Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA
* Author for correspondence (e-mail: bruce.morgan{at}cbrc2.mgh.harvard.edu)
Accepted 13 December 2004
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SUMMARY |
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Key words: Ectodysplasin, Edar, Edaradd, Feather bud, Pattern formation
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Introduction |
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Studies of hair follicle development in the mouse have also identified
analogous roles for the Wnt/ß-catenin and BMP pathways
(Pispa and Thesleff, 2003).
However, another signaling pathway that plays a crucial role in follicle
formation has been identified by study of the underlying causes of the human
anhidrotic ectodermal dysplasia syndromes (HED). These syndromes are
characterized by the dysmorphology or absence of structures that result from
epidermal-mesenchymal interactions, including hair follicles, sweat glands and
teeth. Mutations in the genes for ectodysplasin (ED1), a
secreted signaling molecule of the TNF family, its receptor (EDAR),
and the downstream death domain adaptor ectodysplasin receptor associated
death domain (EDARADD) are responsible for the various forms of
HED (Wisniewski et al., 2002
)
Spontaneous mutations in the murine genes for Eda, Edar and
Eadaradd define the analagous mouse mutants tabby, downless,
and crinkled, all of which exhibit abnormal hair follicle development
(Thesleff and Mikkola,
2002
).
Analysis of primary follicle formation in the mouse mutants suggested that
the ectodysplasin pathway plays a very early role in this process. In mice,
hair follicle formation occurs in three distinct waves
(Mann, 1962). The primary wave
occurs around E14 and produces the tylotrich or guard hairs, which are
ultimately larger than the hairs produced in succeeding waves. Second and
third waves of follicles arise at E17 and after birth in the intervening
spaces between follicles formed in previous waves, and will generate three
types of hairs - awls, zigzags and auchenes. Mutations in the mouse genes
encoding Eda, Edar and Edaradd all result in failure of the
first wave of hair follicle formation, and the mice ultimately lack guard
hairs (Headon et al., 2001
;
Headon and Overbeek, 1999
;
Laurikkala et al., 2002
;
Mikkola et al., 1999
).
However, follicles do form in what are thought to be abnormal versions of the
subsequent waves. Although the resulting hairs are structurally abnormal and
characterized as abnormal awls, this may be due in part to later roles for
ectodysplasin signaling in follicle morphogenesis as both Eda and its
receptor are expressed in the hair follicle bulb. Despite these abnormalities,
it is clear that much of the follicle formation process per se can occur in
the absence of Eda, Edar or Edaradd.
During skin and follicle development in the mouse, all three genes are initially expressed throughout the basal layer of forming epidermis prior to the initial differentiation of the primary follicle placodes. However, as follicle specification progresses, ectodysplasin expression becomes repressed in the epidermal placode of the follicle and thereby restricted to the interfollicular epidermis. By contrast, Edar and Edaradd transcript levels are increased in the placode and decreased in interfollicular epidermis. Like Edar, a number of genes become expressed in a punctate pattern in E14 skin, reflecting their preferential expression in the forming epidermal placodes. However, this punctate pattern was not observed for a battery of markers tested in the Eda pathway mutants, suggesting that the earliest steps in follicle formation may be blocked in the absence of Eda activity.
Particular attention has been paid to the localization of Edar
expression to the forming placodes. This is in part because the localization
of Eda expression to the interfollicular epidermis is not crucial for
pattern formation. Guard hair follicle formation in the tabby mutant
can be rescued either by expression of Eda under the control of the
keratin14 promoter, which results in expression throughout the basal
epidermis and epidermal placode, or by injection of pregnant mice with a
soluble Eda/IgGFC fusion protein that crosses the placenta
(Gaide and Schneider, 2003;
Mustonen et al., 2003
). It is
possible that the Eda pathway may play an unlocalized role upstream of initial
patterning events in achieving the competence to form a placode. However, if
localized signaling through the Eda pathway is required for placode formation,
the restriction of receptor or other transduction components to the nascent
follicle is likely to be a crucial step in the function of this pathway.
Localization is in one sense dependent on Eda signaling; Edar remains
expressed throughout the epithelium at E15 in the tabby
(Eda) mutant mouse when expression is largely restricted to the
epidermal placodes in wild-type skin
(Laurikkala et al., 2002
).
However, when the abnormal awl follicles form at E17, Edar is
preferentially expressed in them, demonstrating that Eda activity is not
directly required for its localization and that it can occur as a consequence
of follicle formation in the absence of Eda signaling.
From the perspective of pattern formation, a crucial question is whether localized Eda/Edar pathway signaling lies upstream or downstream of the interaction between the ß-catenin and BMP pathways postulated to direct early patterning events. Examination of the Eda pathway components in several different transgenic and knockout lines designed to alter ß-catenin pathway signaling in the skin have led to inconsistent answers, in part because of the difficulties of evaluating the precise timing of altered gene activity in the mouse embryo. This lack of temporal precision in the genetic interventions in the mouse, and the difficulty in working with cultured murine skin prior to patterning, have hampered efforts to establish the roles of the Eda pathway in pattern formation and to place them relative to other signaling pathways important for follicle specification. Although these genes are clearly crucial to follicle formation, the nature and timing of that requirement remain unclear. Is the localization of Edar expression and the consequent asymmetry in pathway activation a crucial first step in placode specification and pattern formation? If so, is this upstream and independent of the interactions between the ß-catenin pathway and BMP that have been postulated to direct this early patterning decision? The forming feather tract of the chicken allows examination of the sequence of changes in gene expression during feather rudiment formation because each feather rudiment is added in a defined sequence so that the tract contains an ordered developmental series displayed in a precise spatial array. The feather tract is also amenable to retroviral-mediated alteration of gene activity that is targeted to specific stages of development in vivo. To exploit these advantages, we identified the components of the chicken Eda pathway to investigate whether they are expressed during feather bud formation in a pattern similar to that observed in hair follicle formation, and if so, to place the timing of localized receptor expression relative to other patterning events. Finally, we sought to test the roles of the ß-catenin and BMP signaling pathways postulated to direct pattern formation in the regulation of expression of Eda pathway components.
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Materials and methods |
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Genomic and cDNA sequence analysis
Sequence homologies were determined using the BLAST function of the NCBI
Chicken Genome Resources. Synteny was analyzed using the alignments of the
draft version of the chicken genome to the human genome provided by Ensembl, a
project of the Wellcome Trust and the Sanger Institute. The protein sequences
inferred from the chicken cDNAs for Edar, Eda and Edaradd
were compared with their mouse orthologs using the Clustal W function of
MegAlign (DNAstar).
Riboprobe templates and in situ hybridization
The initial cDNAs isolated for cEdar (843 base pairs),
cEda (945 base pairs) and cEdaradd (869 base pairs)
described above, a Wnt6 clone (675 base pairs) derived from BBSRC
Chick EST clone ID ChEST810f19, and clones described previously
(Noramly et al., 1999;
Morgan et al., 1998
;
Noramly and Morgan, 1998
) were
used as templates to generate riboprobes and perform whole-mount in situ
hybridization as described (Morgan et al.,
1998
). For comparison of gene expression changes, the following
numbers of embryos were used: Edar/Edaradd, n=18; Edar/Bmp2,
n=17; Edar/Wnt6, n=5; Edar/ß-catenin,
n=20; Edar/Bmp4, n=6; Edar/Shh, n=5; Eda/Edar,
n=13; Eda/Edaradd, n=7; Eda/ß-catenin,
n=7; Eda/Wnt6, n=7; Eda/Bmp2, n=7; Eda/Bmp4,
n=6; Eda/Shh, n=5; Edaradd/Bmp4, n=6; Edaradd/Shh,
n=5). Section in situ hybidization was performed as described (Morgan et
al., 1988), and images presented are a composite of a phase contrast image
(30% opacity) overlying a brightfield image.
Viral infection of chicken embryos
Chicken embryos were infected at day 4 of incubation with retroviruses
expressing truncated ß-catenin or BMP4 prepared as described
(Noramly et al., 1999;
Noramly and Morgan, 1998
).
Embryos were harvested between 7.5 and 9.0 days of incubation, and processed
for in situ hybridization with riboprobes for Eda (BMP infected,
n=9; ß-catenin infected, n=41), Edar (BMP
infected, n=5; ß-catenin infected, n=26) or
Edaradd (BMP infected, n=7; ß-catenin infected,
n=16), as well as a riboprobe for the detection of the extent of
viral infection. Representative samples were dehydrated and sectioned.
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Results |
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Analysis of Eda pathway gene expression in sections revealed a striking difference from the pattern observed in the mouse. Although low levels of Eda expression are observed in the epidermis prior to tract patterning and appear to persist in the interfollicular epidermis at the onset of feather bud patterning (Fig. 3A,F), the robust interfollicular pattern of expression observed represents strong expression in the interfollicular dermis (Fig. 3F). Moderate levels of Eda transcripts are observed in the dense dermis as patterning begins (Fig. 3A), while Edar and Edaradd are expressed in the overlying epidermis (Fig. 3B and data not shown). Eda expression is lost in the dermal condensation, while it is increased in the surrounding dermis (Fig. 3F). Edar and Edaradd both become preferentially expressed in the epidermal placode, but the difference between expression levels in placodal and interplacodal epidermis is greater for Edar than Edaradd (Fig. 3C,D,H and data not shown). The later expression of Eda within the feather bud is also in the mesenchyme and persists in the distal mesenchyme of the maturing feather filament, whereas Edar and Edaradd expression remain confined to the bud epithelium (Fig. 3G and data not shown). RT-PCR analysis of isolated epidermis and dermis at different stages of development confirm these tissue distributions, and indicate that both the A1 and A2 isoforms are expressed at significant levels in the dermis throughout this period of development (see Fig. S1 in the supplementary material).
|
The expression patterns of Edar and Edaradd were similar and became observable as discrete spots in the corresponding rudiments of the left and right femoral tracts (data not shown). However, the augmented expression of Eda in interfollicular dermis occurs later in bud development, only after Edar expression has been localized to the epidermal placode, so that spots of Edar expression are observed in the right tract without corresponding holes in the Eda expression pattern in the left tract (Fig. 4A,B). The preferential expression of Edar in the placode is an early event in bud specification and is roughly synchronous with the corresponding change in Bmp2 and Wnt6 expression (Fig. 4C,D, and data not shown). In 12 out of 15 embryos, an equal number of resolved spots of Edar and Bmp2 expression could be observed; in 3 out of 15 embryos an additional spot of Bmp2 expression was observed, indicating that these patterning events occur slightly earlier in the developmental sequence. Consistent with this observation, additional spots of Edar expression were observed when compared with later markers of bud development, including Shh and Bmp4, indicating that local Edar expression occurs early in the process of placode development (Fig. 4E,F, and data not shown). The robust expression of Eda in the interfollicular dermis occurs rather late, after the dermal condensation has begun to differentiate and Shh expression has been initiated in the epidermis. Consistent with this observation, localized expression of earlier markers such as Wnt6, Bmp2 and Cek3 is detected in additional rudiments of one tract when compared with the number of rings of dermal Eda arising around forming rudiments in the corresponding tract (Fig. 4G,H, and data not shown).
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Discussion |
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In the mouse, follicle formation occurs in multiple waves. Both epidermis
and dermis between the primary follicles must remain competent to assume
either follicular or interfollicular fates in subsequent waves. By contrast,
follicle formation occurs in a single wave in the feather tract, so after the
morphogenetic wave has passed through the tract, the developmental plasticity
of either layer need not be maintained. In addition, the pattern of follicle
formation is determinate in the chicken. Each follicle forms in a predictable
time and position relative to its neighbors. By contrast, in the mouse the
precise position and timing of follicle formation varies and patterning is
indeterminate. The determinate patterning of the chicken is likely to be
achieved by coordinating the development of the dense dermis, and consequent
generation of inductive signals, with the development of the epidermis and the
competence to respond to those signals. This allows inductive activity to
reach competent ectoderm in a temporally regulated fashion, as each new bud is
only initiated after the adjacent bud has been established and can exert its
inhibitory influence. Disruption of this coordinated development by combining
competent epidermis with a dermis composed of dispersed and re-aggregated
dermal cells leads to formation of buds with minimal spacing, but the
determinate patterning and morphogenetic wave are abolished
(Jiang et al., 1999) (B.A.M.,
unpublished). It is therefore intriguing to speculate that expression of
Eda in the dermis rather than the epidermis could serve to help
ensure the coordinated development of epidermis and dermis and serve as a
component of the primary inductive signal from the dermis that initiates
feather bud development.
Most patterning events that rely on Eda signaling entail expression of both
ligand and receptor in the epithelial layer
(Pispa and Thesleff, 2003).
The exception is the developing murine salivary gland, where expression of
Eda in the mesenchyme of the gland is thought to act on the receptor
expressed in the gland epithelium to promote branching morphogenesis
(Jaskoll et al., 2003
;
Pispa et al., 2003
). The late
expression of Eda within the bud mesenchyme arises as the feather
makes the transition towards the radial subdivision of the epithelium that is
ultimately manifested as the barbules of the down feather. It is possible that
mesodermal Eda acting on Edar expressed in the epithelium plays a similar
morphogenetic role in both tissues.
The role of Eda signaling in pattern formation in the feather tract
The Eda pathway components were cloned from the chicken in order to exploit
the temporal precision of the feather tract system to place them within the
regulatory hierarchy directing pattern formation in the skin. We find that the
localization of Edar expression to the forming epidermal placode is
an early event in tract patterning, but it does not occur prior to the
localization of other early markers of placode specification. Instead, it
seems to lag slightly behind the localization of Bmp2 and
Wnt6, two events that presage the morphological differentiation of
the placode. This pattern is consistent with a role in promoting placodal
fates subsequent to patterning events that create the initial asymmetry
between the future placode and interplacodal cells, but is less consistent
with a role in generating that asymmetry.
Two signaling pathways thought to be crucial in directing prior patterning events are the Wnt/ß-catenin and BMP pathways. The normal expression pattern of Edar and Edaradd during early tract formation mirrors the pattern of ß-catenin pathway activation throughout early tract patterning. Furthermore, direct activation of the ß-catenin pathway by forced expression of a truncated form of the ß-catenin protein induces the expression of Edar and Edaradd in the infected cells. Finally, forced expression of BMP2, which blocks the local activation of the ß-catenin pathway, also prevents the local expression of Edar and Edaradd. All these observations suggest that the initial localization of Edar and Edaradd expression to the nascent placode is directed by the Wnt/ß-catenin pathway partly in response to inhibitory influences of BMPs. However, the expression of both genes persists in the epidermis of the feather bud after the ß-catenin pathway is no longer active, so other input is required for the maintenance of expression.
The Eda gene has been reported to be a target of Wnt/ß
catenin signaling based on the activity of a Lef1 binding site in the promoter
revealed in co-transfection studies
(Durmowicz et al., 2002). The
pattern of Eda expression in chicken skin is consistent with initial
expression in the epidermis as a consequence of ß-catenin pathway
activation, but Eda expression is reduced in the epidermis and
extinguished in placodes at times when the ß-catenin pathway is still
activated. When exogenous BMP expression suppressed bud development,
Eda expression persisted in the epidermis despite a reduction in
ß-catenin pathway activation. Forced BMP expression in lateral regions
where tract patterning has not begun does not induce Eda expression,
suggesting that BMP acts by blocking signals that normally repress Eda
expression in the epidermal placode. Neither forced activation of the
ß-catenin pathway, nor forced expression of BMP, appear to directly
affect Eda expression in the epidermis during the early stages of
tract patterning. Where forced activation of the ß-catenin pathway
results in ectopic feather bud formation, Eda is induced in the
surrounding mesenchyme, but this is an indirect consequence of bud formation
and does not correlate with the pattern of ß-catenin pathway activation.
At later stages of bud development, the robust expression of Eda in
the posterior distal mesenchyme correlates well with ß-catenin pathway
activation. In total, these observations suggest that ß-catenin signaling
may well play important roles in Eda gene regulation at the earliest
stages of tract development and later bud morphogenesis, but the expression
changes during the early stages of pattern formation in both layers are
regulated by other inputs.
Conserved function of Eda signaling in the development of cutaneous appendages
The analysis of Eda and Edar expression in the developing
feather tract suggests that the localized function of this pathway in
promoting bud development is downstream of an initial patterning event
directed by interaction between the ß-catenin and BMP signaling pathways.
Although this may reflect a difference in the role of this pathway in mammals
and birds, the apparent discrepancies between these conclusions and those
based on the interpretation of experiments performed in the mouse can be
reconciled in a model of conserved Eda pathway function.
Two results from the mouse studies seem inconsistent with this model. The
first is that the local expression of placodal markers is not detected in the
analysis of tabby (Eda) mutant skin, and the second is that
local expression of Edar is observed in epidermis lacking a
functional ß-catenin gene while the local expression of other placodal
markers was not observed. Together, these observations have been interpreted
as evidence that local ectodysplasin signaling is a prerequisite to patterning
events directed by ß-catenin signaling and/or BMP2 in the skin. However,
the interpretation of both experiments is complicated by the fact that the
maintenance of the epidermal placode is dependent on its continued interaction
with the dermal condensation. Disruption of signaling between the epidermal
placode and dermal condensation leads to regression of the placode and
extinction of most placode-specific gene expression. Thus analysis of mutant
skin may fail to detect initial patterning events because the corresponding
gene expression is not maintained in the absence of subsequent events to
induce and maintain the dermal condensation. The experiments that
conditionally inactivated ß-catenin in skin clearly demonstrated that
signaling through this pathway is not required to maintain the asymmetric
expression of Edar (Huelsken et
al., 2001). However, the conclusion that ß-catenin signaling
was blocked prior to pattern formation was based largely on the failure to
detect the local expression of other markers at later time points and did not
consider the requirement for continued signaling to maintain other placodal
gene expression. If, as we propose, ß-catenin signaling actually directs
the localized expression of Edar, the maintenance of localized
Edar expression in the absence of ß-catenin signaling in the
mouse is consistent with our observation in the chicken, where ß-catenin
signaling appears important for the early activation and localization of
Edar expression, but not for the subsequent maintenance of expression
in the placode.
The lack of placodal marker expression in the mutants could also be
explained by a failure to maintain placodes after initial specification.
Gain-of-function experiments have demonstrated that augmented Eda signaling
increases the size of existing placodes, so an abortive placode specified in
the absence of Eda might express lower levels of placodal markers that are
more difficult to detect. However, it would seem likely that the extensive
characterization of these mutants would have detected at least some evidence
of an ephemeral placode population predicted by this model. Thus, we favor the
alternative explanation that there is a requirement for Eda pathway activity
to promote competence to form a placode in the epidermis prior to initial
patterning and localization of Edar expression to the nascent
placode. This requirement is not absolute, as it is ultimately bypassed in
time for subsequent waves of follicle development, but may be crucial to
achieving competence to make a placode during a crucial period for primary
follicle induction. Early Eda signaling may promote the competence to form
placodes in the epidermis, and as patterning directs Edar expression
and Eda signaling preferentially to the forming placode, it could continue to
promote that fate in the placodal cells and counteract placode inhibiting
signals. The phenotypes of Eda overexpression under the control of
the keratin 14 promoter include enlarged follicles but no apparent
change in the timing or density of primary follicles formed
(Mustonen et al., 2003).
However precocious generation of follicles was observed after the primary wave
(Mustonen et al., 2003
). These
phenotypes are all consistent with this model, as precocious Eda signaling
would be expected to be permissive but not sufficient for initiation, and the
subsequent enlargement of placodes and precocious formation of secondary
follicles are both expected of a signal that tips the balance between follicle
promoting and inhibiting signals towards the adoption of follicular fates.
The role of the Eda pathway in feather formation remains to be tested. Nevertheless, this examination of the expression and regulation of the components of this pathway during feather tract development has provided important refinements to the model of Eda pathway function during cutaneous appendage development.
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Supplementary material |
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Note added in proof |
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ACKNOWLEDGMENTS |
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