1 Department of Biological Sciences, Graduate School of Science, Tokyo
Metropolitan University, 1-1 Minamiohsawa, Hachiohji, Tokyo 192-0397,
Japan
2 Department of Developmental Neurobiology, Graduate School of Medicine, Tohoku
University, Sendai, Miyagi 980-8575, Japan
3 Department of Physiology, Keio University School of Medicine, 35 Shinanomachi,
Shinjuku, Tokyo 160-8582, Japan
* Author for correspondence (e-mail: yasugi-sadao{at}c.metro-u.ac.jp)
Accepted 6 April 2005
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SUMMARY |
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Key words: Notch, Delta, Su(H), Proventriculus, Stomach, Gland, Chicken
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Introduction |
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It is well established that the epithelial-mesenchymal interaction is
important for the development of the PV
(Yasugi, 1984;
Yasugi and Fukuda, 2000
).
Recently, several secreted molecules have been identified as signaling factors
regulating the epithelial development of the PV. Bone morphogenetic protein 2
(BMP2), which is secreted from the surrounding mesenchyme, is an important
inducer of gland formation and ECPg expression
(Narita et al., 2000
).
Fgf10, which is expressed in PV mesenchyme
(Shin et al., 2005
), regulates
epithelial cell proliferation and differentiation (M. Shin, S. Noji and S.
Yasuji, unpublished). Fukuda et al.
(Fukuda et al., 2003
) have
shown that a downregulation of Sonic hedgehog (Shh)
expression in the epithelium is necessary for gland formation. Epidermal
growth factor (EGF) signaling can also promote the luminal fate in dispense of
gland cell population (Takeda et al.,
2002
). However, the molecular mechanism(s) that control the binary
fate decision and the spatially patterned differentiation of epithelial cells
remain to be elucidated.
Notch signaling controls cell fate decision and patterned differentiation
in numerous developmental processes (reviewed by
Campos-Ortega, 1993;
Artavanis-Tsakonas et al.,
1999
; Kopan,
2002
). The Notch transmembrane receptors are activated by
cell-surface DSL (Delta, Serrate, Lag2) ligands and mediate direct cell-cell
communication. Ligand binding results in a proteolytic cleavage to release the
intracellular domain of the Notch proteins (NICD), which subsequently
translocates into the nucleus and associates with the DNA-binding CSL
(CBF1/Su(H)/Lag1, also known as RBPj) proteins to activate target genes such
as the Hairy/Enhancer of Split (HES) family of bHLH transcriptional
repressors (Beatus and Lendahl,
1998
; Hu et al.,
2003
). Recently, the Deltex pathway has also been
identified as mediating alternative Notch signaling
(Yamamoto et al., 2001
;
Matsuno et al., 2002
;
Endo et al., 2003
;
Hu et al., 2003
). Numb is an
inhibitory molecule that binds to PEST domain of NICD and disturb nuclear
translocation (Wakamatsu et al.,
1999
; Wakamatsu et al.,
2000
).
In this study, we have investigated the involvement of Notch signaling in the early gland cell differentiation of the chicken PV. We show that Delta1/Notch1 signaling in the PV epithelium is activated in a scattered fashion prior to epithelial invagination, as the earliest indication of fate segregation in the epithelium. We also demonstrate that an activation of Notch signaling promotes gland-specific gene expression, whereas persistence of Notch signaling prevents progress of epithelial cell differentiation, and that an inhibition of Notch signaling leads to luminal differentiation. Taken together, these results suggest that Notch signaling regulates spatiotemporally patterned differentiation of the glandular epithelium in the developing chicken PV.
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Materials and methods |
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Plasmid constructs
FLAG epitope-tagged expression vectors of CNIC (constitutively
active form of chicken Notch1), CNICC89
(CNIC that lacks C-terminal end) and chicken Numb have been
described previously (Wakamatsu et al.,
1999
; Wakamatsu et al.,
2000
). Throughout our study, CNIC and
CNIC
C89 were used to activate Notch1.
CNIC
C89 was more effective than CNIC,
although both of them resulted in the same phenotype.
CNIC
C89 was used in 3-day cultivation experiment to
obtain stable results, while CNIC was used in 36-hour culture
experiments to compare with rescue experiments. pmiwSV-quail Delta1
has also been described previously
(Maynard et al., 2000
;
Endo et al., 2002
).
Xenopus Su(H)DBM was kindly provided by Dr C. Kintner
(Wettstein et al., 1997
) and
the insert was subcloned into pmiwSV (Endo
et al., 2002
). pTP-1Venus will be described elsewhere (J.
Kohyama, A. Tokunaga, Y. Fujita, H. Miyoshi, T. Nagai, A. Miyawaki, K. Nakao,
Y. Matsuzaki and H. Okano, unpublished).
Transfection of plasmids into PV epithelium by electroporation
The apparatus used for electroporation of plasmid DNAs into PV epithelium
was set up as follows (Sakamoto et al.,
2000). Platinum electrodes were fixed on a glass dish and
integrated into a resin chamber (7 mm in height, 8 mm in width and 5 mm in
length). A vessel made of 1.5% agarose/Tyrode's solution gel was put into an
electrode chamber and filled with 14 µl plasmid DNAs in Tyrode's solution.
The outside of the gel vessel was filled with Tyrode's solution. Isolated PV
were cut open and placed in the vessel with their epithelial sides facing to
the cathode to introduce DNAs into the epithelium. For the optimal
transfection, 50 msecond pulses of 30 V and 75 msecond durations were
generated 10 times for stage 28 PV and 15 times for stage 29 PV using CUY 21
(BEX). Tissues were immediately washed with Tyrode's solution and cultured for
indicated hours. Appropriate concentration of each plasmid DNAs were examined
and determined as follows: 200 nM of pEGFP-C1 for 36 hours cultivation and 300
nM for 72 hours culture; 200 nM CNIC
C89 expression
vector for 72 hours cultivation; 50 nM CNIC expression vector for 36
hours cultivation; 200 nM of pTP-1Venus for reporter assay or 100 nM for
cotransfection with CNIC; 300 nM expression vector of chicken
Numb or Xenopus Su(H)DBM were used for inhibitory
experiments and 400 nM for co-transfection with CNIC; and 200 nM
pmiwSV-quail Delta1 for reporter assay.
Organ culture
Explanted PV were laid on a Nuclepore filter (pore size 0.8 µm). This
filter was placed on a stainless steel grid, placed into one well of a 24-well
culture dish (Falcon, 3047) and cultured at the medium-gas interphase in 5%
CO2 and 95% air at 37°C. The culture medium was 199 with
Earle's salt containing an equal volume of embryo extract prepared from stage
38 embryos (Takiguchi et al.,
1988).
In situ hybridization
In situ hybridization with digoxigenin-labeled RNA probe was performed on
8-10 µm cryosections as previously described
(Ishii et al., 1997). cRNA
probes were generated by in vitro transcription from cDNA fragments of
ECPg (Hayashi et al.,
1988
), chicken SP
(Tabata and Yasugi, 1998
),
chicken Notch1, quail Serrate1, quail Delta1,
chicken Numb (Wakamatsu et al.,
1999
; Wakamatsu et al.,
2000
), chicken Notch2, chicken Serrate2 [gifts
from Dr R. Goistuka (Morimura et al.,
2001
)], chicken Hairy1, chicken Hairy2 [gifts
from Dr O. Pourquié, (Palmeirim et
al., 1997
; Jouve et al.,
2000
)], chicken Smad8, Shh [gifts from Dr T. Nohno
(Nohno et al., 1995
;
Ohuchi et al., 1997
)], chicken
Gata5 (Sakamoto et al.,
2000
), chicken Gata4, chicken Gata6
(Laverriere et al., 1994
),
chicken Sox2 (Ishii et al.,
1998
), chicken Sox21
(Uchikawa et al., 1999
),
chicken GK19 (Sato and Yasugi,
1997
) and chicken Fra2
(Matsumoto et al., 1998
).
Immunological staining
M2 anti-FLAG (mouse IgG1, Sigma) and goat anti-mouse IgG conjugated with
Alexa 546 (Molecular Probes) were purchased from commercial suppliers.
Immunological staining on sections was performed as described previously
(Wakamatsu et al., 1993).
Cryosections (8-12 µm) were prepared on VectaBond-coated slides (Vector).
Sections treated with antibodies were also exposed to DAPI (Sigma) to
visualize nuclei, and subsequently mounted with VectaShield mounting medium
(Vector).
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Results |
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The PV epithelium begins to invaginate into the mesenchyme at stage 29. This stage is a crucial early phase of gland formation: epithelial invagination is still very small, but luminal surface indentation starts to be observed. Chicken SP and Smad8 expressions were first detected at this stage (Fig. 1B,E). Expression of Smad8 is restricted to cells in small glands and cells just before invagination (arrowheads in Fig. 1). Delta1 was also first expressed in a subpopulation of uninvaginated epithelial cells in a scattered fashion (Fig. 1H, arrowheads). Mesenchymal expression of Delta1 was maintained at sites where the overlying epithelium did not invaginate. In the invaginated epithelial cells, the expression of Notch1 decreased and that of Hairy1 disappeared (Fig. 1K,Q). By contrast, expression of Notch2 and Hairy2 was upregulated in the invaginating epithelium (Fig. 1N,T).
|
From the analysis of expression patterns, we concluded that Smad8 is a specific marker gene of gland epithelial cells from the early stage of their development, as its expression begins with and persists during the gland formation and is specific to these cells.
Notch signaling is activated in scattered undifferentiated cells fated to the glandular epithelium
We next performed a reporter assay to confirm whether Notch signaling is
indeed activated during the normal development of the PV. pTP-1Venus
was used, a CSL-dependent Venus (a GFP variant) reporter
that carries 12 repeats of CSL-binding sites and that efficiently reflects
Notch signaling activity (J. Kohyama, A. Tokunaga, Y. Fujita, H. Miyoshi, T.
Nagai, A. Miyawaki, K. Nakao, Y. Matsuzaki and H. Okano, unpublished). First,
pTP-1Venus was transfected into stage 28 and 29 PV, and the reporter
activity was observed after 3 hours of explant culture. As 3 hours cultivation
is the shortest time in which to detect reporter-derived proteins, this
condition enables us to observe almost `real-time' activity of Notch
signaling. Reporter activity was detected in scattered cells in uninvaginated
epithelium of stage 29 PV, but was never detected in invaginated epithelium
(Fig. 2A). Reporter activity
was not detected in stage 28 PV (data not shown), in which no Delta1
expression was detected in the epithelium, suggesting that epithelial, not
mesenchymal, Delta1 expression was responsible for the Notch signal
activation in the epithelium. This result indicated that activation of
Su(H)-mediated Notch signaling begins between stage 28 and 29 in cells
scattered in the uninvaginated epithelium. When stage 28 and 29 PV were
cultured for 24 or 48 hours after transfection, the reporter activity was
detected not only in the uninvaginated epithelium in a scattered fashion but
also strongly in invaginated gland cells
(Fig. 2B,C). In this condition,
cells in which Notch signaling had once been activated during cultivation
could be Venus positive. Gland formation in stage 28 PV cultivated
for 24 hours is comparable with that in transiently cultivated stage 29 PV
(Fig. 2A,B). These results
suggest the possibility that cells in which Notch signal was transiently
activated took gland cell fate and subsequently invaginated. Consistently,
Venus-positive cells did not express chicken SP mRNA when
stage 29 PV was transfected with pTP-1Venus and cultured for 3 hours
(Fig. 3).
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Next, to investigate whether Notch signaling is necessary for glandular
cell differentiation, Numb and Su(H)DBM were
overexpressed in the stage 28 PV and the transfected explants were cultured
for 36 hours. Epithelial invagination was morphologically confirmed
(Fig. 9, arrowheads), and
luminal epithelium differentiation was monitored by detecting expression of
chicken SP in neighboring sections
(Fig. 9, rightmost column).
Transfected cells were identified by immunological detection of FLAG-tag on
the transgene-derived Numb protein (Fig.
9G',I'), or by expression of co-transfected
EGFP (Fig.
9C',E'). In the explants with high efficiency of
transfection, these transgenes inhibited gland formation and induced luminal
differentiation (Fig.
9E-F,I-J). The majority of explants with lower efficiency of
transfection, however, often formed some invaginated glands, while transfected
cells contributed only to the luminal epithelium and did not participate in
the invaginated glands (Fig.
9C-D,G-H). As initial transfection efficiency of these inhibitor
constructs and EGFP expression vectors were almost comparable when
explants were cultivated only for 12 hours (data not shown), cells that
escaped from transfection seemed to differentiate only into gland cells. By
contrast, overexpression of a dominant-negative form of Dtx1
(Yamamoto et al., 2001) did
not affect overall gland formation, and dominant-negative
Dtx1-transfected cells could contribute to both glandular and luminal
epithelium (data not shown). These results suggest that
Su(H)-mediated Notch signaling is necessary for the glandular
epithelium differentiation.
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Discussion |
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Inhibition of the gland maturation by Notch signaling
In our assay, transfection of NICD (CNIC and
CNICC89) inhibits the invagination of the glandular
epithelium, as well as the expression of late markers of the gland epithelium
such as ECPg, while the activation of Notch signaling allows the
expression of Smad8. As BMP2 has previously been shown as an
important inducer of gland and ECPg expression
(Narita et al., 2000
), and as
Smad8 is a mediator directly regulated by BMP receptor, Smad8
expression pattern and function closely reflects the early state of glandular
epithelium before secretion of zymogen. Consistently, a transient reporter
assay revealed that Notch-activated cells were interspersed only in
uninvaginated epithelium, but that such cells later contribute to gland
epithelium. We therefore conclude that Notch signaling prevents maturation of
glandular epithelium, while it promotes initial glandular specification. A
similar phenomenon is reported in pancreatic development. In the mouse
pancreas, Notch activity is required for the commitment of precursor cells to
the exocrine lineage (Apelqvist et al.,
1999
; Jensen et al.,
2000
), but also represses the maturation of these cells to express
digestive enzymes by preventing the function of Ptf1-P48 complex
(Esni et al., 2004
).
Similarly, in developing dorsal root ganglia of chicken embryo, continuous and
strong Notch activation inhibits both neuronal and glial terminal
differentiation to maintain progenitor population
(Wakamatsu et al., 2000
),
while transient activation of the signaling promotes glial differentiation
(Morrison et al., 2000
). Many
studies have reported a short time activation and downregulation of Notch
signaling, especially in somitogenesis (reviewed by
Pourquie, 2003
;
Aulehla and Herrmann, 2004
).
Thus, it is reasonable to speculate that Notch signaling initially functions
as a fate determination switch, and subsequently acts to control the
differentiation of immature gland cell precursors.
|
In our study, primary effector molecule(s), which function under Notch
signaling, cannot be determined, as Hairy1 and Hairy2 were
not significantly upregulated by Notch activation. Thus, there is a
possibility that Notch1 targets other gene(s), such as unidentified
Hairy genes and/or Herp family genes (reviewed by
Iso et al., 2003).
Possible crosstalk of Notch signaling with other signaling in glandular differentiation
It has long been shown that an induction by the mesenchyme is necessary for
gland formation of PV epithelium (Haffen
et al., 1987; Mizuno and
Yasugi, 1990
; Yasugi and
Fukuda, 2000
). Narita et al.
(Narita et al., 2000
) have
previously reported that Bmp2, which is specifically expressed in the
PV mesenchyme, can induce gland formation. Recently, both synergistic and
antagonistic relationship between BMP and Notch has been reported
(Dahlqvist et al., 2003
;
de Jong et al., 2004
;
Itoh et al., 2004
). In mouse
neuroepithelial development, BMP2 induces expression of Hes5 and
Hesr1, primary target genes of Notch signaling; Smad1, one of the
mediator of BMP signaling, and NICD form a protein complex, which in turn
regulates transcription of the target genes
(Takizawa et al., 2003
). In
BMP signaling, ligand-induced heterotetrameric receptor complex directly
phosphorylates Smad proteins such as Smad1, Smad5 and Smad8. Thus, Smad8 would
mediate the inductive effect stimulated by BMP2 in gland formation of the PV.
In our study, activation of Notch signal derived from CNIC induced expression
of Smad8. Hence, induction of the downstream component might be one
of the interfaces between the BMP and Notch signals that contribute to gland
formation.
Shh was shown to induce luminal fate and its downregulation is
necessary for glandular differentiation, probably through BMP7, which is
expressed in the mesenchyme adjacent to the luminal epithelium
(Fukuda et al., 2003). In our
study, the activation of Notch signaling downregulates the epithelial
expression of Shh. Therefore, it is possible that Notch signaling
regulates the glandular differentiation partly through the repression of
Shh signaling.
We also demonstrated that EGF signal induces the luminal fate
(Takeda et al., 2002).
Antagonistic interaction between Notch and EGF pathways have been described in
other systems (de Celis et al.,
1997
; zur Lage and Jarman,
1999
; Culi et al.,
2001
). For example, Drosophila ebi, a target gene of EGF
receptor, and a mammalian ortholog of TBL1 associate with Su(H) and
SMRTER/SMRT, a nuclear co-repressor protein, and regulate transcription of
target genes (Culi et al.,
2001
). Thus, the recruitment of Su(H) to the repression complex
may compete with the NICD/Su(H) complex, which activates target genes. Such
antagonistic relations may prevent excess gland formation.
In the normal development, gland formation is a sequential process and the number of glands increases from stage 29 until about stage 33, during the period before ECPg expression begins. In our model (Fig. 10A,B), the epithelial cells are homogenous and undifferentiated (Fig. 10, light blue) until stage 28. From stage 29, slightly before stage 29, Delta1/Notch1 signaling is activated and commits epithelial cells to keep gland progenitor cells (Fig. 10, green) in a scattered fashion, whereas other epithelial cells differentiate into luminal cells (Fig. 10, dark blue). This function of Notch1 might be completed by luminal effectors such as EGF and/or Shh, which prevent formation of excess glands and act in cooperation with inducers of gland cell differentiation such as BMP2. Notch1 activation is sequentially ceased, and progenitor gland cells begin to invaginate and differentiate into early gland cells (Fig. 10, yellow). Notch1 signaling also keeps progenitor gland cells in the undifferentiated state; these cells can then be released to differentiation as the PV becomes large enough to form additional glands. Thus, Delta1/Notch1 signaling definitively regulates early phase of gland formation before the secretion-competent gland maturation in normal development.
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ACKNOWLEDGMENTS |
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