1 Riken Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku
Kobe 650-0047, Japan
2 National Institute of Genetics and the Graduate School for Advanced Studies,
1111 Yata, Mishima, Shizuoka-ken 411-8540, Japan
3 Department of Life Science, Kobe University Graduate School of Science and
Technology, 1-1 Rokkodai-cho, Nada-ku, Kobe-shi, Hyogo, 657-8501, Japan
Author for correspondence (e-mail:
shayashi{at}cdb.riken.jp)
Accepted 16 August 2004
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SUMMARY |
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Key words: Guidance, Trachea, Hedgehog, Dpp, Drosophila
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Introduction |
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The trachea is a respiratory organ consisting of a network of tubular
epithelia that delivers outside air directly to target organs. The tracheal
primordium forms six primary branches that migrate towards specific target
tissues expressing Branchless (Bnl), a Drosophila homolog of FGF
(Sutherland et al., 1996). Bnl
activates Breathless (Btl), an FGF receptor, at the tip of primary branches
and cell process formation (Gabay et al.,
1997
; Glazer and Shilo,
2001
; Ribeiro et al.,
2002
). The dorsal branch (DB) migrates toward the dorsal midline,
where it fuses with another DB from the contralateral side
(Fig. 1A-C, see Movie 1 in the
supplementary material). Two specialized cells are present at each DB tip
(Fig. 1K). Fusion cells lead
the migration and form anastomoses of tracheal tubules
(Samakovlis et al., 1996b
;
Tanaka-Matakatsu et al.,
1996
), whereas terminal cells extend a long cell process called a
terminal branch (Samakovlis et al.,
1996a
). The terminal branch is also present in other branches such
as visceral and ganglionic branches, and in all cases spreads over the surface
of target tissues and serves as an interface for gas exchange by extending
unicellular processes containing a dead-ended lumen, a structure known as the
tracheole. Terminal branching in postembryonic stages is regulated by Bnl,
which is induced as a hypoxic response
(Jarecki et al., 1999
). The
regulation of terminal branch migration in the CNS uses the same molecules
involved in axon guidance (Englund et al.,
2002
). Current knowledge is lacking, however, on the regulation of
directed terminal branch growth over the epidermis, as well as the mechanism
by which it is positioned over the epidermis to maximize oxygen transfer.
|
We have assessed the roles of Hh and Dpp in directed outgrowth of tracheal terminal branch. Focusing on the terminal branches of the DB, we show that the terminal cells are located at a specific position in the dorsal epidermis (DE) defined by orthogonal stripes of Hh and Dpp expression, and that they extend terminal branches along a stripe of Hh expression. Hh acts on terminal cells to promote cell spreading over the epidermal surface. However, Dpp inhibits dorsal outgrowth, and thereby defines the monopolar shape of the terminal branch. We present a model that explains how Hh and Dpp signaling direct terminal branch outgrowth.
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Materials and methods |
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Embryo staining
The following primary antibodies were used: rabbit anti-GFP (MBL),
anti-ß-galactosidase (Cappel), mouse anti-Engrailed 4D9 and anti-Dlg
(Developmental Studies Hybridoma Bank), anti-diphospho MAP kinase (Sigma),
anti-pMAD (Kubota et al.,
2000) and mouse monoclonal anti-mouse SRF (a gift from M. Gilman).
The secondary antibodies used were as follows: Alexa 488-conjugated
anti-rabbit IgG (Molecular Probes) and Cy5-conjugated anti-mouse IgG (Amersham
Biosciences). Fluorescence images were captured using a confocal
laser-scanning microscope (Olympus FV-500), and image processing was performed
with the ImageJ application
(http://rsb.info.nih.gov/ij/index.html).
Time-lapse observations
Unless otherwise noted, embryos heterozygous for btl-Gal4 and
UAS-gfp-moe insertions on the second chromosome were used for
recording. Egg were collected at 22°C. Dechorionated embryos were mounted
on a glass coverslip with rubber cement and were covered with halocarbon oil
700 (Sigma). GFP images were captured by a confocal laser-scanning microscope
(Olympus FV-300) with a 60x oil immersion lens (NA 1.4) in a room
maintained at 22°C. To minimize phototoxicity, we reduced the argon laser
intensity (488 nm, 10 mW) to 1% and opened the pinhole to its maximum size
(300 µm). Typically, 12 x 2 µm z stacks were taken every
1-5 minutes over a period of 6 hours. Images of the stacks were separated into
single sections and manipulated using the ImageMagick software package
(http://www.imagemagick.org/),
and scripts were written in Perl and Ruby. Movies were encoded as MPEG-4
files.
Kinetic analysis of terminal cell movement
Images of terminal cells were aligned such that the anteroposterior and
dorsoventral axes matched the x- and y-axes, respectively.
The junction between fusion and terminal cells that was identified by the
presence of the actin core was chosen as a reference point. Plots were
constructed from measurements of the y-directed component of the
distance to the tip of filopodia at the dorsal- and ventralmost positions as
well as the x-directed component of the distance to the anteriormost
position.
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Results |
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Terminal cells of the DB started to send filopodia toward the ventral direction by 60 minutes (Fig. 1B, green arrowhead; see also Fig. 2A), and later developed as terminal branches (Fig. 1C,I, green arrowhead). The actin core, a cytoplasmic structure that directs the formation of the lumen, was oriented ventrally (Fig. 1C, green arrowhead). Three-dimensional reconstruction confirmed that the terminal branch spread over the basal surface of the DE (Fig. 1I,J, green arrowhead), whereas stalk cells did not make close contact with DE (Fig. 1J, open arrowhead). In subsequent studies, we focused our analyses on the guidance mechanism of unidirectional cellular extensions of the terminal branch.
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Expression of Bnl-FGF during terminal cell differentiation
Bnl is a major signaling molecule that guides primary branch outgrowth
(Sutherland et al., 1996). To
ask whether Bnl plays a role in terminal branch guidance in the DB, we
examined Branchless gene (bnl) expression patterns in stage 15 DE
(Fig. 3A). bnl mRNA
was expressed as spots abutting emerging DB during stages 13-14
(Sutherland et al., 1996
).
This expression decayed by stage 15 and was replaced by a short stripes that
extended along the anteroposterior (AP) compartment boundary
(Fig. 3A). Terminal cells that
had begun to extend terminal branches were found beneath
bnl-expressing cells, and they expressed activated MAP kinase, a
downstream target of FGF signaling (Gabay
et al., 1997
) (Fig.
3B). Given the strong activity of Bnl to induce terminal cell
differentiation (Sutherland et al.,
1996
), a localized source of Bnl in the DE probably promotes
and/or maintains the differentiation of terminal cells at a specific
location.
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The DB tip localizes to a specific position marked by en and dpp
The DB arises from tracheal primordia in the anterior compartment and
extends its tip dorsally and anteriorly to cross the segment boundary to reach
an area beneath the En-expressing region, which is the source of Hh
(Fig. 3C,D). Dpp expression at
stage 14, as monitored with the dpp-lacZ reporter, manifested as a
longitudinal stripe at the leading edge of the DE, mimicking the pattern of
dpp mRNA expression (Fig.
3C) (see Jackson and Hoffmann,
1994). The tip of the DB was located two or three cells behind the
region of dpp-lacZ expression
(Fig. 3C) and accumulated
phosphorylated MAD (pMAD), an indicator of Dpp signal transduction
(Kubota et al., 2000
;
Tanimoto et al., 2000
)
(Fig. 3E). dpp-lacZ
expression persisted at the completion of dorsal closure when outgrown
terminal branch was observed (Fig.
3D). During stage 15 and thereafter, the terminal branch extended
ventrally along the anterior edge of En-expressing cells and away from the
leading edge of the DE (see Fig.
5A-C). These observations raise the possibility that Hh provides a
positional cue that directs the terminal cells and that Dpp plays a role
directing the orientation of terminal branch.
|
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Involvement of Hh signaling in directed terminal branch outgrowth
We studied the function of Hh as a candidate guidance molecule secreted
from the P compartment. First, we altered the pattern of Hh expression in the
epidermis by driving Hh using the ush driver, which activated
expression in a wide anteroposterior stripe along the dorsal midline
(Fig. 5L). This treatment
caused the duplication of terminal cells identified by SRF expression (data
not shown). Some of terminal branches were misrouted along the AP direction or
became stalled at the dorsal midline (Fig.
5K,K', arrowhead), suggesting that extension of terminal
branch outgrowth is misguided by alteration of Hh distribution in the DE.
We next attempted to alter Hh signal transduction activity specifically in
tracheal cells by elevating or reducing the ability of tracheal cells to
respond to Hh via expression of Hh-specific intracellular transducers. The
nascent polypeptide of Ci155 is thought to constitute the inactive form of the
protein in the cytoplasm (Aza-Blanc et al.,
1997). In cells that do not respond to Hh signaling, Ci155
cleavage yields the 75 kDa fragment CiR, which represses several Hh
target genes. Hh signaling is thought to generate another form of Ci,
CiAct, which activates Hh target genes. We used truncated forms of
Ci that mimic the activities of CiAct and CiR to alter
Hh signaling (Hepker et al.,
1997
; Methot and Basler,
1999
).
To confirm that terminal cells located on the basal side of the epidermis were affected by Hh signaling, we monitored Hh activity using a patched-lacZ (ptc-lacZ) reporter gene. ptc-lacZ was detected in terminal cells (Fig. 5M, yellow circle), and expression was significantly lower than that detected in epidermal cells abutting the P compartment, where Hh signaling was maximal (Fig. 5M, yellow arrowhead). ptc-lacZ was activated by CiAct and repressed by CiR, respectively (Fig. 5N,O), suggesting that those effectors may be used to modulate Hh signaling in the trachea.
We reasoned that tracheal cell-autonomous activation of Hh signaling by CiAct would allow terminal cells to migrate independently of external source of Hh. Tracheal cells expressing CiAct displayed aberrant DB migration (Fig. 5E-G, see Movie 3 in the supplementary material). These cells displayed abnormal morphology in that they produced multiple cytoplasmic extensions from a single SRF-expressing cell (100%, n=90, 98% of the DBs contained a single terminal cell, Fig. 5G) and were often displaced from the P compartment (Fig. 5E). Most notably, the orientation of the cytoplasmic extensions was not restricted to the ventral direction; rather, they were oriented in the anterior, and posterior directions (Fig. 5E-G, see Movie 3 in the supplementary material), suggesting that terminal cells and terminal branches must respond to external Hh to precisely localize to P compartment.
However, terminal cells expressing CiR often formed duplicated terminal branch (18.8%, n=250, compared with 3.6%, n=166 in the control strain). Time-lapse observation demonstrated that terminal branch apparently normal with respect to the initial direction of terminal branch extension form first (Fig. 5H-J, white arrowhead), followed by formation of secondary terminal branch that migrate anteriorly outside of EN stripe (Fig. 5H-J, red arrowhead; see Movie 4 in the supplementary material). Anti-SRF staining of such terminal branches revealed that approximately one-third (10/27) of duplicated branches arose from single terminal cells (Fig. 5J, asterisk). The result suggests that Hh signaling activity must be maintained to an appropriate level to restrict the number and the location of terminal branch.
These results suggest that terminal cells respond to Hh expressed in the epidermis and that the maintenance of Hh signal transduction activity at an appropriate level is essential for correct migration of the terminal branch.
Dpp inhibits terminal branch outgrowth
Terminal cells begin terminal branching by extending filopodia in both the
dorsal and ventral directions, but they maintain only the ventral extension at
later stages (Fig. 2B,C). As
Dpp was expressed immediately adjacent to the leading front of the DB at the
onset of terminal branch outgrowth (Fig.
3C), we reasoned that Dpp might constitute an inhibitory signal
for terminal branch outgrowth. To test this idea, we observed terminal
branching in cells with altered levels of Dpp signaling activity in the
trachea. Because Dpp signaling is required for DB specification, it is
important to separate the defects in terminal branching from those resulting
from the earlier requirement for branch specification. In further analyses, we
chose conditions in which most embryos had a normal number of DB cells. Under
such conditions, terminal branches reached the dorsal midline, and their
frequency remained one per DB as assessed by the expression of the terminal
cell marker SRF (data not shown).
When Dpp signaling was constitutively activated by overexpression of dpp by the btl promoter, terminal branch extension stalled and was sometimes curtailed (Fig. 6A). The coiled appearance of the actin core in stalled terminal branches suggests that terminal branch failed to extend in a straight path while maintaining its growth, suggesting that cell-autonomous activation of Dpp signaling is inhibitory to polarized extension of terminal branch.
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Discussion |
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Hh guides terminal branch ourgrowth by promoting cell spreading
Terminal branches extend numerous cell processes that rapidly and
repeatedly extend and retract in many directions. Although cell processes that
extended anteriorly and dorsally were unstable, a subset of cell processes
that extended ventrally along the P compartment became selectively stabilized
(Fig. 2). The behavior of
terminal cells in the anterior compartment was strikingly different from those
in the P compartment (Fig. 4C).
In the anterior compartment, the number and size of the cell processes was
much smaller, suggesting that the P compartment constitutes the preferred
substrate for terminal cell spreading.
Hh is important for promoting terminal cell spreading. Hh is secreted from
the P compartment (Tabata and Kornberg,
1994) and forms symmetrical gradients of cellular responses in
both the anterior and posterior directions within the epidermis
(Struhl et al., 1997
). We
propose that Hh stimulates the adhesion of terminal cells to the epidermis by
activating Ci. Because Hh signaling is submaximal in terminal cells
(Fig. 5M), terminal branch
filopodia that extend randomly would be preferentially stabilized near the
source of Hh. Thus, terminal cell bodies are placed at the point of highest Hh
concentration and terminal branches are stabilized at the apex of the Hh
concentration gradient. Because terminal cell growth continues while the level
of Hh signaling remains below maximum within terminal cells, terminal branches
would be expected to extend along the P compartment
(Fig. 7).
|
Hh signaling has been implicated in another cell adhesion-related process,
namely cell sorting behavior at the AP compartmental boundary in the wing
imaginal disc (Blair and Ralston,
1997; Rodriguez and Basler,
1997
). Because this behavior is regulated transcriptionally by Ci
(Dahmann and Basler, 2000
),
there may be a common downstream target of Ci that acts in both wing disc
cells and terminal cells.
Terminal branch extension is limited to the AP compartmental border,
suggesting that there is an additional mechanism that shifts the terminal
branch to the anterior side of the P compartment. Bnl was expressed as short
stripes in the DE at the time of terminal branching. It was reported that
mesodermal cells also contribute to correct patterning of DB
(Franch-Marro and Casanova,
2000). It will be interesting to address guidance functions of
those components on terminal branch outgrowth.
Negative control of terminal branch extension by Dpp
Dpp was expressed at the dorsal edge of the DE during dorsal closure
(Fig. 3C). This corresponds to
the time when terminal branch outgrowth in the DB started, suggesting that Dpp
affects initial stage of terminal branch outgrowth. We observed that prolonged
activation of Dpp signaling in terminal cells by expression of Dpp prevented
its elongation (Fig. 6A). These
observations suggest that in normal development Dpp prevents dorsally directed
terminal branch extension at the onset of terminal branching
(Fig. 2C, asterisk-labeled
plot), thereby shunting terminal branch extension towards the ventral
direction. We propose that Dpp converts the initial bipolar shape of a
terminal branch into one that is monopolar. Once terminal branch extension is
initiated, its direction may be maintained by localized Bnl expression at the
AP compartment border. Whether this inhibitory effect of Dpp is mediated by
direct signaling to cytoskeletons at the cell periphery or mediated by a
nuclear transduction of the signal, remain to be determined.
Combinatorial control of terminal branching by FGF, Hh and Dpp
Terminal cells undergo an enormous increase in cell volume and surface area
during terminal branching, which continues throughout embryonic and
post-embryonic stages. FGF signaling promotes this process
(Jarecki et al., 1999;
Reichman-Fried and Shilo,
1995
) in two ways, first by activating the target gene SRF, which
is required for terminal branch growth
(Guillemin et al., 1996
), and
second by stimulating rapid filopodial movement
(Ribeiro et al., 2002
). These
two FGF signaling effects seem to be independent of Hh and Dpp. The FGF ligand
Bnl is expressed in epidermal cells beneath terminal cells during terminal
branching. Because this expression is limited to a relatively small region, we
consider it unlikely that FGF signaling is sufficient to provide vectorial
information for terminal branching. We suggest that FGF-driven growth and the
motility of terminal branches are restricted to the P compartment by Hh
signaling, wherein they are further limited by Dpp to establish a monopolar
growth pattern.
Hh functions as both a cell fate determinant and a guidance molecule for terminal branch extension. But how are these two distinct Hh functions coordinated? Inactivation of Hh after initiation of terminal branching via a temperature shift of hhts2 mutant embryos causes a loss of terminal cells (K.K., unpublished), suggesting that maintenance of tracheal cell fate also depends on a late Hh function. Thus, the striped expression of Hh in the epidermis is used simultaneously for epidermal patterning, tracheal cell fate determination and terminal branch guidance, exemplifying a simple strategy to coordinate the patterning of complex organs having multiple tissue types.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/131/21/5253/DC1
* Present address: Department of Biological Sciences, Stanford University,
Stanford, CA 94305, USA
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