Centro de Biología Molecular Severo Ochoa, CSIC and UAM, Cantoblanco, 28049 Madrid, Spain
* Author for correspondence (e-mail: jmodol{at}cbm.uam.es)
Accepted 12 July 2005
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SUMMARY |
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Key words: msh, Iroquois complex, Wing hinge, Notum, Developmental boundary, Drosophila, Dr
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Introduction |
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In the wing disc, the best characterized developmental boundaries are
associated with borders of compartments defined by cell-lineage restrictions
(García-Bellido et al.,
1973) (reviewed by Irvine and
Rauskolb, 2001
; Mann and
Morata, 2000
). The earliest boundary subdivides the disc into
anterior (A) and posterior compartments (P). It is established by the
expression of the selector genes engrailed and invected in
the P compartment. It has been proposed that the selector genes confer
identity to the cells of a compartment and a differential affinity that
prevents cells from apposing compartments to intermingle
(García-Bellido and
Santamaría, 1972
). The end result is a straight boundary
that separates both compartments and which, after final differentiation, does
not correspond with any morphological feature. A dorsoventral (DV)
compartmental subdivision, orthogonal to the AP one, is established by the
expression of the gene apterous (ap) in the D compartment.
In the wing, this boundary runs along the wing margin and separates the dorsal
and ventral wing blades. Compartment borders give rise to specialized cells
that are sources of signaling molecules that organize both cell proliferation
and patterning of the entire disc (for reviews, see
Brook et al., 1996
;
Teleman et al., 2001
;
Vincent and Briscoe,
2001
).
Other developmental boundaries are not associated with cell lineage
restrictions (reviewed by Irvine and
Rauskolb, 2001; Mann and
Morata, 2000
; Tepass et al.,
2002
). This implies that cells can cross the boundary and change
fates. An example is the boundary that separates the presumptive notum from
the dorsal wing hinge territory (Diez del
Corral et al., 1999
). A selector-like role has been attributed to
the genes araucan, caupolican and mirror
(Cavodeassi et al., 1999
;
Cavodeassi et al., 2000
;
Wang et al., 2000
), the three
members of the Iroquois Complex (Iro-C)
(Gómez-Skarmeta et al.,
1996
; McNeill et al.,
1997
). These genes, which encode related homeodomain proteins
conserved from worms to vertebrates (reviewed by
Cavodeassi et al., 2001
), start
to be expressed in the presumptive notal region during the second instar. This
expression is essential for notum specification, as clones of
Iro-C cells induced early within this territory acquire the
identity of the dorsal wing hinge (Diez
del Corral et al., 1999
). Thus, the early domain of expression of
Iro-C defines the extent of the notum territory. Moreover, Iro-C genes appear
to endow cells with special affinity characteristics, so that cells expressing
them assort with each other, rather than with Iro-C non-expressing cells
(Diez del Corral et al., 1999
;
Zecca and Struhl, 2002b
). This
specific affinity might help maintain the relatively straight and sharp
notum/dorsal hinge border in the wing imaginal disc
(Zecca and Struhl, 2002b
).
Similarly to the AP and DV boundaries, the notum/dorsal hinge boundary appears
to be a source of positional information, but the molecules involved have not
been identified (Diez del Corral et al.,
1999
).
Some progress has been made in understanding how the border of the Iro-C
domain that defines the notum/dorsal hinge boundary is established. It
requires the participation of two of the signaling systems that subdivide the
early disc in the proximodistal axis (reviewed by
Klein, 2001). Thus, on the one
hand, signaling by the tyrosine kinase EGF receptor turns on the genes of the
Iro-C (Wang et al., 2000
;
Zecca and Struhl, 2002a
;
Zecca and Struhl, 2002b
). On
the other hand, signaling mediated by the BMP2/4 homolog Dpp, which during the
early/mid second larval instar is active only in the more distal territories
of the disc, represses there the Iro-C and sets the distal border of the Iro-C
domain (Cavodeassi et al.,
2002
). However, at later stages, Dpp signaling occurs in the notum
territory and the border of Iro-C expression becomes refractory to it. This
suggested that additional agents might control the notal-hinge boundary
(Cavodeassi et al., 2002
).
The msh (muscle-segment homeobox) gene (Dr
FlyBase) is a member of the conserved Msx family. It encodes a homeodomain
transcription factor with an Engrailed-type repressor motif
(D'Alessio and Frasch, 1996).
In the embryonic mesoderm, msh specifies subsets of cardiac and
muscle precursors and participates in cross-repressive interactions with other
genes (Jagla et al., 2002
).
msh is also a neural-identity gene that is expressed in the
dorsal-most region of the embryonic neuroectoderm
(D'Alessio and Frasch, 1996
;
Isshiki et al., 1997
). In the
wing imaginal disc, msh imparts a dorsal identity to the dorsal
bristles of the wing margin and to wing veins
(Milán et al.,
2001
).
Here, we report that msh also participates in establishing/maintaining the notum/dorsal hinge boundary. From the second instar stage onwards, msh and Iro-C are expressed in adjacent domains of the imaginal wing disc, that of msh being distal to that of Iro-C. This situation essentially persists in the third instar, where msh is strongly expressed in the presumptive hinge region and Iro-C is expressed in the adjacent territory, the lateral notum. Loss- and gain-of-function analyses indicate that msh represses Iro-C in most of the presumptive dorsal hinge, and Iro-C prevents high level expression of msh in the notum, while it allows low expression of msh in this territory. msh is also necessary for proper development of the hinge and for the patterning of the notum. Moreover, the confrontation of cells expressing msh and Iro-C at the notum/hinge boundary appears to favor the correct growth of the notum and hinge territories.
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Materials and methods |
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Mosaic analysis
Mitotic recombination clones homozygous for the alleles
msh68,
Df(3L)iroDFM3 and Chipe55 were induced
by the FLP-FRT technique (Xu and Rubin,
1993
) by incubating larvae for 1 hour at 37°C. Larvae were
prepared as follows: flies FRT82B
msh
68 arm-lacZ/TM6B were crossed
with either f 36a hs-FLP; FRT82B P(f +)
M(3)w124/TM6B for clones to be examined in adults, or
hs-FLP; FRT82 ubi-GFP M(3)w124/TM6B for clones to be
analyzed in imaginal discs; flies hs-FLP; mwh Df(3L)iroDFM3
FRT80B/TM6B were crossed with hs-FLP; ubi-GFP FRT80B; and flies
FRT42B Chipe55/Cyo were crossed with hs-FLP; FRT42B
ubi-GFP/Cyo flies.
Overexpression clones were obtained by crossing either a UAS-ara
or UAS-msh line with y w hs-FLP122; act-FRT y+ FRT
Gal4 UAS-GFP/SM5 Tb (Ito et al.,
1997) flies. Clones were induced by incubation of larvae at
37°C for 8 minutes (UAS-msh) or 15 minutes (UAS-ara).
Df(3L)iroDFM3 clones in individuals overexpressing
UAS-mshi were obtained by crossing flies hs-FLP; UAS-mshi/Cyo;
Df(3L)iroDFM3 FRT80B/TM6B with flies ap-GAL4; ubi-GFP
FRT80B/TM6B. Clones were induced (37°C, 1 hour) at 60±12 hours
AEL (after egg laying) and the flies were raised at 29°C. Cuticles were
prepared by boiling in KOH and mounted in ethanol/lactic acid (5:6).
Antibody and ß-galactosidase staining
Imaginal discs were fixed and stained as in Xu and Rubin
(Xu and Rubin, 1993).
Antibodies were: rat anti-Ara, which reacts with Ara and Caup proteins
(Diez del Corral et al.,
1999
), rabbit anti-Msh
(McDonald et al., 1998
)
(provided by C. Doe), mouse anti-Wg, rabbit anti-Tsh, mouse anti-Nub (provided
by M. S. Cohen and D.S.H.B.), rat anti-Zfh2
(Whitworth and Russell, 2003
)
and rabbit anti-Sc (Skeath and Carroll,
1991
).
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Results |
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At the notum, when msh68
M+ clones were induced at 24-48 hours AEL, the most frequent
anomalies were a reduction of the scutellum
(Fig. 2C) and the appearance of
depigmented, naked and corrugated cuticle in the lateral posterior scutum
adjacent to the allula and the hinge (not shown). In addition, the
msh clones frequently developed extra macrochaetae
(Fig. 2H-J), mostly in the
dorsocentral (DC) region of the notum and in the scutellum, and occasionally
also induced nearby wild-type cells to differentiate as chaetae, suggesting
cell non-autonomous effects (Fig.
2J). The clones also suppressed extant chaetae
(Fig. 2G-I), the anterior and
posterior supraalars being the most affected, and interfered with the correct
formation of the scuto-scutellar suture
(Fig. 2J). Interestingly, in
clones that comprised the lateral anterior notum, a region where msh
expression has not been detected in the third instar disc, the anterior and
posterior notopleural and the presutural macrochaetae were missing in 70, 10
and 15% of cases, respectively (20 heminota examined).
msh is essential for proper growth and patterning, but not for the specification, of the dorsal hinge territory
To gain insight into the function of msh in the hinge, we examined
the effect of msh68
M+ clones on the expression of genes known to be required for
development of this territory. homothorax (hth),
teashirt (tsh), zfh-2 and wingless
(wg) are expressed at high levels in the presumptive hinge
(Azpiazu and Morata, 2000
;
Casares and Mann, 2000
;
Klein and Martínez-Arias,
1998
; Whitworth and Russell,
2003
) (Fig. 1C and
Fig. 3A,B,E). Their
characteristic patterns of expression were not overtly modified
(Fig. 3A,B,F and data not
shown), which suggested that msh was dispensable for the
specification of the dorsal hinge territory. Using as landmarks the highly
resolved pattern of scute (sc;
Fig. 3C)
(Cubas et al., 1991
;
Skeath and Carroll, 1991
), we
observed a shortening of the distance between the sc proneural
cluster at dorsal radius, in the hinge, and the anterior postalar cluster, in
the lateral notum (Fig. 3C,D).
We also observed the apparent fusion of the distal (d) and proximal (p)
sc clusters of the tegula region
(Fig. 3C,D). These findings
suggested a decrease in the size of the intervening mutant territory, an
interpretation further supported by the absence of the fold of the disc that
separates the notum and hinge regions (Fig.
1C) when these regions are mutant for msh
(Fig. 3A,B, blue arrowheads).
By contrast, the fold that separates the hinge from the wing pouch was
unaffected by the msh clones (Fig.
3A,B, yellow arrowheads). These results, together with the adult
phenotype of the msh
68
M+ clones, indicate that msh, although dispensable
for the specification of the dorsal hinge territory, is required for the
proper growth and patterning/differentiation of this territory.
|
msh downregulates ara/caup in the wing hinge
The msh68 M+
clones derepressed the ara and caup genes of the Iro-C in
the hinge territory (Fig.
4A,B). This upregulation was also observed in non-Minute
msh
68 clones induced at either
24/48 hours AEL (Fig. 4F) or
48/72 hours AEL (Fig. 4C). In
all cases, derepression was cell autonomous, and did not extend into the wing
pouch [the latter defined by the expression of Nubbin
(Ng et al., 1995
)
(Fig. 4A,B) or in a triangular
area that included the prospective tegula
(Fig. 4B, asterisk;
Fig. 4F). Similar
ara/caup derepression was obtained by overexpressing an
msh-interferring RNA (UAS-mshi; ap-Gal4 driver,
Fig. 4D). As Iro-C imparts
notum identity (Diez del Corral et al.,
1999
; Wang et al.,
2000
; Zecca and Struhl,
2002b
), its ectopic expression in the hinge may account for the
notum structures that develop in
msh
68 M+ clones
(Fig. 2F,G). Moreover, forced
expression of ara in the dorsal hinge interferes with its proper
formation (R. Diez del Corral, PhD thesis, Universidad Autónoma
de Madrid, 1998). Thus, the ectopic expression of ara/caup may
contribute to the disappearance of the hinge structures observed in
msh clones (Fig.
2E).
|
Iro-C downregulates msh in the lateral notum
We next examined whether ara/caup might repress msh in
the notum by using clones that lack essentially all Iro-C function
(iroDFM3 mutation). When induced early, these clones
acquire a hinge fate and consequently upregulate tsh
(Diez del Corral et al.,
1999). Thus, as expected they expressed msh at levels
similar to those of the hinge (Fig.
5A). However, iroDFM3 clones induced late in
development do not undergo fate transformations
(Diez del Corral et al.,
1999
). Still these clones, when located within the posterior
lateral notum, increased autonomously the accumulation of Msh
(Fig. 5B), but were unable to
upregulate tsh (not shown). Hence, Iro-C downregulates msh
in this region of the disc even in cells that are not transformed into hinge
cells. In the anterior lateral notum, late clones do not derepress
msh (not shown), suggesting the presence of additional
repressors.
The ability of Iro-C to repress msh was further demonstrated with
clones overexpressing UAS-ara in the hinge. msh was
autonomously repressed (Fig.
5C). This result was verified by driving UAS-ara with
ptc-Gal4 or by constitutively activating the EGFR signaling pathway,
which upregulates Iro-C in the hinge
(Zecca and Struhl, 2002b) (not
shown). Taken together, these data support a mutual repression between
msh and Iro-C in the notum/hinge region of the wing disc.
As indicated above, cells within the notum that lack Iro-C function switch
fate and autonomously develop as dorsal hinge
(Diez del Corral et al.,
1999). We now find that msh is necessary for proper
development of the hinge. Thus, it seemed pertinent to examine the fate of
cells that were simultaneously depleted of Iro-C and msh activities.
Accordingly, we induced iroDFM3 clones in discs expressing
UAS-mshi (ap-Gal4 driver) and examined the clones in the
third instar discs (adults failed to emerge). In the dorsal wing and hinge,
clones appeared with normal frequency (Fig.
5D). However, in the notum territory, clones did not survive or
were very small, when compared with the twin wild-type clones
(Fig. 5D). Thus, in this
territory, cells that are neither specified as notum nor can properly develop
as hinge are not viable or are outcompeted by the wild-type cells.
|
Because in the second instar disc, Dpp signaling confines ara/caup
expression to the notal region of the disc
(Cavodeassi et al., 2002), we
examined whether this inhibition was mediated by msh. The expression
of msh under loss- and gain-of-function conditions for Dpp argued
against this possibility (not shown). Wg signaling is most important to form
and pattern the hinge and the wing (Couso
et al., 1993
; Ng et al.,
1996
; Sharma and Chopra,
1976
). Again, loss- and gain-of-function conditions for Wg did not
prevent expression of msh in the dorsal hinge (not shown), indicating
that Wg does not control msh.
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Discussion |
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msh is required for dorsal hinge development
In the developing wing disc, msh is expressed most strongly in the
territory of the dorsal hinge, the region between the notum and the dorsal
wing blade territories. Removal of msh in clones results in
malformations that range from small defects, such as an outheld wing, to
partial or even complete loss of most hinge structures. In the latter cases,
the hinge may be posteriorly misplaced and ectopically attached to the
scutellum. In addition, in a fraction of flies ectopic notum tissue appears
contiguous to the extant hinge. Because at least a large part of the hinge
tissue is still present, we surmise that the absence of recognizable hinge
structures is due to the failure of their proper differentiation. This
phenotype correlates well with that observed in third instar wing discs
displaying msh- clones. Indeed, even large clones that
remove msh from most of the dorsal hinge territory allow the
specification of this territory, as demonstrated by the relatively unmodified
characteristic patterns of expression of genes such as wg, zfh-2, hth
and tsh, and the presence of recognizable proneural clusters of
sc expression. Moreover, the presence in mutant hinges of relatively
well resolved clusters of sc expression
(Fig. 3D) indicate that the
prepatterning of the hinge can proceed to a large extent in the absence of
msh. We conclude that msh is largely dispensable for
specification of the dorsal hinge territory, but it is required for the final
stages of its patterning and differentiation.
|
So far, several genetic interactions have been identified that together
permit to suggest a mechanism that partially answers this question
(Fig. 6). In the second instar
disc, the EGFR pathway activates ap and Iro-C
(Wang et al., 2000;
Zecca and Struhl, 2002a
;
Zecca and Struhl, 2002b
). The
distinct but overlapping domains of expression of these genes, the dorsal
compartment (ap) and the notum territory (Iro-C), may be defined by
differential sensitivity to EGFR signaling
(Zecca and Struhl, 2002a
) or,
alternatively, in the case of Iro-C, by Dpp signaling
(Cavodeassi et al., 2002
). In
these early stages, Dpp signaling is active only in the distal part of the
disc, where it represses the Iro-C and sets its distal limit of expression.
Hence the antagonistic actions of the EGFR and the Dpp pathways would define
the position of the distal limit of the Iro-C domain, and therefore the
position of the notum/hinge subdivision.
We now find that at approximately the time Iro-C starts to be expressed in
the more proximal part of the disc, i.e. that which will become the notum,
expression of msh, by means of ap, is turned on in the
adjacent dorsal hinge territory (see also
Milán et al., 2001).
These essentially complementary patterns of expression are maintained, with
some qualifications, in the third instar disc. Loss- and gain-of-function
experiments show that msh prevents ara/caup from being
expressed in the hinge; and ara/caup restrain msh from being
expressed in the notum at the high levels typical of the hinge (although it is
expressed at a low level in part of the notum). This mutual repression also
occurs late during development.
|
The relevance of the mutual repression between Iro-C and msh is also manifested by their respective overexpression. Ectopic Iro-C products in the hinge impair the proper differentiation of hinge structures (R. Diez del Corral, PhD thesis, Universidad Autónoma de Madrid, 1998). High levels of Msh in the notum turn on a hinge-specific marker like zfh-2 (Fig. 3G) and are detrimental for notum development (Fig. 4G).
In the third instar disc, the distal border of the Iro-C domain is no
longer straight and displays a pronounced `bay' where ara/caup are
downregulated (Fig. 1C, blue
arrow, red channel). This roughly coincides with the area of highest
expression of msh in the lateral notum. msh is probably
responsible for this downregulation of ara/caup, as the `bay'
disappears in msh clones (Fig.
4F). Moreover, the abutting domains of msh and Iro-C in
the ventral hinge and pleura, respectively
(Fig. 1C), suggest that a
similar mutual repression may occur there to establish the subdivision between
these neighboring regions. Finally, the removal of msh does not
activate Iro-C in the anterior part of the hinge territory
(Fig. 4B), suggesting again
that agents other than msh and Dpp
(Cavodeassi et al., 2002) help
maintain Iro-C expression confined to the notum territory.
Organizing properties of the notum/hinge boundary
Iro-C clones located within the medial notum not only
undergo an autonomous transformation to dorsal hinge. They also become
surrounded by a fold similar to that which separates the notum and hinge
territories, and they modify the expression of several markers in the
surrounding wild-type tissue in a way consistent with a transformation of this
tissue towards lateral notum (Diez del
Corral et al., 1999). These nonautonomous effects suggest that
signals emerge from the Iro-C clones, and that these signals
alter the fate of the aposed notum tissue. Hence, it was inferred that, in the
wild-type disc, signaling would take place across the hinge/notum boundary and
this would help pattern at least the lateral notum
(Diez del Corral et al.,
1999
). This is reminiscent of the DV and AP compartment
boundaries, where signaling mediated by the diffusible molecules Wg, and Hh
and Dpp, respectively, are key to stimulating the growth and pattern of the
wing disc (for reviews, see Brook et al.,
1996
; Teleman et al.,
2001
; Vincent and Briscoe,
2001
). However, in the hinge/notum boundary, the signaling agents
have not been identified. They could be either diffusible molecules or
cell-bound molecules that mediate this cell to cell communication.
Now, we find that the imaginal disc territories flanking the notum/hinge
border are reduced in size when they are mutant for msh
(Fig. 3). We do not know
whether this effect is due to decreased cell proliferation, increased cell
death or both, and whether it mostly affects the hinge or the lateral notum.
However, it is clear that by removing msh and allowing Iro-C to be
expressed in the hinge, the msh clones suppress the confrontation of
proper hinge cells with notum cells. It is tempting to speculate that this
could affect the net growth of the territory by removing positional values
(García-Bellido et al.,
1994) and/or by suppressing or making ineffective the postulated
signaling associated with the hinge/notum border. Consistently, a reduced size
of the notum plus hinge region (and a simplification of the patterning) is
also observed in discs overexpressing UAS-ara in the dorsal
compartment (Diez del Corral et al.,
1999
) (E.V.-C. and J.M., unpublished), a condition that removes
most msh expression from the hinge. The failure of
Iro-C clones within the notum territory to grow and survive
when they are also depleted of Msh (Fig.
5D) might result from the absence of proper signaling across a
boundary where wild-type notum cells confront Iro-C
msh cells. Considering that the activity of the
EGFR signaling pathway is necessary for notum cell proliferation
(Díaz-Benjumea and
García-Bellido, 1990
;
Simcox et al., 1996
;
Wang et al., 2000
), it would
be of interest to examine whether this pathway is involved in, or is modulated
by, the presence of the notum/hinge boundary.
In Drosophila, the Iro-C genes and msh respectively
participate in the DV subdivision of the eye
(Cavodeassi et al., 1999;
McNeill et al., 1997
) and of
the neuroectoderm (reviewed by Cornell and
Ohlen, 2000
;
Gómez-Skarmeta et al.,
2003
; Skeath,
1999
). In vertebrates, although to our knowledge no instance of
mutual repression between homologs of Iro-C and msh has been
described, members of each family participate in establishing borders by
repression with other genes in the spinal cord, the brain (reviewed by
Gómez-Skarmeta et al.,
2003
) and between rhombomeres
(Lecaudey et al., 2004
).
Clearly, both genes are used frequently to subdivide territories and establish
alternative differentiation pathways at each side of the border that separates
them.
msh helps patterning the notum
Throughout the third instar, msh is expressed at relatively low
levels in the posterior notum territory. Here, removal of msh most
often results in impaired growth of the scutellum, absence of the
scutellum/scutum suture and alterations of the bristle pattern. Interestingly,
the lateral/anterior notum macrochaetae are often missing, even though they
arise in a region apparently devoid of msh expression. This suggests
that either msh is expressed there at very low but functional levels,
or that the suppression of macrochaetae results from non-autonomous effects of
the absence of Msh from neighboring territories. It should be noted that
non-autonomous macrochaetae suppression is also associated with
Iro-C clones that cause notum to hinge transformations
(Diez del Corral et al.,
1999). This has suggested that modification of the putative
signaling across the notum/hinge boundary interferes with macrochaetae
patterning at the notum. It is possible that the msh clones might
also interfere, as indicated above, with signaling from this border. If so,
the presence of clusters of sc expression at the anterior lateral
notum within large msh clones
(Fig. 3D) suggest that this
interference might occur at a stage later than the emergence of the proneural
clusters.
The absence of msh function does not modify the expression of
Iro-C in the lateral notum or the characteristic patterns of expression of
eyg and hth (E.V.-C., unpublished), genes that are high in
the hierarchy that control notum development
(Aldaz et al., 2003;
Aldaz et al., 2005
). But it
removes the scutum/scutellar suture and promote development of extra bristles
in the dorsocentral and scutellar regions. Again, these are phenotypes
suggestive of an interference with the late patterning and differentiation of
these structures.
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ACKNOWLEDGMENTS |
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