi{at}cdb.riken.jp)
Accepted 11 August 2006
 |
SUMMARY |
|---|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
Key words: Fez (Fezf1) Fez-like (Fezf2), Zinc finger, Forebrain, Telencephalon, Diencephalon, Zona limitans intrathalamica, Thalamus, Prethalamus, Pretectum, Prosomere, Mouse, Transcriptional repressor
|
INTRODUCTION |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
). Among them, Puelles and Rubenstein and colleagues proposed
a neuromeric organization of the forebrain on the basis of the differential
expression of neural marker genes and morphological considerations (the so
called `prosomeric model') (Puelles and
Rubenstein, 1993; Puelles and
Rubenstein, 2003; Rubenstein
et al., 1994; Rubenstein et
al., 1998). In the most recent model
(Puelles and Rubenstein,
2003), the forebrain can be divided into rostral and caudal
regions. The rostral part of the forebrain is the telencephalon and can be
divided into several anatomical and functional territories, including the
pallium, subpallium, preoptic area and hypothalamus. The caudal part of the
forebrain is the diencephalon and can be divided into three transverse
subdivisions known as prosomeres: the prethalamus (also called the ventral
thalamus, p3), thalamus (also known as the dorsal thalamus, p2), and pretectum
(p1). The eminentia thalamic, habenula/epithalamus and posterior commissures
are located dorsally to the prethalamus, thalamus and pretectum,
respectively.
Although the structures of the diencephalic subdivisions become obvious in
mice late in gestation, individual subdivisions can be distinguished by their
expression of genetic markers at the beginning of forebrain patterning.
Members of the Dlx family of genes are expressed in the prethalamus,
Gbx2 is expressed in the thalamus
(Bulfone et al., 1993) and
Ebf1 and Lhx1 are expressed in the anterior and posterior
pretectum, respectively (Barnes et al.,
1994; Garel et al.,
1997). Studies of genetically modified mice have revealed several
genes involved in the patterning and/or development of the diencephalon. These
include Pax6, Otx2, Emx2 and Six3
(Kimura et al., 2005;
Kurokawa et al., 2004a;
Kurokawa et al., 2004b;
Lagutin et al., 2003;
Stoykova et al., 1996;
Suda et al., 2001). However,
it is largely unknown how these genes function in the formation of the
diencephalon subdivisions and what other genes are involved in diencephalon
patterning.
The zona limitans intrathalamica (ZLI) is located on the boundary between
the prethalamus and thalamus (Larsen et
al., 2001; Shimamura et al.,
1995). The ZLI marks the interface between regions of different
ability to respond to inductive signals such as Fgf8 and Shh; for instance, in
neural tissue rostral to the ZLI, Fgf8 induces the expression of
Foxg1 (also called BF-1), but caudal to the ZLI it induces
the expression of En2 (Shimamura
and Rubenstein, 1997). The ZLI also has inductive influences on
the adjacent subdivisions (prethalamus and thalamus). Shh expressed
in the ZLI is involved in development of the prethalamus and thalamus in chick
and zebrafish embryos; inhibition of Shh signaling represses the expression of
the prethalmus and thalamus markers
(Kiecker and Lumsden, 2004;
Scholpp et al., 2006;
Vieira et al., 2005). In chick
embryos, the future position of the ZLI is at the abutting expression domains
of two homeobox genes, Six3 rostrally and Irx3 caudally
(Kobayashi et al., 2002).
Six3 and Irx3 regulate expression of each other, and the
misexpression of Six3 or Irx3 affects the formation of the
prethalamus and thalamus (Braun et al.,
2003; Kobayashi et al.,
2002). Irx3 expression confers competence to respond to
the Fgf8 and Shh inductive signals by expressing thalamus-specific genes
(Kiecker and Lumsden, 2004;
Kobayashi et al., 2002). The
expression of Six3 and Irx3 is regulated by Wnt signaling
(Braun et al., 2003); Wnt1,
Wnt3 and Wnt3a are expressed in the dorsal neural tissue caudal
to the prospective ZLI when the expression of Six3 and Irx3
begins (Braun et al., 2003;
Lagutin et al., 2003;
Roelink and Nusse, 1991;
Salinas and Nusse, 1992).
These reports suggest that Wnt signaling controls the rostro-caudal polarity
of the forebrain through the regulation of Six3 and Irx3,
and the mutually repressive interaction of Six3 and Irx3
controls the position of the ZLI and thus confers differential competence to
respond to the inductive signals to form the prethalamus and thalamus. This
hypothesis is based mainly on the results of misexpression studies and explant
assays in the chicken embryo, but there is little genetic evidence to support
it. Six3-deficient mice display a strong reduction of the neural
tissue rostral to the ZLI, but still express Shh in the ZLI and
rudimentary rostral tissue (Lagutin et
al., 2003), suggesting that other genes may cooperate with or
function parallel to Six3 to determine the position of the ZLI or
control the formation of the rostral diencephalon.
Fez (Fezf1 - Mouse Genome Informatics) and
Fez-like (Fezl, Fezf2 - Mouse Genome Informatics) are
closely related genes that encode transcriptional repressors containing six
C2H2-type zinc fingers and an Eh1 (Engrailed homology 1) repressor motif, and
were originally isolated as anterior neuroectoderm-specific genes in
Xenopus and zebrafish (Hashimoto
et al., 2000; Matsuo-Takasaki
et al., 2000). Orthologs of these two genes exist in the puffer
fish, zebrafish, mouse and human (Hirata
et al., 2006). In mouse and zebrafish, Fez and
Fezl are expressed in overlapping domains in the forebrain during
development (Hashimoto et al.,
2000; Hirata et al.,
2006; Hirata et al.,
2004; Matsuo-Takasaki et al.,
2000). A number of studies have previously investigated the
specific roles of Fez and Fezl in neural development in both
zebrafish and mice. The zebrafish mutant too few (tfu) has a
fezl gene mutation and displays a loss or reduction of dopaminergic
neurons in the hypothalamus (Levkowitz et
al., 2003). Fezl-deficient mice show no abnormalities in
the dopaminergic neurons, but do show abnormal formation of the subplate
neurons and thalamocortical axons, and loss of the fornix/fimbria system
(Hirata et al., 2004).
Fezl has also been shown to be required for the development of
subcerebral projection neurons in layer V of the neocortex
(Chen et al., 2005a;
Chen et al., 2005b;
Molyneaux et al., 2005).
Fez-deficient mice display abnormal olfactory sensory neuronal
projections and olfactory bulb formation
(Hirata et al., 2006). The
relatively weak forebrain phenotypes of Fez and
Fezl-deficient mice suggest that Fez and Fezl
function redundantly in the patterning and development of the forebrain.
Here, we generated mice deficient in both the Fez and Fezl genes. The Fez;Fezl-deficient mice showed defects in the rostro-caudal patterning of the diencephalon. We found that Fez and Fezl redundantly control the rostro-caudal patterning of the diencephalon by repressing the caudal diencephalon fate in the prospective prethalamic region, and that ZLI formation depends on Fez/Fezl-mediated formation of diencephalon subdivisions.
|
MATERIALS AND METHODS |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
). However, comparing the sequences of zebrafish fez
(AB207804) and fezl (AB041824), mouse Fez homolog
(AK014242), and the full-length clone of mouse Fezl (AB042399)
(Hashimoto et al., 2000;
Hirata et al., 2006) revealed
that the mouse gene reported by Matsuo-Takasaki et al. is more similar to
zebrafish fezl than to Xenopus Fez
(Hashimoto et al., 2000;
Matsuo-Takasaki et al., 2000).
Therefore, we refer to AB042399 as mouse Fezl
(Hashimoto et al., 2000;
Hirata et al., 2004), and to
AK014242, which is more similar to Xenopus Fez, as mouse Fez
(Hirata et al., 2006).
Fezl+/- and Fez+/- mice were
previously described (Hirata et al.,
2006; Hirata et al.,
2004). Both the Fez+/- and
Fezl+/- heterozygous mice were originally established in a
129sv genetic background and backcrossed to the C57BL/6 background for several
generations. Fez+/-Fezl+/- double heterozygous
mice were generated by crossing Fez+/- and
Fezl+/- heterozygotes, and were used to generate
Fez-/-Fezl+/-,
Fez+/-Fezl-/- and
Fez-/-Fezl-/- embryos. Mice were housed in an
environmentally controlled room at the Animal Facility of the Center for
Developmental Biology (CDB), RIKEN, under the guidelines for animal
experiments from RIKEN CDB. The genotypes of newborn mice and embryos were
determined by PCR analysis (Hirata et al.,
2006; Hirata et al.,
2004). The primer sequences and PCR conditions are available on
request. Noon of the day on which the vaginal plug was detected was designed
as embryonic day (E) 0.5.
Histological sections and Nissl staining
Brains or embryos were fixed with Carnoy's solution at room temperature
overnight. Specimens were dehydrated and embedded in paraffin. Serial sections
were prepared and stained with 0.1% Cresyl Violet (MERCK).
RNA probes and in situ hybridization
Embryos were fixed overnight at 4°C in 4% paraformaldehyde (PFA) in
PBS. Specimens were gradually dehydrated in ethanol/H2O and stored
in ethanol at -20°C. The protocol for in situ hybridization was described
previously (Hirata et al.,
2006; Hirata et al.,
2004). Single-stranded digoxigenin-UTP-labeled (Roche) RNAs were
used. In situ signals were detected with an anti-digoxigenin antibody and BM
Purple (Roche). For two-color staining of the histological sections in
Fig. 6D, Fez and
Irx1 probes labeled with FITC-UTP and digoxigenin-UTP (Roche), were
used respectively; BM Purple and Fast Red (Roche) were used for staining. For
Fig. 6H-M, Fez and
Fezl probes were labeled with FITC-UTP and Irx1 probe with
digoxigenin-UTP. The hybridized signals for Fez and Fezl
were detected by an alkaline phosphatase-conjugated anti-Fluorescein antibody
(Roche) and BM Purple, and those for Irx1 were detected by a
peroxidase-conjugated anti-digoxigenin antibody (Roche) and tyramide signal
amplification system (TSA-Plus Fluorescein System, PerkinElmer). The precise
protocols for in situ hybridization are available on request. The probes were:
Dlx1 (Bulfone et al.,
1993), Gbx2 (Bulfone
et al., 1993), Lhx1
(Fujii et al., 1994),
Ebf1 (Garel et al.,
1997), Sox14
(Hashimoto-Torii et al.,
2003), Emx2 (Yoshida
et al., 1997), Pax6
(Walther and Gruss, 1991),
Shh (Echelard et al.,
1993), Tcf4
(Ishibashi and McMahon, 2002),
Lhx5 (Nakagawa and O'Leary,
2001), Fgf8 (Crossley
and Martin, 1995), Irx1 (a gift of T. Ogura),
Wnt3a (Takada et al.,
1994), En2 (Joyner
and Martin, 1987), Foxg1
(Tao and Lai, 1992),
Fez (Hirata et al.,
2006) and Fezl
(Hirata et al., 2004). In situ
hybridization images were taken using an AxioPlan2 microscope or a SteREO
Lumar V12, equipped with an AxioCam CCD camera (Zeiss). Figures were assembled
using AxioVision version 4.3 and Adobe Photoshop CS2.
Generation and genotyping of transgenic mice
We isolated an approximately 8.2 kbp enhancer/promoter region of
Fezl from the bacterial artificial chromosome clone containing the
coding and non-coding regions of Fezl
(Hirata et al., 2004). To make
the Fezl enhancer/promoter-driven lacZ
(ß-galactosidase) transgene constructs, the 8.2 or 2.7 kbp
enhancer/promoter region of Fezl was connected to lacZ cDNA
at the position of the translational initiation site of Fezl
(Fezl8.2p-lacZ, Fezl2.7p-lacZ). For misexpression of Fezl,
its 2.7 kbp enhancer/promoter was connected to Fezl or Fez
cDNA, followed by internal ribosomal entry site (IRES)-Gap43-Venus
(Fezl2.7p-Fezl-IRES-Venus and Fezl2.7p-Fez-IRES-Venus)
(IRES-Gap43-Venus, a gift of Y. Yoshihara). Similarly, Otx2 FM
enhancer (1.4 kbp) (Kurokawa et al.,
2004a) and the promoter of mouse heat shock protein 68 (pHsp68)
(Sasaki and Hogan, 1996) were
connected to Fezl cDNA and IRES-Gap43-Venus
(OtxFM-Hsp68-FeZLIRES-Venus). The transgene-derived Fezl
expression was monitored as Venus expression with an epifluorescence
microscope AxioPlan2. Genotypes of the transgenic mice were analyzed by PCR
with 5'-AAACCCTGGCGTTACCCAACT-3' and
5'-ACGACAGTATCGGCCTCAGGA-3' for the lacZ reporter lines,
5'-TGTGTCTGCAGAGAGTGCTGGCCTG-3' and
5'-CTGGCTGCTGCTCACCCCAAGCTTT-3' for the
Fezl2.7p-Fezl-IRES-Venus and OtxFM-Hsp68-Fezl-IRES-Venus
lines and 5'-AAAACGTATTTAGCCGAAAGGAAT-3' and
5'-ACTTTACACACGAAGGGTCTGG-3' for the
Fezl2.7p-Fez-IRES-Venus lines. Transient transgenic embryos were
generated and ß-galactosidase staining was performed as described
previously (Kimura et al.,
1997; Kimura et al.,
2000).
|
|
RESULTS |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
; Hirata et al.,
2004) and generated mice deficient homozygously or heterozygously
in the Fez and/or Fezl genes
(Fig. 1).
Fez-/-Fezl+/- embryos showed a small olfactory
bulb at E15.5 (Fig. 1F), as
Fez-/- embryos do
(Hirata et al., 2006).
Fez+/-Fezl-/- embryos showed defects in the
formation of the dentate gyrus at E17.5
(Fig. 1K).
Fez-/-Fezl-/- embryos showed more severe
phenotypes in the olfactory bulb and hippocampus: nearly complete loss of the
olfactory bulb, stronger reduction of the CA3 region and loss of dentate gyrus
in the hippocampus. Fez-/-Fezl-/- embryos also
showed impaired neocortex formation. In addition,
Fez-/-Fezl-/- embryos were found to have
abnormalities in the formation of diencephalon, including loss of prethalamus
and a strong reduction of the thalamus in size
(Fig. 1H, arrowheads). These
diencephalon defects were not observed in the
Fez-/-Fezl+/- and
Fez+/-Fezl-/- embryos
(Fig. 1F,G), indicating a
redundant role of Fez and Fezl in the formation of
diencephalon. Although it is intriguing to study the phenotypes of the
olfactory bulb, hippocampus and neocortex in these mice, we restricted the
focus of our study to the role of Fez and Fezl in
diencephalon formation.
|
Loss of the prethalamus and expansion of the caudal diencephalon in Fez, Fezl double mutants
We next examined the Fez;Fezl-deficient mice with various genetic
markers at E12.5. Dlx1 is expressed in the ventral telencephalon
(including the medial and lateral ganglionic eminences), hypothalamus and
prethalamus, but not the thalamus (Fig.
2A) (Bulfone et al.,
1993; Stuhmer et al.,
2002). In the Fez-/-Fezl-/-
embryos, Dlx1 expression was maintained in the ganglionic eminences
and hypothalamus, but was completely absent in the diencephalon
(Fig. 2D). Gbx2 is
expressed strongly in the thalamus and weakly in the ganglionic eminences
(Fig. 2E)
(Bulfone et al., 1993). In
Fez-/-Fezl-/- embryos, Gbx2 expression
in the thalamus was markedly reduced and shifted rostrally, but not abrogated
(Fig. 2H). Lhx1 is
expressed in the posterior pretectum and ZLI
(Fig. 2I)
(Barnes et al., 1994;
Fujii et al., 1994;
Mastick et al., 1997;
Suda et al., 2001). Although
its expression in the posterior pretectum was not affected significantly, we
found that it was not expressed in the ZLI in the
Fez-/-Fezl-/- embryos
(Fig. 2L). Ebf1 is
expressed in the anterior pretectum (Garel
et al., 1997; Suda et al.,
2001) (Fig. 2M),
and its expression was expanded rostrally in the
Fez-/-Fezl-/- embryos
(Fig. 2P). Sox14 is
expressed in the rostral part of the thalamus
(Hashimoto-Torii et al., 2003)
(Fig. 2Q), and its expression
was absent in the Fez-/-Fezl-/- embryos
(Fig. 2T). Neither the
Fez-/-Fezl+/- nor the
Fez+/-Fezl-/- embryos showed abnormal
expression of Dlx1, Gbx2, Lim1, Ebf1 or Sox14 at E12.5
(Fig. 2B,C,F,G,J,K,N,O,R,S),
further confirming the strictly redundant function of Fez and
Fezl in the diencephalon patterning. The data indicate that, in the
Fez-/-Fezl-/- embryos at E12.5, the prethalamus
did not form, the thalamus formed at a reduced size and the anterior pretectum
expanded rostrally, suggesting that Fez and Fezl play an
important role in rostro-caudal patterning of the diencephalon. Although we
detected Tuj-1-postive postmitotic neurons in the thalamus at E11.5 in the
Fez-/-Fezl-/- embryos (data not shown), the
Fez-/-Fezl-/- embryos failed to form the
rostral part of the thalamus (Sox14-positive region), the formation
of which is known to depend on Shh from the ZLI
(Hashimoto-Torii et al.,
2003). The data indicate that the redundant function of
Fez and Fezl also controls the rostro-caudal patterning of
the thalamus directly or indirectly.
|
|
), and its expression domain was reduced in the
Fez-/-Fezl-/-, but not in the
Fez-/-Fezl+/- or
Fez+/-Fezl-/- embryos
(Fig. 3B-D). This is consistent
with the reduction of the neocortex and loss of the hippocampus, as
Emx2 (and Emx1) is required for neocortical and hippocampal
formation (Pellegrini et al.,
1996; Yoshida et al.,
1997). Pax6 is initially expressed in the dorsal
telencephalon and diencephalon, but its expression in the thalamus is reduced
by E10.5 (Fig. 3E)
(Mastick et al., 1997;
Stoykova et al., 1996;
Stoykova and Gruss, 1994;
Warren and Price, 1997). The
rostral and caudal limits of Pax6 expression in the diencephalon were
the same in Fez-/-Fezl-/- embryos as in wild
type, Fez-/-Fezl+/- and
Fez+/-Fezl-/- embryos
(Fig. 3E-H). However, the
Pax6 expression in the thalamus was not reduced in the
Fez-/-Fezl-/- embryos
(Fig. 3H), suggesting that the
rostro-caudal patterning, but not the formation of the diencephalon, was
affected in the Fez-/-Fezl-/- embryos. The
Dlx1 expression in the prethalamus was already absent at E10.5 in
Fez-/-Fezl-/- embryos
(Fig. 3L), indicating that the
prethalamus was not established. Shh is expressed in the anterior
entopeduncular area (AEP) of the ventral telencephalon, the basal plate of the
entire neuroectoderm (including the hypothalamus) and the ZLI
(Fig. 3M)
(Echelard et al., 1993;
Ericson et al., 1995) in the
wild-type, Fez-/-Fezl+/- and
Fez+/-Fezl-/- embryos, but its expression in
the ZLI was absent in the Fez-/-Fezl-/- embryos
(Fig. 3M-P), suggesting that
the ZLI was not established in the absence of Fez and Fezl.
Tcf4 is expressed at a high level in the thalamus and pretectum
(Cho and Dressler, 1998;
Korinek et al., 1998) in the
wild type, Fez-/-Fezl+/- and
Fez+/-Fezl-/- embryos, whereas the
Tcf4-high domain expanded rostrally in the
Fez-/-Fezl-/- embryos
(Fig. 3Q-T). Lhx5 is
expressed in the prethalamus in the wild type,
Fez-/-Fezl+/- and
Fez+/-Fezl-/- embryos
(Fig. 3U-W)
(Nakagawa and O'Leary, 2001),
but was not detected in the Fez-/-Fezl-/-
embryos (Fig. 3X). Taking these
data together, loss of the prethalamus and expansion of the caudal
diencephalon took place before E10.5, and the ZLI, the prethalamus-thalamus
boundary, was not established in the absence of Fez and
Fezl.
Fez and Fezl are involved in early rostro-caudal forebrain patterning
Formation and patterning of the forebrain are regulated by transcription
factors and inductive signals expressed in specific rostro-caudal positions in
the neuroectoderm at the beginning of neurogenesis and neural patterning. We
examined gene expression in wild type and
Fez-/-Fezl-/- embryos at around E9.5. The
expression domain of Emx2 and Pax6 in the dorsal
telencephalon was already reduced in the
Fez-/-Fezl-/- embryos at E9.5
(Fig. 4A-D). Fgf8 was
expressed in the commissural plate, the infundibulum of the hypothalamus, the
dorsal part of the prethalamus (eminentia thalami) and the mid-hindbrain
boundary (isthmus) in wild-type embryos
(Fig. 4E)
(Crossley and Martin, 1995),
whereas its expression in the prospective prethalamus was specifically absent
in the Fez-/-Fezl-/- embryos
(Fig. 4F). Wnt3a is
expressed in the dorsal neural tissue caudal to the prospective ZLI
(Fig. 4G)
(Roelink and Nusse, 1991;
Salinas and Nusse, 1992), and
the rostral limit of its expression was shifted rostrally in the
Fez-/-Fezl-/- embryos
(Fig. 4H). En2
expression in the midbrain was not affected in the
Fez-/-Fezl-/- embryos
(Fig. 4I,J)
(Joyner and Martin, 1987). All
these data indicate that the diencephalon patterning was already affected when
neural patterning began. In chick, ZLI is positioned on the boundary of the
expression domains of Six3 and Irx3, and Six3 and
Irx3 can repress the expression of each other, possibly determining
the position of the ZLI (Kobayashi et al.,
2002). In mouse, Irx1 and Irx3 display a similar
expression profile in the neuroectoderm, but the rostral limit of the
Irx1 expression is more rostral than that of Irx3 and is
positioned on the ZLI (Bosse et al.,
1997; Cohen et al.,
2000). We examined the expression of Irx1 in wild-type
and double-mutant embryos (Fig.
5). The rostral limit of Irx1 expression had shifted
rostrally at E9.0, suggesting that Fez and Fezl are required
to repress the Irx1 expression in the rostral diencephalon. We found
that the expression of Six3 was not affected at E8.5 and 9.5
(Fig. 5I,J, data not shown for
E8.5), suggesting that the expansion of the caudal diencephalon in the
Fez-/-Fezl-/- embryos was independent of
Six3.
|
;
Hirata et al., 2004)
(Fig. 6B). At E12.5,
Fez and Fezl are expressed in the pallium, septum,
hypothalamus and prethalamus, which are located rostral to the ZLI
(Hirata et al., 2004;
Hirata et al., 2006). We
examined the early expression domains of Fez and Fezl, and
compared them with those of Irx1. At E8.5, the expression domain of
Fez was slightly wider than that of Fezl
(Fig. 6A,B), and the caudal
limit of Fez abutted the rostral limit of Irx1
(Fig. 6D). Two-color staining
for Fez or Fezl with Irx1 revealed that the
expression of Fez and Fezl was strictly rostral to that of
Irx1 at E9.5 (Fig.
6H-M).
Fez and Fezl repress the caudal diencephalon fate
The expression of Fez and Fezl suggests that Fez
and Fezl function in the region rostral to the ZLI and repress the
caudal diencephalon fate. To address this issue, we misexpressed Fez
or Fezl caudal to the ZLI using the Fezl gene
enhancer/promoter or the Otx2 forebrain-midbrain (FM) enhancer. We
constructed ß-galactosidase (lacZ) reporter genes in which the
lacZ gene was connected to the 8.2 kbp or 2.7 kbp enhancer/promoter
region upstream of the translational initiation site of the mouse
Fezl gene (Fig. 7A),
and examined the lacZ expression in the resulting transgenics
(Fig. 7B-D). The 8.2 kbp
Fezl enhancer/promoter recapitulated the expression in the forebrain
at E8.5 (Fig. 7B). By contrast,
the 2.7 kbp Fezl enhancer/promoter (Fezl2.7p) drove the
lacZ expression in a wider region at E8.5 than the 8.2 kbp promoter
did (Fig. 7C). At E9.5 in
transgenic mice with the 2.7 kbp Fezl promoter-lacZ, lacZ
activity was detected in a wider region than the endogenous Fezl
expression (Fig. 7D),
indicating that the enhancer/promoter could drive expression caudal to the
ZLI. Using Fezl2.7p, we expressed Fezl or Fez cDNA
ectopically in the caudal diencephalon. We monitored the exogenous
Fezl or Fez expression with a green fluorescence protein
variant, Venus (IRES-Venus) (Nagai et al.,
2002). In embryos with the Fezl2.7p-Fezl-IRES-Venus or
Fezl2.7p-Fez-IRES-Venus transgene, the expression of Foxg1
in the telencephalon (Tao and Lai,
1992) was not affected, but the expression of Irx1 was
reduced and its rostral limit was shifted caudally at E9.5
(Fig. 8B,C,S). The rostral
limit of Irx1 corresponded to the caudal limit of the exogenous
Fezl-IRES-Venus expression in these transgenic embryos
(Fig. 8A,R). Similarly, in the
Fezl2.7p-Fezl-IRES-Venus and Fezl2.7p-Fez-IRES-Venus
transgenic embryos, the Tcf4-high domains, corresponding to the
thalamus and pretectum, were strongly reduced at E10.5
(Fig. 8E,F,U). In transgenic
embryos strongly expressing Fezl, Dlx1 expression expanded caudally
(n=1/2), with Gbx2 expression being prominently reduced
(n=2/3) at E12.5 (Fig.
8,M,N,P,Q). Furthermore, the misexpression of Fezl by
Fezl2.7p abolished Shh expression in the ZLI and ventral
diencephalon (n=2/4) or shifted the ZLI-specific Shh
expression caudally (n=2/4) at E10.5
(Fig. 8H,I,K). The
misexpression of Fez by Fezl2.7p abolished Shh
expression in the ZLI (data not shown, n=1/1). We also used an
Otx2FM enhancer, which can drive a transgene in the midbrain,
diencephalon and archicortex (Kurokawa et
al., 2004a), to misexpress Fezl. Fezl misexpression under
this enhancer also suppressed Irx1 expression without affecting
Foxg1 expression (Fig.
8W). These data indicate that Fez and Fezl can
suppress the caudal diencephalon fate.
|
|
DISCUSSION |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
; Hirata et al.,
2004). Fez and Fezl, respectively, begin
expression at E8 and 8.5 (Fig.
6) (Hirata et al.,
2006; Hirata et al.,
2004). We detected a defect in the rostro-caudal polarity of the
diencephalon: rostral expansion of the Irx1 expression at E9.0,
indicating that the Fez/Fezl-mediated diencephalon patterning starts
soon after the onset of Fez and Fezl expression. Marker
analyses showed that the prethalamic region was not established; instead, the
caudal diencephalon, which includes the thalamus and the anterior pretectum,
expanded rostrally in the double-mutant embryos (Figs
3,
4). There are two possible
explanations for the phenotype of Fez;Fezl-deficient embryos: (1)
transformation of the prethalamus into the thalamus; and (2) truncation of the
prethalamus and the rostral shift of the caudal neural tissue. We found that
the size of the diencephalon was not significantly different in the
double-mutant embryos, compared with the wild-type embryos, when the
rostro-caudal patterning in the diencephalon became abnormal (Figs
3,
4). Our data strongly suggest
that the transformation of the prethalamus into the caudal diencephalon takes
place during early neural patterning in the absence of Fez and
Fezl (Fig. 9). Future
studies including the Cre-loxP-mediated cell-fate mapping of Fez and
Fezl-expressing cells will definitely clarify this issue. The
misexpression of Fez or Fezl suppressed the caudal
diencephalon fate and induced the expression of Dlx1, which normally
marks the prethalamus, in the region caudal to the ZLI
(Fig. 8). All of these data
indicate that Fez and Fezl function to repress the caudal
diencephalon fate and establish the prethalamus fate
(Fig. 9). Although the caudal
diencephalon was initially expanded, the thalamus eventually became smaller
and the rostral part of the thalamus was missing in the
Fez;Fezl-deficient embryos at E12.5 (Figs
1,
2). The later development of
the thalamus is known to be dependent on inductive signals from the ZLI
(discussed below). The loss of the ZLI in the Fez;Fezl-deficient
embryos secondarily affects the development of the thalamus in these embryos
(Fig. 9).
Both FEZ and FEZL contain an Eh1 repressor motif, which interacts with the
Groucho/TLE family of transcriptional co-repressors
(Bae et al., 2003;
Kobayashi et al., 2001;
Muhr et al., 2001;
Shimizu et al., 2002). The Eh1
repressor motif of zebrafish Fezl is required for at least part of the Fezl
function in this animal (Levkowitz et al.,
2003), suggesting that FEZ and FEZL function as transcriptional
repressors to regulate patterning of the diencephalon. In the
Fez;Fezl double-mutant embryos, expression domains of the caudal
diencephalic genes, such as Irx1, Wnt3a and Tcf4
(high-expression domain), expanded rostrally, and misexpression of
Fez or Fezl caudal to the ZLI inhibited the expression of
Irx1 and Tcf4 in the caudal diencephalon (Figs
4,
5,
8). Fez and
Fezl are expressed in the region rostral to the rostral limit of
Irx1 expression, which marks the prospective position of the ZLI.
Taking these findings together, we conclude that FEZ and FEZL directly or
indirectly repress the caudal diencephalon genes in the rostral diencephalon
(Fig. 9). Identification of
target genes for FEZ and FEZL and/or chromatin immunoprecipitation assay of
FEZ/FEZL-binding genomic fragments will help to clarify the precise mechanism
by which Fez and Fezl control the rostro-caudal polarity of
diencephalon.
|
) and
functions as a transcriptional repressor
(Kobayashi et al., 2001;
Lopez-Rios et al., 2003;
Zhu et al., 2002).
Six3-deficient mice show strong reduction of the neural tissue
rostral to the ZLI (Lagutin et al.,
2003). Six3 negatively controls the expression of
Irx3 in chick (Kobayashi et al.,
2002). These reports suggest that the role of Fez and
Fezl in diencephalon patterning is similar to that of Six3,
at least in part. However, Six3-deficient mice have rudimentary
tissue rostral to the ZLI, and express Shh in the ZLI
(Lagutin et al., 2003), and
Fez;Fezl-double mutants display complete loss of the prethalamus and
ZLI, implying there is a difference between the functions of Six3 and
Fez/Fezl. We examined the expression of Six3 in the
Fez-/-Fezl-/- embryos, but did not observe any
significant alteration in the Six3 expression at E8.5 and 9.5
(Fig. 5, data not shown for
E8.5), suggesting that Six3 does not function downstream of
Fez and Fezl. Rather, Six3 may function upstream
of, or in parallel with, Fez and Fezl. Future studies
examining Fez and Fezl expression in Six3-deficient
embryos and combinatory gene disruption of Six3 and Fez
and/or Fezl will clarify this issue.
How Fez and Fezl expression is regulated remains unclear.
There are several genes with expression domains that overlap with those of
Fez and Fezl. They include Pax6, Emx1/2, Dlx1/2/5/6
and Otx1/2 in addition to Six3
(Bulfone et al., 1993;
Oliver et al., 1995;
Simeone et al., 1992a;
Simeone et al., 1993;
Simeone et al., 1992b;
Stuhmer et al., 2002;
Walther and Gruss, 1991).
These genes might be involved in the regulation of Fez and
Fezl expression. The expression of zebrafish fezl and
Xenopus Fez is negatively regulated by Wnt signaling
(Hashimoto et al., 2000) (M.
Matsuo-Takasaki, personal communication). Thus, the initial expression of
Fez and Fezl may be controlled by the rostro-caudal polarity
information, in which Wnt signaling is strongly involved
(Niehrs, 2004). In this
context, Fez and Fezl may link the rostro-caudal polarity
information to the subdivision formation in the diencephalon.
Role of Fez and Fezl in formation of the ZLI
The ZLI position is predicted as abutting the expression domains of rostral
Six3 and caudal Irx3 in chick embryos
(Kobayashi et al., 2002). We
found that it is predicted by the expression of rostrally expressed
Fez and Fezl and caudally expressed Irx1 in mouse
embryos (Fig. 6). Furthermore,
the deficiency of both Fez and Fezl led to loss of the ZLI,
and misexpression of Fez or Fezl could inhibit ZLI formation
or shift its position (Figs 3,
8). These data indicate that
Fez and Fezl are involved in the formation and position of
the ZLI. The ZLI initially forms as a wedge-shaped structure on the boundary
between the prethalamus and thalamus, which is characterized by a gap in
Lfrg expression; subsequently, it collapses to a narrow band
(Zeltser et al., 2001). It is
not clear whether Fez and Fezl are expressed in the
prospective ZLI domain, although they are not expressed in the ZLI at E12.5
(Hirata et al., 2006;
Hirata et al., 2004).
Fez and Fezl are expressed in the prethalamus, but they do
not induce Shh expression there. Thus, Fez and Fezl
are not likely to be instructive factors, but rather to function as permissive
factors. Alternatively, Fez and Fezl may regulate ZLI
formation indirectly and non-cell-autonomously by controlling formation of the
prethalamus. Grafting experiments in chick embryos show that Shh
expression is induced in the interface between the prechordal (rostral to ZLI)
and epichordal plate neuroepithelia (caudal to ZLI)
(Vieira et al., 2005),
suggesting that an interaction between prethalamus and thalamus is involved in
the induction of ZLI. The complete loss of the prethalamus in the
Fez-/-Fezl-/- embryos might lead to the loss of
non-cell-autonomous signals (secreted or membrane-associated molecules) from
the prethalamus and subsequently result in loss of the ZLI. In this scenario,
formation of the ZLI may be controlled by signals from both the prethalamus
and caudal diencephalon. Zli formation is also dependent on Shh emanating from
the basal plate (Zeltser,
2005). Thus, Fez and Fezl cooperate with Shh
from the basal plate to determine the position of the ZLI.
|
|
; Scholpp et al.,
2006; Vieira et al.,
2005). Shh expressed in the ZLI is involved in the formation and
patterning of the thalamus (Kiecker and
Lumsden, 2004; Scholpp et al.,
2006; Vieira et al.,
2005). In the Fez-/-Fezl-/-
embryos, the Shh-expressing ZLI was not established, and the thalamus
became small, although the caudal diencephalon initially expanded rostrally.
Therefore, the reduced thalamus is likely to be a secondary consequence of the
loss of the ZLI in the Fez-/-Fezl-/- embryos
(Fig. 9). Consistent with this,
the Fez-/-Fezl-/- embryos showed complete loss
of the Sox14 expression (Fig.
2), which is dependent on Shh from the ZLI
(Hashimoto-Torii et al.,
2003). Our findings support the inductive role of the ZLI in
thalamus development. In summary, Fez and Fezl are essential factors for development of the forebrain, playing an important role in rostro-caudal patterning of the diencephalon and in ZLI formation. The involvement of repressor-type zinc-finger proteins in forebrain formation provides a new mechanism for the formation and patterning of the forebrain subdivisions.
|
ACKNOWLEDGMENTS |
|---|
|
Footnotes |
|---|
Present address: Center for Neuroscience Research, Children's National
Medical Center, Washington DC 20010-2970, USA
|
REFERENCES |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
Bae, Y. K., Shimizu, T., Yabe, T., Kim, C. H., Hirata, T.,
Nojima, H., Muraoka, O., Hirano, T. and Hibi, M. (2003). A
homeobox gene, pnx, is involved in the formation of posterior neurons in
zebrafish. Development
130,1853
-1865.
Barnes, J. D., Crosby, J. L., Jones, C. M., Wright, C. V. and
Hogan, B. L. (1994). Embryonic expression of Lim-1, the mouse
homolog of Xenopus Xlim-1, suggests a role in lateral mesoderm differentiation
and neurogenesis. Dev. Biol.
161,168
-178.[CrossRef][Medline]
Bosse, A., Zulch, A., Becker, M. B., Torres, M., Gomez-Skarmeta,
J. L., Modolell, J. and Gruss, P. (1997). Identification of
the vertebrate Iroquois homeobox gene family with overlapping expression
during early development of the nervous system. Mech.
Dev. 69,169
-181.[CrossRef][Medline]
Braun, M. M., Etheridge, A., Bernard, A., Robertson, C. P. and
Roelink, H. (2003). Wnt signaling is required at distinct
stages of development for the induction of the posterior forebrain.
Development 130,5579
-5587.
Bulfone, A., Puelles, L., Porteus, M. H., Frohman, M. A.,
Martin, G. R. and Rubenstein, J. L. (1993). Spatially
restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the
embryonic day 12.5 mouse forebrain defines potential transverse and
longitudinal segmental boundaries. J. Neurosci.
13,3155
-3172.[Abstract]
Chen, B., Schaevitz, L. R. and McConnell, S. K.
(2005a). Fezl regulates the differentiation and axon targeting of
layer 5 subcortical projection neurons in cerebral cortex. Proc.
Natl. Acad. Sci. USA 102,17184
-17189.
Chen, J. G., Rasin, M. R., Kwan, K. Y. and Sestan, N.
(2005b). Zfp312 is required for subcortical axonal projections
and dendritic morphology of deep-layer pyramidal neurons of the cerebral
cortex. Proc. Natl. Acad. Sci. USA
102,17792
-17797.
Cho, E. A. and Dressler, G. R. (1998). TCF-4
binds beta-catenin and is expressed in distinct regions of the embryonic brain
and limbs. Mech. Dev.
77, 9-18.[CrossRef][Medline]
Cohen, D. R., Cheng, C. W., Cheng, S. H. and Hui, C. C.
(2000). Expression of two novel mouse Iroquois homeobox genes
during neurogenesis. Mech. Dev.
91,317
-321.[CrossRef][Medline]
Crossley, P. H. and Martin, G. R. (1995). The
mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions
that direct outgrowth and patterning in the developing embryo.
Development 121,439
-451.[Abstract]
Echelard, Y., Epstein, D. J., St-Jacques, B., Shen, L., Mohler,
J., McMahon, J. A. and McMahon, A. P. (1993). Sonic hedgehog,
a member of a family of putative signaling molecules, is implicated in the
regulation of CNS polarity. Cell
75,1417
-1430.[CrossRef][Medline]
Ericson, J., Muhr, J., Placzek, M., Lints, T., Jessell, T. M.
and Edlund, T. (1995). Sonic hedgehog induces the
differentiation of ventral forebrain neurons: a common signal for ventral
patterning within the neural tube. Cell
81,747
-756.[CrossRef][Medline]
Fujii, T., Pichel, J. G., Taira, M., Toyama, R., Dawid, I. B.
and Westphal, H. (1994). Expression patterns of the murine
LIM class homeobox gene lim1 in the developing brain and excretory system.
Dev. Dyn. 199,73
-83.[Medline]
Garel, S., Marin, F., Mattei, M. G., Vesque, C., Vincent, A. and
Charnay, P. (1997). Family of Ebf/Olf-1-related genes
potentially involved in neuronal differentiation and regional specification in
the central nervous system. Dev. Dyn.
210,191
-205.[CrossRef][Medline]
Hashimoto, H., Yabe, T., Hirata, T., Shimizu, T., Bae, Y.,
Yamanaka, Y., Hirano, T. and Hibi, M. (2000). Expression of
the zinc finger gene fez-like in zebrafish forebrain. Mech.
Dev. 97,191
-195.[CrossRef][Medline]
Hashimoto-Torii, K., Motoyama, J., Hui, C. C., Kuroiwa, A.,
Nakafuku, M. and Shimamura, K. (2003). Differential
activities of Sonic hedgehog mediated by Gli transcription factors define
distinct neuronal subtypes in the dorsal thalamus. Mech.
Dev. 120,1097
-1111.[CrossRef][Medline]
Hirata, T., Suda, Y., Nakao, K., Narimatsu, M., Hirano, T. and
Hibi, M. (2004). Zinc finger gene fez-like functions in the
formation of subplate neurons and thalamocortical axons. Dev.
Dyn. 230,546
-556.[CrossRef][Medline]
Hirata, T., Nakazawa, M., Yoshihara, S., Miyachi, H., Kitamura,
K., Yoshihara, Y. and Hibi, M. (2006). Zinc-finger gene Fez
in the olfactory sensory neurons regulates development of the olfactory bulb
non-cell-autonomously. Development
133,1433
-1443.
Ishibashi, M. and McMahon, A. P. (2002). A
sonic hedgehog-dependent signaling relay regulates growth of diencephalic and
mesencephalic primordia in the early mouse embryo.
Development 129,4807
-4819.[Medline]
Joyner, A. L. and Martin, G. R. (1987). En-1
and En-2, two mouse genes with sequence homology to the Drosophila engrailed
gene: expression during embryogenesis. Genes Dev.
1, 29-38.[Medline]
Kiecker, C. and Lumsden, A. (2004). Hedgehog
signaling from the ZLI regulates diencephalic regional identity.
Nat. Neurosci. 7,1242
-1249.[CrossRef][Medline]
Kiecker, C. and Lumsden, A. (2005).
Compartments and their boundaries in vertebrate brain development.
Nat. Rev. Neurosci. 6,553
-564.[CrossRef][Medline]
Kimura, C., Takeda, N., Suzuki, M., Oshimura, M., Aizawa, S. and
Matsuo, I. (1997). Cis-acting elements conserved between
mouse and pufferfish Otx2 genes govern the expression in mesencephalic neural
crest cells. Development
124,3929
-3941.[Abstract]
Kimura, C., Yoshinaga, K., Tian, E., Suzuki, M., Aizawa, S. and
Matsuo, I. (2000). Visceral endoderm mediates forebrain
development by suppressing posteriorizing signals. Dev.
Biol. 225,304
-321.[CrossRef][Medline]
Kimura, J., Suda, Y., Kurokawa, D., Hossain, Z. M., Nakamura,
M., Takahashi, M., Hara, A. and Aizawa, S. (2005). Emx2 and
Pax6 function in cooperation with Otx2 and Otx1 to develop caudal forebrain
primordium that includes future archipallium. J.
Neurosci. 25,5097
-5108.
Kobayashi, D., Kobayashi, M., Matsumoto, K., Ogura, T.,
Nakafuku, M. and Shimamura, K. (2002). Early subdivisions in
the neural plate define distinct competence for inductive signals.
Development 129,83
-93.
Kobayashi, M., Nishikawa, K., Suzuki, T. and Yamamoto, M.
(2001). The homeobox protein Six3 interacts with the Groucho
corepressor and acts as a transcriptional repressor in eye and forebrain
formation. Dev. Biol.
232,315
-326.[CrossRef][Medline]
Korinek, V., Barker, N., Willert, K., Molenaar, M., Roose, J.,
Wagenaar, G., Markman, M., Lamers, W., Destree, O. and Clevers, H.
(1998). Two members of the Tcf family implicated in
Wnt/beta-catenin signaling during embryogenesis in the mouse. Mol.
Cell. Biol. 18,1248
-1256.
Kurokawa, D., Kiyonari, H., Nakayama, R., Kimura-Yoshida, C.,
Matsuo, I. and Aizawa, S. (2004a). Regulation of Otx2
expression and its functions in mouse forebrain and midbrain.
Development 131,3319
-3331.
Kurokawa, D., Takasaki, N., Kiyonari, H., Nakayama, R.,
Kimura-Yoshida, C., Matsuo, I. and Aizawa, S. (2004b).
Regulation of Otx2 expression and its functions in mouse epiblast and anterior
neuroectoderm. Development
131,3307
-3317.
Lagutin, O. V., Zhu, C. C., Kobayashi, D., Topczewski, J.,
Shimamura, K., Puelles, L., Russell, H. R., McKinnon, P. J., Solnica-Krezel,
L. and Oliver, G. (2003). Six3 repression of Wnt signaling in
the anterior neuroectoderm is essential for vertebrate forebrain development.
Genes Dev. 17,368
-379.
Larsen, C. W., Zeltser, L. M. and Lumsden, A.
(2001). Boundary formation and compartition in the avian
diencephalon. J. Neurosci.
21,4699
-4711.
Levkowitz, G., Zeller, J., Sirotkin, H. I., French, D.,
Schilbach, S., Hashimoto, H., Hibi, M., Talbot, W. S. and Rosenthal, A.
(2003). Zinc finger protein too few controls the development of
monoaminergic neurons. Nat. Neurosci.
6, 28-33.[CrossRef][Medline]
Lopez-Rios, J., Tessmar, K., Loosli, F., Wittbrodt, J. and
Bovolenta, P. (2003). Six3 and Six6 activity is modulated by
members of the groucho family. Development
130,185
-195.
Mastick, G. S., Davis, N. M., Andrew, G. L. and Easter, S. S.,
Jr (1997). Pax-6 functions in boundary formation and axon
guidance in the embryonic mouse forebrain. Development
124,1985
-1997.[Abstract]
Matsuo-Takasaki, M., Lim, J. H., Beanan, M. J., Sato, S. M. and
Sargent, T. D. (2000). Cloning and expression of a novel zinc
finger gene, Fez, transcribed in the forebrain of Xenopus and mouse embryos.
Mech. Dev. 93,201
-204.[CrossRef][Medline]
Molyneaux, B. J., Arlotta, P., Hirata, T., Hibi, M. and Macklis,
J. D. (2005). Fezl is required for the birth and
specification of corticospinal motor neurons. Neuron
47,817
-831.[CrossRef][Medline]
Muhr, J., Andersson, E., Persson, M., Jessell, T. M. and
Ericson, J. (2001). Groucho-mediated transcriptional
repression establishes progenitor cell pattern and neuronal fate in the
ventral neural tube. Cell
104,861
-873.[CrossRef][Medline]
Nagai, T., Ibata, K., Park, E. S., Kubota, M., Mikoshiba, K. and
Miyawaki, A. (2002). A variant of yellow fluorescent protein
with fast and efficient maturation for cell-biological applications.
Nat. Biotechnol. 20,87
-90.[CrossRef][Medline]
Nakagawa, Y. and O'Leary, D. D. (2001).
Combinatorial expression patterns of LIM-homeodomain and other regulatory
genes parcellate developing thalamus. J. Neurosci.
21,2711
-2725.
Niehrs, C. (2004). Regionally specific
induction by the Spemann-Mangold organizer. Nat. Rev.
Genet. 5,425
-434.[Medline]
Oliver, G., Mailhos, A., Wehr, R., Copeland, N. G., Jenkins, N.
A. and Gruss, P. (1995). Six3, a murine homologue of the sine
oculis gene, demarcates the most anterior border of the developing neural
plate and is expressed during eye development.
Development 121,4045
-4055.[Abstract]
Pellegrini, M., Mansouri, A., Simeone, A., Boncinelli, E. and
Gruss, P. (1996). Dentate gyrus formation requires Emx2.
Development 122,3893
-3898.[Abstract]
Puelles, L. and Rubenstein, J. L. (1993).
Expression patterns of homeobox and other putative regulatory genes in the
embryonic mouse forebrain suggest a neuromeric organization. Trends
Neurosci. 16,472
-479.[CrossRef][Medline]
Puelles, L. and Rubenstein, J. L. (2003).
Forebrain gene expression domains and the evolving prosomeric model.
Trends Neurosci. 26,469
-476.[CrossRef][Medline]
Roelink, H. and Nusse, R. (1991). Expression of
two members of the Wnt family during mouse development-restricted temporal and
spatial patterns in the developing neural tube. Genes
Dev. 5,381
-388.
Rubenstein, J. L., Martinez, S., Shimamura, K. and Puelles,
L. (1994). The embryonic vertebrate forebrain: the prosomeric
model. Science 266,578
-580.
Rubenstein, J. L., Shimamura, K., Martinez, S. and Puelles,
L. (1998). Regionalization of the prosencephalic neural
plate. Annu. Rev. Neurosci.
21,445
-477.[CrossRef][Medline]
Salinas, P. C. and Nusse, R. (1992). Regional
expression of the Wnt-3 gene in the developing mouse forebrain in relationship
to diencephalic neuromeres. Mech. Dev.
39,151
-160.[CrossRef][Medline]
Sasaki, H. and Hogan, B. L. (1996). Enhancer
analysis of the mouse HNF-3 beta gene: regulatory elements for node/notochord
and floor plate are independent and consist of multiple sub-elements.
Genes Cells 1,59
-72.[Abstract]
Scholpp, S., Wolf, O., Brand, M. and Lumsden, A.
(2006). Hedgehog signalling from the zona limitans intrathalamica
orchestrates patterning of the zebrafish diencephalon.
Development 133,855
-864.
Shimamura, K. and Rubenstein, J. L. (1997).
Inductive interactions direct early regionalization of the mouse forebrain.
Development 124,2709
-2718.[Abstract]
Shimamura, K., Hartigan, D. J., Martinez, S., Puelles, L. and
Rubenstein, J. L. (1995). Longitudinal organization of the
anterior neural plate and neural tube. Development
121,3923
-3933.[Abstract]
Shimizu, T., Yamanaka, Y., Nojima, H., Yabe, T., Hibi, M. and
Hirano, T. (2002). A novel repressor-type homeobox gene, ved,
is involved in dharma/bozozok-mediated dorsal organizer formation in
zebrafish. Mech. Dev.
118,125
-138.[CrossRef][Medline]
Simeone, A., Acampora, D., Gulisano, M., Stornaiuolo, A. and
Boncinelli, E. (1992a). Nested expression domains of four
homeobox genes in developing rostral brain. Nature
358,687
-690.[CrossRef][Medline]
Simeone, A., Gulisano, M., Acampora, D., Stornaiuolo, A.,
Rambaldi, M. and Boncinelli, E. (1992b). Two vertebrate
homeobox genes related to the Drosophila empty spiracles gene are expressed in
the embryonic cerebral cortex. EMBO J.
11,2541
-2550.[Medline]
Simeone, A., Acampora, D., Mallamaci, A., Stornaiuolo, A.,
D'Apice, M. R., Nigro, V. and Boncinelli, E. (1993). A
vertebrate gene related to orthodenticle contains a homeodomain of the bicoid
class and demarcates anterior neuroectoderm in the gastrulating mouse embryo.
EMBO J. 12,2735
-2747.[Medline]
Stoykova, A. and Gruss, P. (1994). Roles of
Pax-genes in developing and adult brain as suggested by expression patterns.
J. Neurosci. 14,1395
-1412.[Abstract]
Stoykova, A., Fritsch, R., Walther, C. and Gruss, P.
(1996). Forebrain patterning defects in Small eye mutant mice.
Development 122,3453
-3465.[Abstract]
Stuhmer, T., Puelles, L., Ekker, M. and Rubenstein, J. L.
(2002). Expression from a Dlx gene enhancer marks adult mouse
cortical GABAergic neurons. Cereb. Cortex
12, 75-85.
Suda, Y., Hossain, Z. M., Kobayashi, C., Hatano, O., Yoshida,
M., Matsuo, I. and Aizawa, S. (2001). Emx2 directs the
development of diencephalon in cooperation with Otx2.
Development 128,2433
-2450.
Takada, S., Stark, K. L., Shea, M. J., Vassileva, G., McMahon,
J. A. and McMahon, A. P. (1994). Wnt-3a regulates somite and
tailbud formation in the mouse embryo. Genes Dev.
8, 174-189.
Tao, W. and Lai, E. (1992).
Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork
head gene family, in the developing rat brain. Neuron
8, 957-966.[CrossRef][Medline]
Vieira, C., Garda, A. L., Shimamura, K. and Martinez, S.
(2005). Thalamic development induced by Shh in the chick embryo.
Dev. Biol. 284,351
-363.[Medline]
Walther, C. and Gruss, P. (1991). Pax-6, a
murine paired box gene, is expressed in the developing CNS.
Development 113,1435
-1449.[Abstract]
Warren, N. and Price, D. J. (1997). Roles of
Pax-6 in murine diencephalic development. Development
124,1573
-1582.[Abstract]
Yoshida, M., Suda, Y., Matsuo, I., Miyamoto, N., Takeda, N.,
Kuratani, S. and Aizawa, S. (1997). Emx1 and Emx2 functions
in development of dorsal telencephalon. Development
124,101
-111.[Abstract]
Zeltser, L. M. (2005). Shh-dependent formation
of the ZLI is opposed by signals from the dorsal diencephalon.
Development 132,2023
-2033.
Zeltser, L. M., Larsen, C. W. and Lumsden, A.
(2001). A new developmental compartment in the forebrain
regulated by Lunatic fringe. Nat. Neurosci.
4, 683-684.[CrossRef][Medline]
Zhu, C. C., Dyer, M. A., Uchikawa, M., Kondoh, H., Lagutin, O.
V. and Oliver, G. (2002). Six3-mediated auto repression and
eye development requires its interaction with members of the Groucho-related
family of co-repressors. Development
129,2835
-2849.[Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Yokosuka, A. Hagiwara, T. R. Saito, N. Tsukahara, M. Aoyama, Y. Wakabayashi, S. Sugita, and M. Ichikawa Histological Properties of the Nasal Cavity and Olfactory Bulb of the Japanese Jungle Crow Corvus macrorhynchos Chem Senses, September 1, 2009; 34(7): 581 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N.-E. Szabo, T. Zhao, M. Cankaya, T. Theil, X. Zhou, and G. Alvarez-Bolado Role of Neuroepithelial Sonic hedgehog in Hypothalamic Patterning J. Neurosci., May 27, 2009; 29(21): 6989 - 7002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Russek-Blum, A. Gutnick, H. Nabel-Rosen, J. Blechman, N. Staudt, R. I. Dorsky, C. Houart, and G. Levkowitz Dopaminergic neuronal cluster size is determined during early forebrain patterning Development, October 15, 2008; 135(20): 3401 - 3413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lavado, O. V. Lagutin, and G. Oliver Six3 inactivation causes progressive caudalization and aberrant patterning of the mammalian diencephalon Development, February 1, 2008; 135(3): 441 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Blechman, N. Borodovsky, M. Eisenberg, H. Nabel-Rosen, J. Grimm, and G. Levkowitz Specification of hypothalamic neurons by dual regulation of the homeodomain protein Orthopedia Development, December 15, 2007; 134(24): 4417 - 4426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Scholpp, I. Foucher, N. Staudt, D. Peukert, A. Lumsden, and C. Houart Otx1l, Otx2 and Irx1b establish and position the ZLI in the diencephalon Development, September 1, 2007; 134(17): 3167 - 3176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Jeong, Z. Einhorn, P. Mathur, L. Chen, S. Lee, K. Kawakami, and S. Guo Patterning the zebrafish diencephalon by the conserved zinc-finger protein Fezl Development, January 1, 2007; 134(1): 127 - 136. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
