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First published online 4 July 2007
doi: 10.1242/dev.02878
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1 Medical Research Council Centre for Developmental Neurobiology, King's College
London, 4th Floor New Hunt's House, Guy's Hospital, London SE1 1UL, UK.
2 Temasek Life Sciences Laboratory, 1 Research Link, National University of
Singapore, Singapore 117604, Republic of Singapore.
Author for correspondence (e-mail:
marita{at}tll.org.sg)
Accepted 14 May 2007
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: SoxNeuro, Dichaete, shavenbaby, Drosophila epidermal growth factor receptor (Der)- and Wingless (Wg)-pathway activities, Epidermal differentiation
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Sanson, 2001). These studies
have identified the transcription factor shavenbaby (svb) as
the most downstream target of the signaling cascades that pattern the ventral
epidermis (Payre et al.,
1999). Recent studies have shown that svb is necessary
and sufficient to direct denticle formation in a cell-autonomous manner by
regulating the expression of genes whose products are involved in epidermal
cell-shape remodeling (Chanut-Delalande et
al., 2006). In each segment of the ventral epidermis, svb
is expressed in a discreet domain of six rows of cells. The spatial limits of
this domain reflect the inputs of Der- and Wg-pathway activities on the
transcriptional regulation of svb expression: Der pathway activity
stimulates and Wg pathway activity represses svb expression
(Szuts et al., 1997). The expression of svb in a discreet and invariable domain poses a question that appears in many developmental contexts: how do individual cells integrate opposing extrinsic information such that the response of the cell is non-stochastic and invariable? Circumstantial evidence suggests that svb is not a direct target gene of the Wg signaling cascade. Our study shows that the high mobility group (HMG)-domain protein SoxNeuro (SoxN) has a dual role in the establishment and maintenance of a discreet domain of svb expression. First, SoxN expression is activated by Der- and repressed by Wg-pathway activities. SoxN is necessary for the expression of svb and is sufficient to cell-autonomously activate svb expression even in the presence of high levels of Wg signaling. Hence, SoxN represents a molecular link between these signaling cascades and the expression of svb. Moreover, we show that svb is required for the maintenance of but not for the establishment of the late epidermal SoxN expression. This indicates a reciprocal regulatory relationship between svb and SoxN. Second, many vertebrate Sox proteins have been shown to antagonize Wg pathway activity. We present evidence that this function is conserved in Drosophila SoxN. Hence, the spatial limits of both SoxN expression and Wg pathway activity are determined by a negative-feedback loop. These results suggest that the expression of svb in a discreet domain is resolved at the level of SoxN. Furthermore, we show that a closely related HMG-domain protein, Dichaete, is co-regulated with SoxN and has a redundant, albeit weaker, function in the activation of svb expression and in the restriction of Wg pathway activity.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Overton et al.,
2002). SoxNU6-35 contains a C to T transition
that results in a nonsense codon at amino acid position 133;
SoxNGA1192 contains a C to T transition that results in
nonsense codon at amino acid position 172. The putative translation products
of both mutant alleles do not contain the HMG domain. The following
Gal4 driver lines and UAS-constructs were used:
scaGal4 (which drives expression in the ventral ectoderm from early
stage 9 onward) and wgGal4 were obtained from the Bloomington Stock
Center. enGal4 (Brand and
Perrimon, 1993), armVP16Gal4
(Sanson et al., 1996) was
kindly provided by J. P. Vincent (MRC National Institute for Medical Research,
London, UK); UAS-SoxN
(Overton et al., 2002).
pangolin2 (synonymous with dTCF2)
(van de Wetering et al., 1997)
and wgcx4 (Baker,
1988) were obtained from the Bloomington Stock Center.
Dr72 was kindly provided by S. Russell
(Soriano and Russell, 1998).
UAS-EgfrAct, UAS-derDN and
UAS-wgHA were kindly provided by J. Bateman and J. Ng (both
from King's College London, London, UK), respectively. The amorphic allele
svb1 was kindly provided by F. Payre
(Payre et al., 1999).
UAS-SoxN-YFP was generated by Gateway cloning of the
complete SoxN coding sequence into the pTVW vector.
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).
Immunohistochemistry
Embryos were collected, fixed and immunostained as previously described
(Yang et al., 1997). Primary
antibodies were polyclonal mouse anti-SoxN (1:1000)
(Buescher et al., 2002);
polyclonal rabbit anti-Dichaete (1:1000)
(Nambu and Nambu, 1996);
monoclonal mouse anti-Engrailed/Invected (also known as Engrailed, En) (4D9;
developed by C. Goodman). The Engrailed/Invected hybridomas were obtained from
the Developmental Studies Hybridoma Bank developed under the auspices of the
National Institute of Child Health and Human Development (NICHD) and
maintained by the University of Iowa, Iowa City, IA. Histochemical detection
was performed with Jackson ImmunoResearch HRP-conjugated secondary antibodies
and visualized by the glucose-oxidase-DAB-nickel method, as described
(Shu et al., 1988).
Fluorescent secondary antibodies were obtained from Jackson ImmunoResearch
(Cy3- and FITC-conjugated anti-mouse and anti-rabbit antibodies).
In situ hybridization
RNA in situ hybridization was carried out as described previously
(Tautz and Pfeifle, 1989). For
the generation of the svb RNA probe, a svb-specific DNA
fragment of approximately 1.5 kb length was amplified from genomic DNA using
PCR and subsequently used as a template for in vitro transcription with T7 RNA
polymerase.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The present study was performed using two independent,
putatively amorphic alleles of SoxN, which have essentially identical
mutant phenotypes: SoxNGA1192
(Buescher et al., 2002) (also
see Materials and methods) and SoxNU6-35
(Overton et al., 2002).
SoxN homozygous mutant embryos die late in embryogenesis, after the
secretion of cuticle. The SoxN mutant phenotype is characterized by a
moderate loss of denticles and a corresponding increase of naked cuticle
(Fig. 1B,B'). To
understand the role of SoxN in the formation of denticles, we first examined
the expression pattern of SoxN. During embryogenesis, SoxN protein expression
undergoes dynamic changes (Buescher et al.,
2002; Cremazy et al.,
2000). To determine the precise boundaries of SoxN expression
within segments, we double-stained wild-type embryos with anti-SoxN and
anti-En, the latter providing a stable landmark throughout embryogenesis. From
stage 5 to late stage 8, SoxN is expressed throughout the ventral ectoderm
(Fig. 1C)
(Buescher et al., 2002;
Cremazy et al., 2000;
Overton et al., 2002). From
stage 9 onwards, SoxN protein decays; this is first observed in a narrow
stripe just anterior to the En domain, so that, at late stage 9, SoxN protein
remains present in the entire epithelium with the exception of the Wg
expression domain (Fig. 1D).
After stage 9, SoxN protein expression further decays throughout the segment.
From early stage 12 onwards, SoxN expression is re-initiated in segmental
stripes of 6-cell width at the lateral periphery of the ventral epidermis.
Subsequently, these stripes expand along the dorsoventral (D/V) axis and, from
stage 13 onwards, span the ventral epidermis. SoxN remains expressed in
6-cell-wide stripes until the end of embryogenesis
(Fig. 1E). However, we noticed
that, after stage 13, the level of SoxN expression is further upregulated in
the two posterior-most rows of cells (Fig.
1F, arrows). En and SoxN stripes partially overlap so that the
anterior-most row of SoxN expression co-localizes with the posterior row of En
expression (Fig. 1F). These
results indicate that, during the embryonic stages in which epidermal cell
fate is specified, SoxN expression is restricted to those cells that will
differentiate to produce denticles. Most notably, the SoxN and
svb expression domains completely coincide
(Fig. 1, cartoon).
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). This prompted us to examine whether the late expression of
SoxN is regulated by the same signaling cascades. In wg null mutant
embryos (wgcx4) SoxN expression did not decay after stage
8 and remained ubiquitous until the end of embryogenesis
(Fig. 1G). In fact, the
aberrant expression patterns of SoxN and svb in wg
mutant embryos were very similar (compare
Fig. 1G with 1H). However,
derepression of SoxN in a wg mutant background did not result in
uniform levels of SoxN expression throughout the ventral epidermis. Instead,
the level of ectopic SoxN expression remained lower than that of SoxN within
its endogenous domain, suggesting that the establishment of wild-type levels
of SoxN expression might require additional stimulating input(s). Onset and
location of SoxN expression in epidermal stripes suggests that the activation
of the Der pathway via its ligand Spi might stimulate SoxN expression.
Activation of the Der pathway throughout the ventral epidermis with the
armadillo (arm)-VP16 driver
(armVP16Gal4-UAS-EgfrAct) indeed
resulted in a posterior expansion of SoxN expression by two to three rows of
cells (Fig. 1I). Conversely,
reduction of Der pathway activity throughout the ventral epidermis
(armVP16Gal4-UAS-EgfrDN) resulted in a
strong loss of SoxN expression (Fig.
1J). Taken together, our data indicate that the late expression of
SoxN in epidermal stripes is positively regulated by Der- and negatively
regulated by Wg-pathway activities. Hence, the co-expression of SoxN
and svb reflects their regulation by the same signaling cascades.
SoxN is necessary and sufficient to activate the expression of svb downstream of the Der- and Wg-pathway activities
Our observations raise the issue as to whether the expression of
SoxN and svb are regulated in parallel by the Der- and
Wg-pathway activities, or whether Spi and Wg might regulate the expression of
SoxN, which could in turn activate the expression of svb. To
address this, we first examined whether loss of SoxN results in a
loss of svb expression. In stage-14 SoxN mutant embryos, we
found that svb expression was strongly reduced compared with
wild-type, indicating that SoxN is necessary for the expression of
svb (Fig. 2A,B). To
determine whether SoxN is sufficient to cause ectopic svb
expression/denticle formation, we used a number of Gal4 lines that
drive expression in different parts of the ventral epidermis, and observed
that misexpression of SoxN resulted in ectopic denticle formation. For
example, misexpression of SoxN in the anterior row of the En stripe
(enGal4-UAS-SoxN) resulted in ectopic denticle
formation within this row of cells (Fig.
2C). Misexpression of SoxN with the armVP16Gal4 driver
(armVP16Gal4-UAS-SoxN-YFP) resulted in ectopic
denticle formation in most of the ventral epidermis except for in narrow
stripes anterior to the row 1 denticles. In these regions, ectopic denticle
formation remained sparse. The ectopic denticle formation reflected the
ectopic expression of svb in broadened segmental stripes, which were
separated by narrow gaps with little or no svb expression
(Fig. 2E). Although the
armVP16Gal4 driver has been described as directing the expression of
transgenes in a ubiquitous manner, staining of
armVP16Gal4-UAS-SoxN-YFP embryos with anti-GFP
indicated that this was not the case. Instead, we observed
YFP-immunoreactivity in broad stripes, which were separated by narrow stripes
with little or no YFP (Fig.
2F). This suggests that the ectopic expression of
svb/ectopic denticle formation in
armVP16Gal4-UAS-SoxN-YFP embryos reflects the
distribution of SoxN-YFP.
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;
Haremaki et al., 2003;
Mansukhani et al., 2005;
Zorn et al., 1999). To
determine whether the SoxN-mediated formation of denticles within the
wg expression domain might be due to a reduction of Wg pathway
activity, we co-expressed wg together with SoxN
(wgGal4-UAS-SoxN-YFP-UAS-wgHA).
We observed ectopic denticle formation in cells that expressed high levels of
wg, as shown by anti-hemagglutinin (anti-HA) staining
(Fig. 2I). These results
indicate that SoxN activates the expression of svb downstream of Wg
pathway activity.
In wg null mutant embryos, svb is expressed throughout
the ventral epidermis and the resulting cuticle is covered by a lawn of
denticles (Fig. 3A)
(Payre et al., 1999). Our
results suggest that ectopic denticle formation in wg mutants might
result from the derepression of SoxN, which, in turn, activates the
expression of svb. Removal of SoxN function in a wg mutant
background resulted in cuticles with few or no ectopic denticles, indicating
that ectopic denticle formation in wg mutants is, at least in part,
dependent on SoxN (Fig. 3B). We
confirmed this result by analyzing the function of SoxN in the absence of
pangolin (pan, dTCF), the nuclear effector of Wg signaling
(van de Wetering et al.,
1997). pan2 mutant larvae were covered by a
lawn of denticles (Fig. 3C).
Reduction of SoxN function (pan2;SoxN/+) resulted in fewer
ectopic denticles, whereas removal of all SoxN function
(pan2;SoxN) resulted in a SoxN mutant cuticle
phenotype (Fig. 3D,E). Hence,
SoxN acts genetically downstream of wg to activate the expression of
svb.
As shown above, SoxN expression is activated by Der pathway activity. This
suggests that SoxN might act downstream of Spi to activate svb. To
confirm this hypothesis we analyzed the epistatic relationships of the Der
pathway, SoxN and svb. Previous studies had shown that activation of
the Der pathway throughout the ventral epidermis results in the formation of
ectopic denticles (Payre et al.,
1999; Szuts et al.,
1997). We confirmed this result using the scabrous
(sca)-Gal4 driver to misexpress an activated form of the
epidermal growth factor receptor (Egfr)
(scaGal4-UAS-EgfrAct). scaGal4
drives the expression of transgenes throughout the ventral epidermis from
stage 9 onwards. Activation of the Der pathway throughout the ventral
epidermis resulted in the formation of three to four rows of ectopic denticles
posterior to the wild-type row-6 denticles
(Fig. 3F). Removal of SoxN
function in embryos misexpressing EgfrAct
(SoxN;scaGal4-UAS-EgfrAct) strongly
reduced ectopic denticle formation, indicating that the ability of Der pathway
activity to direct denticle formation is at least in part dependent on SoxN
function (Fig. 3G).
Taken together, our results show that SoxN directs the formation of denticles downstream of Der- and Wg-pathway activities and upstream of svb. Hence, SoxN links the Der- and Wg-signaling cascades with svb, expression of which itself is necessary and sufficient to direct denticle formation.
svb function is necessary for the maintenance of epidermal SoxN expression
The expression of SoxN in epidermal stripes of 6-cell width is established
by stage 13 and is maintained until the end of embryogenesis. As shown above,
the establishment of the SoxN expression domain results from the opposing
activities of the Der and Wg pathways. However, the maintenance of SoxN
expression until the end of embryogenesis might depend on additional factors.
From late stage 13 onwards, SoxN and svb are co-expressed.
Taking into account that Svb is a transcription factor, it is conceivable that
Svb acts to support the late expression of SoxN. To analyze whether Svb plays
a role in the maintenance of SoxN expression, we stained
svb1 mutant embryos with anti-SoxN antibody. At embryonic
stage 13, SoxN expression in wild-type and svb1 mutant
embryos showed no appreciable differences, indicating that svb
function is not required for the establishment of the SoxN expression domain
(Fig. 4A,B). This result is
consistent with our observation that the epidermal expression of SoxN precedes
and is necessary for the expression of svb. However, in stage-16
svb1 mutant embryos, the expression of SoxN was strongly
reduced as compared with wild-type embryos, indicating that svb
function is necessary for the maintenance of SoxN expression
(Fig. 4C,D). Taken together,
our results demonstrate a reciprocal regulatory relationship between SoxN and
svb: SoxN is required for the establishment of the expression of
svb; in turn, svb is necessary to maintain the expression of
SoxN.
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|
;
Overton et al., 2002). We
wondered whether Dichaete might also have a function in the activation of
svb expression/denticle formation. Previous studies have shown that,
during the embryonic stages 5 to 9, Dichaete expression partially overlaps
that of SoxN (Overton et al.,
2002). We sought to determine whether there is any overlap between
SoxN and Dichaete expression during later stages of embryonic development.
Double-staining of wild-type embryos with anti-SoxN and anti-Dichaete
antibodies revealed that SoxN and Dichaete co-localized in the ventral
epidermis from stage 12 until the end of embryogenesis
(Fig. 5A). Furthermore, like
SoxN, Dichaete expression was negatively regulated by Wg pathway activity: in
wg null mutant embryos (wgcx4), Dichaete was
derepressed and found throughout the ventral epidermis, although its
expression levels were not uniform (Fig.
5B). In addition, we found that Dichaete expression is positively
regulated by Der pathway activity: misexpression of
EgfrAct
(armVP16Gal4-UAS-EgfrAct) resulted in an
expansion of Dichaete expression; whereas a reduction of Der pathway activity
(armVP16Gal4-UAS-derDN) caused a partial
loss of Dichaete expression (Fig.
5C and data not shown). As shown above, during the late stages of
embryogenesis, the maintenance of SoxN expression depends on
svb. To determine whether the late expression of Dichaete requires
svb function, we stained svb1 mutant embryos with
the anti-Dichaete antibody. At embryonic stage 13, no significant difference
was observed between wild-type and svb1 mutant embryos
(Fig. 4E,F). However, at stage
16, Dichaete expression was found to be reduced in svb1
mutant embryos as compared with wild type
(Fig. 4G,H). This indicates
that svb is required for the maintenance but not for the
establishment of the Dichaete expression domain. Taken together, these results
show that, from mid-embryogenesis onwards, SoxN and Dichaete are co-regulated
and, as a result, co-expressed.
Previous studies have shown that loss of Dichaete results in an aberrant
cuticle pattern (Nambu and Nambu,
1996). However, these defects mainly reflect the early function of
Dichaete in segmentation rather than a specific function in the regulation of
svb expression. To determine whether Dichaete has a more specific
function in regulating the expression of svb/denticle formation, we
lowered the level of Dichaete function in a SoxN mutant background
(SoxN;Dichaete/+). We observed that this change strongly enhanced the
SoxN mutant phenotype, because denticle formation was nearly
completely abolished (Fig.
5D-F). This indicates that Dichaete has a function in the
regulation of svb expression that is revealed in the absence of
SoxN. This conclusion is supported by the observation that
misexpression of Dichaete in the ventral epidermis results in ectopic denticle
formation (P.M.O. and S. Russell, unpublished results).
|
; Haremaki et al.,
2003; Mansukhani et al.,
2005; Zorn et al.,
1999). Sox proteins were shown to reduce Wg signaling by
sequestering nuclear ß-catenin and preventing its binding to TCF factors.
Nuclear ß-catenin acts as a transcriptional co-activator at Wg target
genes by associating with dTCF (Cadigan and
Nusse, 1997). A possible role for Drosophila Sox proteins
in antagonizing Wg signaling has not been explored so far. This prompted us to examine whether SoxN and Dichaete might have a function in restricting Wg pathway activity. Due to the function of SoxN and Dichaete in the regulation of svb expression, analysis of the cuticle phenotype, the classic read-out for Wg signaling, does not provide a suitable model. Instead, we analyzed the expression of the en gene, which is positively regulated by Wg signaling. During the embryonic stages 9 and 10, the maintenance of En expression in epithelial stripes requires Wg signaling and the width of the En stripe is a read-out of the strength of Wg signaling. Staining of late-stage-10 SoxN mutant embryos revealed an expansion of the En stripe from the wild-type 2-cell width to a 3- to 4-cell width at the ventral midline (compare Fig. 6A with 6C). This observation demonstrates that, in SoxN mutant embryos, Wg pathway activity is increased. Conversely, misexpression of SoxN (armVP16Gal4-UAS-SoxN) resulted in a partial decay of en expression from stage 10 onwards, indicating a reduction in Wg pathway activity (Fig. 6B). These results show that SoxN negatively regulates Wg pathway activity in the ventral epidermis. To determine whether Dichaete can antagonize Wg pathway activity, we reduced Dichaete function in a SoxN mutant background (SoxN;D/+) and examined late-stage-10 embryos with the anti-En antibody. We observed an expansion of the En stripe from a 3- to 4-cell width in SoxN single mutant embryos to a 5- to 6-cell width in SoxN;D/+ embryos at the ventral midline (Fig. 6D). This result indicates that Dichaete and SoxN have redundant functions in restricting Wg pathway activity.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The
expression of svb is regulated by the opposing gradients of two
signaling molecules: Spi, which activates, and Wg, which represses,
svb expression. svb is expressed in segmentally reiterated,
epidermal stripes, which invariantly encompass six rows of cells. This raises
the question of how is opposing extrinsic information integrated to establish
a distinct domain of svb expression with a sharp posterior
border? In this study, we demonstrate that the HMG-domain proteins SoxN and Dichaete represent a molecular link between the expression of svb and the upstream Der- and Wg-signaling cascades. We show that SoxN and Dichaete are expressed in the ventral epidermis at the time when epidermal cell fates are specified. The late phase of SoxN and Dichaete expression is stimulated by Der- and repressed by Wg-pathway activity. These regulatory mechanisms result in the expression of SoxN and Dichaete in those six rows of cells within each abdominal segment that differentiate to produce trichomes. SoxN and, to a lesser extent, Dichaete, are necessary and sufficient to activate the expression of svb. Furthermore, our results show that the well-described repression of svb by Wg is due to the repression of SoxN, which, in turn, results in the loss of svb activation. Likewise, the Spi-mediated activation of svb expression relies on the activation of SoxN, which, in turn, activates svb. This indicates that the competition of Der- and Wg-pathway activities for the specification of trichome-producing versus smooth cell fates is resolved at the level of SoxN and Dichaete.
These results do not provide much insight into the issue of how opposing extrinsic information is integrated such that a sharp posterior border of svb expression is achieved. Instead, they raise the question of how is a sharp posterior border of SoxN and Dichaete expression established/maintained? Our findings suggest that this is achieved by a combination of negative- and positive-feedback loops (Fig. 6, cartoon). First, we provide evidence that SoxN and Dichaete negatively regulate Wg pathway activity. This negative-feedback loop provides a likely mechanism for the establishment and maintenance of a sharp posterior border of SoxN and Dichaete expression. The issue arises of how robust this system might be in the face of fluctuating levels of Wg pathway activity. The efficiency with which SoxN and Dichaete restrict Wg pathway activity will crucially rely on the levels of SoxN and Dichaete protein. In this context, it is noteworthy that the levels of SoxN protein, but not Dichaete, are several-fold higher in the two posterior-most rows of the SoxN stripe compared with the anterior four rows (Fig. 1F). The regulatory mechanisms that underlie the different levels of SoxN expression are currently unclear. Second, we provide evidence that the maintenance of SoxN and Dichaete expression is supported by a positive-feedback loop: svb, the expression of which is activated by SoxN and Dichaete, is itself required for the maintenance of SoxN and Dichaete expression (Fig. 6, cartoon). Together, these mechanisms contribute to an invariant read-out of cell identity from opposing Der- and Wg-pathway activities.
In Drosophila, SoxN and Dichaete are necessary and sufficient to
activate the expression of svb, which in turn directly regulates the
expression of genes involved in trichome morphogenesis
(Chanut-Delalande et al. 2006).
Is a function in hair formation of the Sox proteins conserved in other
species, including vertebrates? A previous study has shown that the mouse Sox9
protein is required for the differentiation of hair-producing epidermal cells
and acts genetically downstream of sonic hedgehog pathway activity
(Vidal et al., 2005). This
study did not address whether Sox9 regulates the expression of movo1
(Ovol1), the mouse ortholog of svb
(Dai et al., 1998).
Nevertheless, the demonstrated roles of SoxN, Dichaete and Sox9 raise the
exciting question of do Sox proteins have an essential function in the
activation of an epidermal differentiation program that is conserved across
species as distantly related as mice and flies?
Note added in proof
A study by Chao et al. confirms our observation that SoxN controls Wg
signaling (Chao et al., 2007).
This study suggests that SoxN does not antagonize Wg signaling by sequestering
armadillo.
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ACKNOWLEDGMENTS |
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Footnotes |
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