Department of Orthopaedic Surgery, University of California at San Francisco, 533 Parnassus Avenue, U-453, San Francisco, CA 94143-0514, USA
* Author for correspondence (e-mail: ras{at}itsa.ucsf.edu)
Accepted 31 January 2005
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SUMMARY |
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Key words: Feather morphogenesis, Quail-duck chimeras, Neural crest transplants, Epithelial-mesenchymal interactions, Modularity, Plasticity, Evolutionary developmental biology, bmp4, bmp2, shh, delta
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Introduction |
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Arguably, the most crucial developmental process underlying feather
morphogenesis is the series of reciprocal signaling interactions between the
dermis and epidermis of the embryonic integument. Yet, identifying specific
properties that would enable these signaling interactions to fluctuate in time
and space, and thus, impart plasticity in the molecular and histogenic
programs of feather development, has been elusive. One informative
experimental approach might be to change the embryonic history of either the
dermis or the epidermis in a manner that would alter the subsequent signaling
interactions between these tissues and reveal inherent properties of the
integumentary system such as the hierarchical levels of organization,
inductive potentials or limits of competency. Fate-map studies have
demonstrated that in the trunk and posterior portions of the head, the dermis
is derived from mesodermal mesenchyme of dermomyotomal and somatopleural
origin, while in the face and neck the dermis arises from neural crest
mesenchyme (Noden, 1978;
Noden, 1986
;
Couly et al., 1992
;
Olivera-Martinez et al., 2000
;
Fliniaux et al., 2004
;
Olivera-Martinez et al.,
2004a
). Neural crest mesenchyme is generated along the dorsal
margins of the neural tube during neurulation and undergoes extensive
migration throughout the craniofacial complex. These cells also differentiate
into pigment-producing melanocytes, which become secondarily associated with
the epidermis and are the source of color throughout the body
(Cramer, 1991
;
Le Douarin and Dupin, 1993
;
Bronner-Fraser, 1994
;
Hirobe, 1995
). The epidermis
is a stratified epithelium of non-neural ectodermal origin that produces the
keratinized structural tissues characteristic of feathers
(Couly and Douarin, 1988
;
Pera et al., 1999
;
Yu et al., 2004
).
Heterotopic, heterochronic, heterospecific and heterogenetic tissue
recombinations have demonstrated that the time of appearance, location, size,
number and morphological identity of feathers are determined by the dermis
(Cairns and Saunders, 1954;
Saunders and Gasseling, 1957
;
Rawles, 1963
;
Wessells, 1965
;
Dhouailly, 1967
;
Dhouailly, 1970
;
Linsenmayer, 1972
;
Dhouailly, 1973
;
Dhouailly and Sawyer, 1984
;
Song and Sawyer, 1996
;
Prin and Dhouailly, 2004
), but
the specific cellular and molecular mechanisms through which this information
is conveyed are unclear. Mesenchyme becomes competent to induce feathers at an
early embryonic stage prior to any obvious morphological changes in either the
mesenchyme itself or in the overlying epithelium
(Widelitz et al., 1997
). The
first morphological indication of feather formation is the aggregation of
mesenchyme into a thin, uniform layer of dense dermis beneath the epithelium
(Wessells, 1965
;
Brotman, 1977
;
Mayerson and Fallon, 1985
).
The local epithelium then thickens into a specialized epidermal placode, the
mesenchyme aggregates into a dermal condensation, the placode and mesenchyme
rise above the integumentary surface, and both tissues undergo proliferation,
cell movements and differentiation (Pispa
and Thesleff, 2003
;
Olivera-Martinez et al.,
2004b
). Presumably, the dermis releases a primary signal, which
instructs the epithelium to begin making a placode. This initial induction
depends on the mesenchyme reaching a critical threshold of aggregation size
and expressing higher levels of cell-adhesion molecules
(Jiang et al., 1999
). Although
the identity of the first dermal signal is not known, likely candidates
include molecules in the Bone Morphogenetic Protein (BMP) and Fibroblast
Growth Factor (FGF) families (Tao et al.,
2002
; Pispa and Thesleff,
2003
; Mandler and Neubuser,
2004
). A decade of molecular research on feather morphogenesis
suggests that a general hierarchical sequence of signaling events may be from
the BMP and FGF pathways, to the Sonic Hedgehog (SHH) and Wnt pathways, to the
Delta/Notch pathway, to numerous transcription factors and structural genes
(Chuong et al., 2001
;
Song et al., 2004
).
The order of events in chick feather development is well known based on
studies in the trunk, and is described elsewhere in relation to the Hamburger
and Hamilton (HH) staging system
(Hamburger and Hamilton, 1951;
Lucas and Stettenheim, 1972
;
Mayerson and Fallon, 1985
;
Widelitz et al., 1997
;
Yu et al., 2004
). Feathers
form as buds in consecutive rows that make up tracts or pterylae, and in the
head these are termed `capital tracts'
(Lucas and Stettenheim, 1972
).
Individual rows are added sequentially so that a given tract can include
feather buds at successive stages of development. The spacing between buds and
between rows appears to be determined by lateral inhibition from preceding
buds (Davidson, 1983
;
Jung et al., 1998
;
Noramly and Morgan, 1998
). We
hypothesize that the dermis of the capital tracts regulates the expression of
genes known to play a role during feather morphogenesis, such as members and
targets of the BMP, SHH and Delta/Notch pathways. As a functional test of our
hypothesis, we use the quail-duck chimeric system
(Schneider and Helms, 2003
;
Tucker and Lumsden, 2004
),
which is a potent experimental method for identifying molecular and cellular
spatiotemporal patterning mechanisms. Japanese quail have cranial feathers
that are relatively large, widely spaced and pigmented, whereas those of the
white Pekin duck are smaller, closely arranged and un-pigmented
(Lucas and Stettenheim, 1972
).
Moreover, quail and duck have highly divergent embryonic growth rates (17
versus 28 days to hatching; Fig.
1D). By exchanging premigratory cranial neural crest cells between
quail and duck embryos, we challenge host epidermis to respond to
species-specific variations in molecular signals that are promulgated by donor
neural crest-derived dermis. We find that donor neural crest alters the
spatial pattern and changes the time at which host cranial feathers form by
regulating the expression of key molecular mediators. Such results demonstrate
the essential role played by the dermis and the plasticity inherent in the
overlying epidermis, and provide insight into developmental mechanisms that
may have directed the variegated course of feather evolution.
|
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Materials and methods |
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Histology and immunocytochemistry
Control and chimeric embryos from HH29 to HH42 were fixed in Serra's (100%
ethanol:37% formaldehyde:glacial acetic acid, 6:3:1) overnight at 4°C. To
visualize the appearance of epidermal placodes and early feather buds, some
embryos were stained with 0.02% ethidium bromide for 10 minutes at room
temperature, rinsed in PBS and imaged under epifluorescent illumination.
Embryos were dehydrated, paraffin embedded, cut into 7 or 10 µm sections,
and mounted on glass slides. Representative sections were stained with
Milligan's Trichrome (Presnell and
Schreibman, 1997) for histological visualization of the dermis and
epidermis. To detect quail cells in chimeric embryos, representative sections
were immunostained with the quail nuclei-specific Q¢PN antibody
(Developmental Studies Hybridoma Bank, DSHB) following a previously published
protocol (Schneider, 1999
).
This technique permanently labels quail cells by using a secondary antibody
that is reacted with diaminobenzidine (DAB; Sigma). Sections were imaged using
differential interference contrast microscopy
(Fig. 1F).
Gene expression analyses
In situ hybridization was performed as described
(Albrecht et al., 1997).
Sections adjacent to those used for histological and immunocytological
analyses were hybridized with 35S-labeled chicken riboprobes to
genes expressed in integumentary mesenchyme and epithelia including members
of: the Bone Morphogenetic Protein pathway, bmp4 and bmp2
(ligands), follistatin (antagonist) and bmpr1a (receptor);
the Hedgehog pathway, shh (ligand) and ptc (receptor); and
the Delta/Notch pathway, delta1 (ligand) and notch1
(receptor). Sections were counterstained with a fluorescent blue nuclear stain
(Hoechst Stain; Sigma). Hybridization signals were detected using dark-field
optics and the nuclear stain was visualized using epifluorescence. The
spatiotemporal expression patterns and levels of these genes throughout
integumentary mesenchyme and epithelia of chimeras were compared with that
observed in control quail and duck at each stage analyzed.
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Results |
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|
Neural crest regulates histogenic programs of cranial feather morphogenesis
To elucidate the cellular nature of these transformations, we compared
histological sections of stage-matched control and chimeric quck embryos at
key time points during feather morphogenesis. In control quail and duck
embryos, dense dermis and epidermal placodes have yet to form in the capital
tracts at HH33 but appear from HH34 onwards
(Fig. 1A;
Fig. 3A). Dermal condensations
can be detected by HH35, and by HH36 some feather buds have begun to rise
above the level of the integument (Fig.
1A; Fig. 3D,E;
Fig. 4B). By HH37, the height
of these feather buds has become equal to or slightly longer than their width,
and by HH39, some of the more mature quail feathers contain brown and black
pigment at their distal tips (Fig.
2L; data not shown). Quck chimeras collected at HH33, however,
have dermal condensations and elevated placodes that resemble those found on
control quail at HH36 (n=4; Fig.
3B-D). Quck at HH32 have dermal condensations and placodes
equivalent to those present in HH35 controls (n=4; data not shown),
and quck analyzed at HH31 already have dense dermis and placodes like those
observed in controls at HH34 (n=3;
Fig. 3X-Z). Thus, in quck, the
histogenic program of feather morphogenesis is shifted forward by three
embryonic stages.
|
Neural crest regulates expression of the BMP, SHH and Delta/Notch pathways
To test the extent to which the dermis regulates molecular programs for
feather development, we performed in situ hybridization to assay for changes
in the expression of members and targets of the Bone Morphogenetic Protein,
Sonic Hedgehog and Delta/Notch pathways. Our analyses conducted on control
embryos collected from HH29 to HH38 demonstrate that the timing of expression
for bmp4, bmp2, follistatin, bmpr1a, shh, ptc, delta1 and
notch1 in the capital tracts is equivalent between stage-matched
quail and duck. In sharp contrast, we find that in chimeric quck embryos the
timing of gene expression is accelerated by three stages in both quail
donor-derived dermis, and duck host-derived epidermis, which is consistent
with our morphological and histological results. Prior to HH34, none of these
genes is expressed in either the epidermis or dermis of control embryos
(Fig. 3F; data not shown),
except for bmpr1a and notch1, which are expressed
continuously from at least HH29 in most tissues throughout the craniofacial
region (data not shown). However, in chimeric quck collected at HH33, all of
these feather markers are detected throughout the capital tracts in domains
equivalent to those observed in control quail at HH36
(Fig. 3G-V). Specifically, in
quck at HH33, we find bmp4 and delta1 expression restricted
to the quail donor-derived dermal condensations of short feather buds
(Fig. 3G,S), shh in
host-derived epidermal placodes (Fig.
3O), and bmp2, follistatin, bmpr1a, ptc and
notch1 in both tissues (n=4;
Fig. 3I,K,M,Q,U). These are the
same expression patterns observed in control quail at HH36 (n=3;
Fig. 3H,J,L,N,P,R,V). To
determine how much earlier these genes could be experimentally induced, we
collected chimeric quck at HH32, HH31, HH30 and HH29. We detect transcripts of
bmp4, bmp2, follistatin, bmpr1a, shh, ptc, delta1 and notch1
in chimeric quck collected at HH32 (n=4), even though in control
embryos ptc, shh, delta1 and follistatin do not appear in
developing feather buds prior to HH35 (n=4; data not shown).
Similarly, bmp4 and bmp2 are expressed in nascent feather
buds of chimeric quck collected at HH31 (n=3), whereas control
embryos express these genes in the equivalent region no earlier than HH34
(n=4; Fig.
3A',B'; data not shown). We do not detect any evidence
of expression for these genes in the cranial integument prior to HH31 in
chimeric quck, despite an abundance of quail donor-derived mesenchyme in the
presumptive capital tracts (data not shown).
Donor neural crest can also delay the timing of feather morphogenesis
As another functional test of our hypothesis that the dermis regulates the
expression of genes known to play a role during feather morphogenesis, we
performed reciprocal transplants of premigratory cranial neural crest cells
from duck into quail, generating chimeric `duail' embryos. In general, we find
that duck donor neural crest delays the molecular and histogenic programs of
feather morphogenesis in quail hosts by three embryonic stages (n=8).
Duail chimeras were collected at HH36, which is when stage-matched control
quail embryos have consecutive rows of feather buds across the entire dorsal
surface of the cranial epithelium (Fig.
2I). However, the capital tracts of these duail chimeras contain
extensive epidermal regions that lack feather placodes (n=3;
Fig. 4A). The absence of
epidermal placodes is similar to that observed on duck donor controls prior to
HH34 (Fig. 2G).
To assess if the delay in duail feather development results from duck donor neural crest-mediated changes in gene expression, we processed sections histologically, with the Q¢PN anti-quail antibody, and for in situ hybridization. We find that in chimeric duail cases collected at HH36, those cranial regions lacking feather buds contain dermis derived from duck donor neural crest, while the epidermis originates from the quail host (n=3). Conversely, where there is no duck donor mesenchyme (i.e. Q¢PN-positive dermis derived from the quail host), feather buds are present (Fig. 4B-E). Molecular analysis of these duail chimeras at HH36 reveals that bmp4, bmp2, follistatin, shh, ptc and delta1 are expressed in feather buds derived from quail host tissues, but not in regions where the dermis is derived from duck donor neural crest (n=3; Fig. 4F-K; data not shown). After HH37, duck-derived dermis along with quail host-derived epidermis form well developed feather placodes like those found on duck controls subsequent to HH34 (n=4; Fig. 4L-N). We also find that some pigmented feather buds in duail embryos older than HH38 are derived primarily from duck dermis, which is a source of normally non-pigment-producing melanocytes (Fig. 4M).
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Discussion |
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Our quail-duck experimental approach augments results from previous
inter-specific feather studies in several important ways and as a consequence
reveals novel mechanisms of integumentary development. The fact that certain
species-specific differences in feather morphology are conveyed by the dermis
is well established based upon other recombinations such as those using chick
and duck tissues (Dhouailly,
1967; Dhouailly,
1970
). But in order to understand developmental mechanisms through
which the dermis exerts its influence on the epidermis, we use quail instead
of chick. This takes advantage of the substantial difference in maturation
rates between quail and duck, and capitalizes on the ubiquitous quail nuclear
marker not present in chick or duck, which allows us to distinguish between
donor and host tissues. Our experiments also entail in ovo transplants of
premigratory neural crest cells destined to form the craniofacial mesenchyme
rather than in vitro recombinations of stage-matched dermis and epidermis that
had already become components of the integument. This permits progressively
asynchronous donor mesenchyme and host epithelium to interact with one another
continuously from the moment they first meet, and allows us to observe
resultant neural crest-mediated changes to molecular and histogenic programs
underlying feather development. Thus, by design, our experiments illuminate
the overriding regulatory capabilities of the mesenchyme, as well as the
plasticity inherent in the overlying epithelium during cranial integumentary
development. Such results can probably be extrapolated to include integument
throughout the body.
Neural crest regulates expression of genes essential to feather morphogenesis
To determine the extent to which individual signaling pathways known to
play a role in feather morphogenesis are regulated by the neural crest, we
compared control and chimeric embryos at successive stages using in situ
hybridization to assay for temporal changes in the expression of members of
the BMP, SHH and Delta/Notch signaling pathways. As feather formation requires
precisely timed dermal-epidermal signaling interactions, we hypothesized that
expression of genes mediating these interactions would be altered in chimeric
embryos because of intrinsic differences in growth rates between donor and
host cells. For each signaling pathway that we examined, we observed a
significant change in the timing of expression coincident with the embryonic
stage of the donor neural crest-derived dermis
(Fig. 5).
|
Thus, our molecular analyses demonstrate that neural crest cells function
as the dominant source of spatial and temporal patterning information via the
regulation of genes essential to cranial feather morphogenesis. Such results
are consistent with those from previous quail-duck transplants, where quail
donor neural crest cells were shown to govern beak morphology by executing
autonomous molecular programs and by regulating gene expression in the
mesenchyme and epithelia of the developing facial primordia
(Schneider and Helms, 2003).
Beyond the molecules examined here, we predict that other genes, including
members and targets of the FGF, Epidermal Growth Factor and Wnt pathways,
which play a role during feather morphogenesis
(Noji et al., 1993
;
Tanda et al., 1995
;
Song et al., 1996
;
Widelitz et al., 1996
;
Noramly et al., 1999
;
Widelitz et al., 1999
;
Olivera-Martinez et al., 2001
;
Tao et al., 2002
;
Atit et al., 2003
;
Chodankar et al., 2003
;
Chang et al., 2004
;
Mandler and Neubuser, 2004
;
Rouzankina et al., 2004
;
Song et al., 2004
), would be
differentially regulated by donor neural crest. In the future, combining our
chimeric approach with more quantitative and comprehensive methods of gene
expression analysis, such as microarrays, could yield new candidate molecules
that underlie feather morphogenesis.
The mesenchyme controls signaling interactions with the epithelium
Epithelial-mesenchymal signaling interactions drive the development of
numerous vertebrate structures from the level of entire organ systems, such as
the case for the limbs and facial primordia
(Saunders and Gasseling, 1968;
Wedden, 1987
;
Richman and Tickle, 1992
;
Francis-West et al., 1998
;
Schneider et al., 1999
;
Shigetani et al., 2000
;
Schneider et al., 2001
;
Hu et al., 2003
), to the level
of individual tissues, such as in relation to hair, glands, teeth and bone
(Salaun et al., 1986
;
Fisher, 1987
;
Lumsden, 1988
;
Sharpe and Ferguson, 1988
;
Dunlop and Hall, 1995
;
Mitsiadis et al., 1998
;
Pispa and Thesleff, 2003
).
During their interactions, the epithelium and mesenchyme presumably function
by providing instructive information or by creating a permissive environment
that enables morphogenesis to proceed. The most common approach employed to
define the role of either the epithelium or the mesenchyme at each step of the
process has involved recombination of dissected tissues in vitro. In this
context, cranial osteogenesis has been shown to be regulated by stage-specific
interactions between neural crest mesenchyme and adjacent epithelia
(Hall, 1978
;
Hall and Tremaine, 1979
;
Bee and Thorogood, 1980
;
Bradamante and Hall, 1980
;
Tyler and McCobb, 1980
;
Hall, 1982
;
Hall and Coffin-Collins, 1990
;
Mina et al., 1994
;
Dunlop and Hall, 1995
;
Vaglia and Hall, 1999
;
Couly et al., 2002
). Although
the epithelium is required in this process, its role appears to be permissive
rather than instructive. The same appears to hold true for feather bud
morphogenesis. For example, recombinations of differently staged dermis and
epidermis from wild-type and featherless mutants demonstrate that, early on,
the dermis is endowed with the ability to induce epidermal placodes, but this
propensity is rapidly lost in the absence of proper epidermal interactions
(Viallet et al., 1998
). In
other situations, however, the epithelium can serve an instructive role during
pattern formation, dictating where teeth form
(Thesleff and Sharpe, 1997
;
Tucker et al., 1998
;
Wang et al., 1998
) and
whether epidermis generates scales or feathers
(Widelitz et al., 2000
;
Prin and Dhouailly, 2004
).
Our chimeric data support the notion that integumentary epithelium behaves
permissively, while the dermis acts instructively to establish the timing and
spacing of feather bud development. However, this does not rule out the
possibility that the epithelium can provide instructive information during
later stages of differentiation, particularly when branching patterns may be
transmitted from the epidermis in a species-specific manner
(Harris et al., 2002;
Yu et al., 2002
). We presume
that in our chimeras, host epidermis provides a developmental context that is
equivalent in many ways to what the donor dermis would normally encounter in
its native environment. This may be accomplished as a consequence of earlier
programmatic events and signaling interactions whereby donor neural crest
mesenchyme transmutes host epithelium to reflect the morphogenetic identity of
the donor. Alternatively, the embryonic milieu of the host may remain
permissively naïve in a way that encourages the donor cells to carry out
autonomous programs. In either case, the donor neural crest functions by
elaborating a molecular set of instructions intrinsic to its own genome and by
inducing a donor-specific program of gene expression and histogenesis, which
overrides that of the host. The result is that instructive donor dermis can
only make feather buds like those of the donor, whereas permissive host
epidermis can make feather buds like those of either the host or the
donor.
Developmental modules and plasticity may facilitate feather evolution
Traditionally, development or ontogeny has been characterized as a series
of embryonic events ordered into a discrete chronological sequence. The
relation of one event to the next can be merely temporal where each event is
arranged after the other without any underlying mechanistic connection, or can
be causal, where each event is a prerequisite for a subsequent event via
processes like induction (Alberch,
1985). While defining events as either temporally or causally
related may underestimate the dynamic, continuous and integrative nature of
developmental systems, such a method is useful for distinguishing
phenomenological associations from morphogenetic programs that function as
modules during the course of ontogeny and phylogeny. Because modules consist
of causally coupled processes, they may be more likely to undergo rapid and
dramatic transformations that are due to changes in the timing and rates of
developmental events such as those associated with heterochrony
(Raff and Kaufman, 1983
;
Hall, 1984
;
Smith, 2003
).
Feather formation is an especially good example of an iterative module comprising causally linked developmental events, yet fundamental parameters that define this module have not been sufficiently understood. We have shown that the dermis establishes where and when molecular and histogenic programs of cranial feather development begin to operate and we have gauged the degrees of plasticity inherent in the overall system. Once these programs are initiated, the entire sequence of events seems to unfold automatically, albeit shifted in time and space. In the case of the quck, epidermal differentiation can be induced by the dermis three stages earlier than normal, while in the duail, epidermal differentiation can be delayed three stages. By extension then, our results indicate that the molecular and histogenic programs underlying feather bud formation can be shifted through a total window of at least six developmental stages, which for each species represents almost 15% of their total incubation period. Yet, what we do not know from our studies are the absolute limits of the plasticity of the system. For example, cranial epidermal placodes do not form prior to HH31 in quck chimeras. This could be due to an epithelium that is either incompetent to respond to dermal signals or unable to create a permissive environment any earlier. Alternatively, the dermis may not yet be capable of instructing the epidermis until HH31. A further possibility has nothing to do with the tissues themselves but rather constraints imposed by the quail-duck chimeric system, which is limited by innate differences in the maturation rates between these birds. Using other avian species that have either relatively shorter or longer incubation periods could circumvent this restriction and reveal further the extent to which the developmental module underlying feather morphogenesis is free to vary.
Defining the limits of flexibility or plasticity inherent in developmental
systems such as the feather module is a necessary step for identifying
molecular and cellular mechanisms that may have played a generative and
regulatory role during the course of morphological evolution. Plasticity is a
measure of the capacity of ontogenetic programs to respond to internal and
external perturbations and produce an integrated and sustainable phenotype. By
combining plasticity with modularity, organisms have the remarkable potential
to react spontaneously to new conditions and new gene functions, and generate
new phenotypes (West-Eberhard,
2003; Schlosser and Wagner,
2004
). Our transplants reveal that host epidermis has a rather
seamless ability to accommodate and integrate morphogenetic modifications
introduced by an internal stimulus, which in this instance involves neural
crest-mediated changes to the spacing and timing of molecular and histogenic
events. These properties of modularity and plasticity, which allow our
chimeras to `adapt' to an experimentally induced process, are likely to be the
same features that enable organisms to evolve when variations are introduced
by more natural means.
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ACKNOWLEDGMENTS |
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