|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online 28 February 2007
doi: 10.1242/dev.02822
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Developmental Biology and Neurosciences, Graduate School of Life
Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan.
2 Division of Developmental Neuroscience, CTAAR, Tohoku University School of
Medicine, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
3 Division of Biological Science, Graduate School of Science, Nagoya University,
Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan.
* Author for correspondence (e-mail: tam{at}biology.tohoku.ac.jp)
Accepted 25 January 2007
 |
SUMMARY |
|---|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
Key words: Limb bud, Axis formation, Cell fate, Boundary, Chick
|
INTRODUCTION |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
During limb morphogenesis in tetrapod development, structures along the
proximal-distal (PD) axis are established as a series of cartilage elements
with an appropriate number and distinct morphology, and pattern formation of
the structures serves as a fascinating model system for studying the
establishment of domains in a developmental field. In a limb, there is a
single long cartilage in the most proximal region (stylopod) followed by two
long cartilage elements (the zeugopod), and the most distal structures of the
limb are carpals/tarsals and digits (the autopod). Many studies on chick
embryos, including observation of cartilage formation
(Hinchliffe, 1977
), apical
ectodermal ridge (AER) removal experiments
(Saunders, 1948;
Summerbell, 1974;
Lewis, 1975;
Summerbell, 1976) and X-ray
irradiation experiments (Wolpert,
1969), have suggested that the structure generated from the distal
limb bud changes from the proximal part to the distal part as development
proceeds. AER removal experiments have demonstrated that zeugopod
specification has already started by chick stage 18-19, followed by autopod
specification at stage 22-23 (Saunders,
1948; Summerbell,
1974; Lewis, 1975;
Summerbell, 1976). The
`progress zone (PZ)' model, a widely accepted model for PD patterning in the
limb bud, proposed on the basis of results of AER removal experiments and
other experiments (Wolpert,
1969; Wolpert et al.,
1975; Summerbell and Lewis,
1975), suggests that limb mesenchymal cells sequentially form more
distal domains as they change their positional value, a characteristic of
cells that determines which cartilaginous elements the cells will form with
respect to the PD axis. It is assumed that a clock-like mechanism recording
the time that mesenchymal cells spend in the PZ controls the positional value
of a cell along the PD axis, but the molecular nature of this model remains
unsolved.
An alternative model for PD axis formation, the prespecification model, has
also been proposed (Stocum,
1975; Dudley et al.,
2002; Sun et al.,
2002). This model, a sort of subdivision model, assumes that cells
in the early limb bud are previously specified as a pre-pattern of three
layers for each future structure of the stylopod, zeugopod and autopod. This
model is based not on a clock-like mechanism but a mechanism by which cells
are specified into all regions along the PD axis at an early stage; e.g.
gradation of a molecule along the axis. Evolutionary morphology
(Richardson et al., 2004) and
the results of a study on Gli3 and plzf functions in PD patterning
(Barna et al., 2005) suggested
that the distal and proximal structures of a limb are specified independently,
supporting the prespecification model.
The exact mechanism of PD axis formation remains unclear because many
results of experiments (Dudley et al.,
2002; Sun et al.,
2002; Tickle and Wolpert,
2002; Saunders,
2002; Wolpert,
2002; Richardson et al.,
2004; Barna et al.,
2005) can be mostly explained by both ideas. In order to further
understand how limb mesenchymal cells acquire positional identity in terms of
the PD axis, it is important to elucidate their developmental destiny. Fate
mapping, in which natural cell fate is solely traced as strictly as possible,
is a simple but informative system for this purpose
(Clarke and Tickle, 1999), and
excellent fate maps of the chick limb bud
(Saunders, 1948;
Stark and Searls, 1973;
Summerbell, 1976;
Bowen et al., 1989;
Vargesson et al., 1997) have
resolved many issues of pattern formation in the developing limb. In the
present study, we developed detailed and accurate fate maps of distal limb bud
cells at early and late stages of limb development in order to address some
fundamental questions about regionalization of cell fate along the PD axis.
Our fate mapping of distal mesenchymal cells shows that there is no boundary
of cell fate between the prospective autopod and zeugopod at an early stage
(stage 19), whereas the regionalization for a more proximal region between the
prospective stylopod and zeugopod can be seen at this early stage. The
regionalization of the prospective zeugopod and autopod appears to be
completed by stage 23. Detailed observations of HOXA11 and HOXA13
immunoreactivity show that the distal limb bud has no mosaic condition of
expression of these proteins. Our findings demonstrate that only the distal
limb bud is maintained in a mixable unregionalized condition and that each
limb structure is likely to be regionalized in the proximal-to-distal
direction.
|
MATERIALS AND METHODS |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
). Limb bud cells were labeled with the lipophilic
dye DiI (1,1-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine
perchlorate; Molecular Probes) and DiO (3,3'-dioctadecyloxacarbocyanine,
perchlorate; Molecular Probes) prepared after the method of Li and Muneoka
(Li and Muneoka, 1999). To
standardize the size of samples, embryos with limb buds of similar sizes were
selected from embryos of the same stage. Areas used for mapping were about
1200 µm along the anterior-posterior axis and about 250 µm along the
proximal-distal axis of stage 19 limb buds, and about 1200 µm along the
anterior-posterior axis and 1200 µm along the proximal-distal axis of stage
23 limb buds. Dye administration by pressure of expiration was performed using
a pulled micropipette with a tip opening of approximately 6-15 µm in
diameter. In order to determine the position and area injected with dye,
labeled limb buds were observed and photographed under a fluorescence
microscope immediately after dye administration, and then the size of the dye
spot and the distance from the AER were calculated with the aid of a
micrometer (see Fig. 1A,D,G,J).
For accurate evaluation of the injection point at stage 23, the distal limb
bud was excised out on a dish after labeling, observed under a microscope, and
then put back on the amputated plane of the same limb bud with a tungsten
wire. The prospective middle finger region [estimated after Vargesson et al.
(Vargesson et al., 1997)] was
targeted for the injection point. At 2 days after the above process, operated
limb buds were photographed and stained for cartilage. Whole-mount in situ
hybridization for proteoglycan-H (for samples labeled at stage 19), a good
marker for cartilage condensation
(Mallein-Gerin et al., 1988),
and Alcian Blue staining (for samples labeled at stage 23) were used for
cartilage pattern observation. Whole-mount in situ hybridization was performed
as described by Yonei et al. (Yonei et
al., 1995), and digoxigenin-labeled RNA probes were prepared
according to the method of Yokouchi et al.
(Yokouchi et al., 1991). For
Alcian Blue staining, embryos were fixed overnight in 10% formalin in Tyrodes
solution, stained with 0.1% Alcian Blue in 70% ethanol with 0.1 M HCl at
37°C overnight, dehydrated, and cleared in methyl salicylate. In some
experiments, sections were cut with a cryostat following a protocol described
by Li and Muneoka (Li and Muneoka,
1999).
Real-time RT-PCR and immunohistochemistry for HOXA11 and HOXA13
RNA was isolated from the distal limb bud using an RNeasy total RNA
isolation kit (Qiagen). Quantitative analysis was performed using a
Lightcycler Quick System 350S (Roche) for 40 cycles of a two-step PCR
amplification (95°C for 5 seconds and 60°C for 20 seconds). The
amounts of amplified PCR products were monitored in each cycle during PCR with
SYBR Green I (Roche) added as a fluorescent material. HOXA11- and
HOXA13-specific primers, yielding product sizes as indicated were
HOXA11 (169 bp) [forward primer,
5'-ATCTTCCGGCAACAATGAGG-3' (20mer); reverse primer,
5'-CAGATTGAGCATTCGGGAGA-3' (20mer)], HOXA13 (173bp)
[forward primer, 5'-GTGGAACGGGCAAGTGTACT-3' (20mer); reverse
primer, 5'-GCGTATTCCCTTTCGAGTTC-3'], ß-actin (165bp) [forward
primer, 5'-TCTGACTGACCGCGTTACTC-3' (20mer); reverse primer,
5'-CCATCACACCCTGATGTCTG-3' (20mer)]. These primer sets were based
on the chick HOXA11 mRNA sequence (GenBank NM_204619),
HOXA13 mRNA sequence (GenBank AY030050), and ß-actin mRNA
sequence (GenBank L08165), respectively. Relative standard curves for
HOXA11 and HOXA13 were constructed using fivefold serial
dilutions of cDNA derived from distal limb bud at stage 24 and 26,
respectively. Data were based on a threshold cycle (Ct) in which the signal
was higher than that of the background. For quantitative comparison of gene
expression, the amount of HOXA11 and HOXA13 expression was
standardized with that of ß-actin. The relative amount of HOXA11
and HOXA13 expression of cDNA derived from the chick limb region at
stage 20 was taken as 1.0. Gene expression levels in samples were compared
using Student's matched-pair t-test.
Immunohistochemical staining using a specific antibody against chick HOXA11
and HOXA13 was performed as described previously
(Yamamoto et al., 1998;
Hashimoto et al., 1999;
Suzuki and Kuroiwa, 2002).
|
RESULTS |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
) showed
that three areas at different locations along the PD axis of chick stage 19
limb buds contribute to the stylopod, zeugopod and autopod, respectively,
suggesting that segments for each future structure have already been specified
as distinct domains at this stage. To obtain further information about the
boundaries between these domains along the PD axis, we began by constructing a
detailed fate map of a stage 19 limb bud to examine prospective fates of limb
mesenchymal cells along the PD axis.
In order to examine the prospective fate of the distal limb bud, some
distal mesenchymal cells were labeled with DiI and observed 2 days later.
Before constructing fate maps, we evaluated our procedure for fate mapping
from several viewpoints. First, we confirmed that there was no leaky diffusion
of DiI during experiments. When the operated embryo was fixed after DiI
administration and left on a dish for 2 days at 4°C, there was no
diffusion of DiI fluorescence in the embryo within 2 days (see Fig. S1A-C in
the supplementary material). Taken together with the fact that DiI and DiO
have been widely used for studying cell fate
(Clarke and Tickle, 1999;
Kimura et al., 2006), it is
certain that fluorescence for DiI and DiO in living embryos at 2 days after
labeling does not include leaky diffusion, indicating that the signal
represents only the distribution of cells labeled 2 days ago and their
progeny. We also evaluated whether the dorsal view of limb buds indicates the
correct position of labeled cells in the cartilage-forming core region. DiI
fluorescence was detected in a straight belt along the dorsal-ventral axis in
longitudinal sections (see Fig. S1D-H in the supplementary material),
revealing that the fluorescence observed from the dorsal side of the limb bud
corresponds to that in the core region. A condensed cell population forming
cartilage was sometimes labeled in the core region, confirming that our
labeling method gives rise to no bias toward cell type. In addition, it is
likely that the central region (cartilage-forming area) and peripheral region
(non-cartilaginous area) of the limb bud have similar prospective fates along
the PD axis.
When the area 0-40 µm from the AER was labeled (Fig. 1A), the DiI-labeled area was found in the autopod 2 days later (Fig. 1B,C). The area 0-60 µm from the point in the AER labeled with DiI (Fig. 1D) was distributed to the distal part of the zeugopod and the entire autopod (Fig. 1E,F). The area 120-180 µm from the AER (Fig. 1G) was found in a region from the proximal end of the zeugopod to a proximal point in the autopod (Fig. 1H,I). The area 180-230 µm from the AER (Fig. 1J) was found in the inside of the zeugopod (Fig. 1K,L). These results, particularly the results shown in Fig. 1D-F, suggested that the area 0-60 µm from the AER contains cells that can contribute to the formation of both the autopod and zeugopod (Fig. 1E,F). To further examine whether the distal area forms the zeugopod as well as the autopod, double labeling was performed; an area 50 µm from the AER was first labeled with DiI (Fig. 2A) and the proximal edge of the DiI distribution was labeled with DiO 2 days later (Fig. 2B-D). Another 2 days later, DiO-labeled cells were clearly observed in a distal portion of the zeugopod (Fig. 2E,F), indicating that the proximal end of the first-labeled area contributed to the formation of the zeugopod.
|
Our fate map demonstrates that prospective stylopod and zeugopod regions
are located in relatively distinct domains in a stage 19 limb bud, as
suggested by a previous study (Dudley et
al., 2002). In contrast to this, prospective autopod and zeugopod
regions tend to overlap each other at 50-160 µm from the AER, and these two
regions seem not to have an obvious boundary of cell fate (see also
Fig. 7A).
To obtain direct evidence supporting this idea, two distant regions in a stage 19 limb bud were simultaneously labeled with DiI and DiO. When two proximal regions were labeled with DiI (220-240 µm from the AER; Fig. 4A) and DiO (250-330 µm from the AER; Fig. 4B), DiI- and DiO-labeled cells contributed to the zeugopod and stylopod, respectively, showing that there are distinct domains for prospective zeugopod and stylopod regions at stage 19 (Fig. 4C-F). When two distal regions were labeled with DiI (0-70 µm from the AER; Fig. 4G) and DiO (120-170 µm from the AER; Fig. 4H), DiI- and DiO-labeled cells were mixed at the cartilage zeugopod-autopod boundary (Fig. 4I-L). Similar results were obtained (Fig. 4M-T) when an area 10-50 µm from the AER was labeled with DiI (Fig. 4M) and a more proximal area (150-210 µm) was labeled with DiO (Fig. 4N). Detailed observation of red and green fluorescence in sections revealed clear overlapping of DiI and DiO at the same level (Fig. 4O-T). These results strongly support the idea that the boundary of prospective zeugopod and autopod regions is indefinite at stage 19 in the chick.
|
|
|
HOXA11 and HOXA13 expression in distal mesenchymal cells of the limb bud at various stages
Our fate mapping, demonstrating that mixed cell fate (zeugopod and autopod
at stage 19, and metacarpal and phalanx at stage 23) was maintained in the
distal limb bud, suggests that the distal region contains some different cell
populations in mosaic. To investigate this possibility, we examined protein
expression in the distal limb bud at the cellular level. We chose two
molecules, HOXA11 and HOXA13, as markers for molecular properties in the
distal region. Expression patterns of these genes are known to change in the
region (Yokouchi et al., 1991;
Nelson et al., 1996), and
moreover, our quantitative real-time RT-PCR analysis revealed that these two
marker genes also have different amounts of transcripts in distal limb buds
(see Fig. S2 in the supplementary material).
To determine whether the cells of the distal limb bud have different
combinations of these markers, we investigated localization of HOXA11 and
HOXA13 proteins recognized by specific antibodies for each protein
(Yamamoto et al., 1998;
Hashimoto et al., 1999;
Suzuki and Kuroiwa, 2002). At
stage 20, neither HOXA11 nor HOXA13 immunoreactivity was detected in the
distal mesenchyme (Fig.
6A,Fa-Fc). At stage 21, HOXA11 immunoreactivity was detected in
the distal mesenchyme in a graded manner along the PD axis (high in the distal
and low in the proximal domain; Fig.
6B,Ga-Gc). At stage 22, HOXA13-positive cells were first detected
in the distal-peripheral mesenchyme in a layer about five cells thick within
the HOXA11-positive domain (Fig.
6C,Ha-Hc). At stage 24, HOXA11-HOXA13-double-positive mesenchymal
cells had expanded in the core of the distal limb bud
(Fig. 6Ia-Ic). At stage 26, the
expression domain of HOXA13 had expanded to a more proximal region, and almost
all of the immunoreactivity for HOXA11 protein had disappeared in the
HOXA13-positive domain (Fig.
6E,Ja-Jc). As a result, no mosaic localization of these proteins
was observed at any stage examined. Confocal microscopy at single cell
resolution further supported this (Fig.
6K-N). At stage 24, both HOXA11 and HOXA13 proteins were expressed
in all of the nuclei in the distal limb bud. Both signals were observed as
particles patchily distributed in nuclei, and these signals were sometimes
colocalize, and all mesenchymal cells we observed were HOXA11-positive and
HOXA13-positive in the distal region of a stage 24 limb bud
(Fig. 6N).
|
|
DISCUSSION |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
) showing
that cells marked 100-200 µm and 200-300 µm from the AER ended up
exclusively in the zeugopod and stylopod, respectively. In contrast to this
agreement, our fate map suggests that there is still a large overlap between
the prospective zeugopod and autopod regions at this stage [the wrist (carpal)
region is defined as a part of the autopod in this study]. The most distal
region, at 0-160 µm was classified as the prospective autopod, whereas the
prospective zeugopod ranged from 50 to 240 µm
(Fig. 3A,
Fig. 7A). The extent of overlap
(around 110 µm) corresponds to 69% of the prospective autopod region
(around 160 µm) and 58% of the prospective zeugopod region (around 190
µm). Many spots labeled at 50-160 µm from the AER were found in both the
zeugopod and autopod, and, moreover, two distant spots were merged with each
other. We propose that distal mesenchymal cells of a stage 19 limb bud
intermingle with each other along the PD axis and that there is no boundary of
cell fate between the prospective autopod and zeugopod at this stage. Although
this idea appears to oppose the conclusion in the previous report
(Dudley et al., 2002) that
future structures of the stylopod, zeugopod and autopod are specified as a
pre-pattern of three regions at this early stage, the actual data do not
contradict each other but can be reconciled. We showed that there were some
points that only contributed to the stylopod, zeugopod or autopod [see sample
numbers 25, 26, 27 (stylopod), 18, 21, 23 (zeugopod), 1, 2 (autopod) in
Fig. 3] as was reported by
Dudley et al. (Dudley et al.,
2002). Our detailed labeling revealed the overlap between autopod
and zeugopod, which was missed by Dudley et al.
(Dudley et al., 2002) because
they failed to examine intermediate injection levels. Our results, showing
that the proximal part of a stage 19 limb bud is regionalized but that the
distal bud is not, suggest that the early stage limb bud has some different
properties along the PD axis. Since all limb mesechymal cells at this stage
are thought to be within range of the FGF signaling from the AER [as evaluated
by expression of FGF-responding genes
(Minowada et al., 1999;
Corson et al., 2003;
Eblaghie et al., 2003;
Kawakami et al., 2003)], it is
interesting that the proximal and distal cells behave differently under the
FGF signaling. In this sense, we suggest that the early limb buds already have
a partial regionalization along the PD axis.
|
How do mesenchymal cells acquire positional identity along the PD axis?
From our fate maps, we found considerable cell mixing in the distal limb
bud. At stage 19, the main region where cell mixing occurs is located around
160 µm from the AER (Fig.
7A). For example in Fig.
3A, the bar of sample 1 (0-30 µm from the AER) and the bar of
sample 17 (160-210 µm from the AER), which had been located distant from
each other at stage 19, overlapped at the wrist level after 2 days, indicating
that these two distant areas at stage 19 include cells that move in this area
and can be distributed at the same level. At stage 23, such a region with
cells of mixed origins can also be observed in a similar range (0-150 µm;
Fig. 7B). This situation,
wherein cells may change their proximal-distal location, seems to be a
characteristic of the distal limb bud because at both stage 19 and stage 23
proximal mesenchymal cells showed much smaller dispersion and little mixing
along the PD axis (indicated by short bars in the proximal region in
Fig. 3 and
Fig. 5). At stage 19,
prospective stylopod and zeugopod domains only have small overlap outside the
distal region 160 µm from the AER (Fig.
7A). Similarly, at stage 23, the prospective zeugopod and autopod
are regionalized in the proximal (more than 150 µm from the AER) limb bud
(Fig. 7B). These results
suggest that regionalization and compartmentalization along the PD axis are
organized in the proximal limb bud. Our detailed observation of HOXA11 and
HOXA13 distribution at the single cell resolution
(Fig. 6), showing that
individual cells go through transitions of expression, does not support the
possibility that the distal region, in which mixed cell fate is maintained,
contains some different cell populations in mosaic. It is unlikely that cell
mixing in the distal limb bud occurs between cells that have different HOXA
expression.
|
Although it seems that the mixable situation of the distal limb bud is reminiscent of the `progress zone'in the progress zone model, our diagrams suggested that the distal fate does not represent an equivalency of positional identity in a certain distal region, an implicit trait of the `progress zone'. The diagrams indicate that there are some regional differences in terms of prospective fate even within the distal 150 µm area. At stage 19, for example, we can see at least two distinct regions in the distal area that have different fates: the region 0-50 µm from the AER is an exclusive autopod-forming region, whereas the more proximal region (50-160 µm from the AER) contributes to the formation of both the autopod and zeugopod (see Fig. 7A). Also at stage 23, the distal domain can be separated into two regions: future phalanx-forming region (distal 0-60 µm area) and more proximal region (60-150 µm area) (see Fig. 7B). Although it appears that the distal region contains mesenchymal cells that have equal developmental potential, the regionalization along the PD axis may emerge at the distal tip and gradually proceed to the proximal end, and in this sense, all cells at different positions along the PD axis may possess slightly different identities even in the distal domain.
HOXA11 and HOXA13 are accurate molecular markers for the PD axis in the
limb, the final expression domains of which are exclusive to each other along
the PD axis. Whereas they seems not themselves involved in specifying the limb
segments (but rather for differentially controlling growth within distinct
segments), HOXA11 and HOXA13 are the best markers we have for these limb
segments. These molecules, however, do not always have the same expression in
the limb bud but show drastic changes in expression spatially and temporally.
In the distal region of the developing limb bud, HOXA11 and HOXA13 show
different levels of expression as the limb bud grows (see Fig. S2 in the
supplementary material). This may be because the amounts of HOXA11 and HOXA13
transcripts increase in each distal cell, and it is also likely that the
change in expression domain contributes to the change in expression level in
the distal region. As can be seen in the
Fig. 6, onset of HOXA13
expression in the limb bud occurs as a small narrow domain of the
posterior-distal peripheral region (see also
Yokouchi et al., 1991;
Nelson et al., 1996). The
domain then expands anteriorly and proximally to encompass the entire autopod.
In addition, the HOXA13-expressing domain does not fully cover the prospective
autopod region until stage 26 (data not shown), suggesting that change in HOXA
expression occurs also in the more proximal limb bud. The above observations
do not support the idea of the progress zone model - that all cells within the
progress zone should make their internal `clock' active and change the clock
coordinately - but they rather indicate heterogeneity in the distal region. As
discussed already, however, the heterogeneity of HOXA expression is not due to
mosaic distribution of HOXA11- and HOXA13-expressing cells but due to regional
difference along the PD axis, suggesting that cells in different positions
along the PD axis gradually acquire different properties. The sequential
difference in cell affinity and graded accumulation of N-cadherin protein
along the PD axis (Yajima et al.,
1999; Yajima et al.,
2002) also support this idea.
Overall, our results suggest that, (1) a limb bud at stage 19 has already regionalized the proximal compartments (for the stylopod and zeugopod) in terms of developmental fate as the pre-specification model proposes; (2) the early-stage limb bud does not have clear regionalization of the distal region (for the zeugopod and autopod) as the progress zone model suggests; (3) it is around stage 23 that three compartments for the stylopod, zeugopod and autopod are established in the limb bud; (4) the distal region has a mixable condition that allows cells to intermingle with each other; and (5) regional heterogeneity along the PD axis exists even in the distal region. Molecular mechanisms for each process of the PD axis formation remain to be elucidated.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/134/7/1397/DC1
|
ACKNOWLEDGMENTS |
|---|
|
REFERENCES |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
Barna, M., Pandolfi, P. P. and Niswander, L.
(2005). Gli3 and Plzf cooperate in proximal limb patterning at
early stages of limb development. Nature
436,277
-281.[CrossRef][Medline]
Bowen, J., Hinchliffe, J. R., Horder, T. J. and Reeve, A. M.
(1989). The fate map of the chick forelimb-bud and its bearing on
hypothesized developmental control mechanisms. Anat.
Embryol. 179,269
-283.[CrossRef][Medline]
Clarke, J. D. and Tickle, C. (1999). Fate maps
old and new. Nat. Cell Biol.
1,E103
-E109.[CrossRef][Medline]
Corson, L. B., Yamanaka, Y., Lai, K. M. and Rossant, J.
(2003). Spatial and temporal patterns of ERK signaling during
mouse embryogenesis. Development
130,4527
-4537.
Dudley, A. T., Ros, M. A. and Tabin, C. J.
(2002). A re-examination of proximodistal patterning during
vertebrate limb development. Nature
418,539
-544.[CrossRef][Medline]
Eblaghie, M. C., Lunn, J. S., Dickinson, R. J., Munsterberg, A.
E., Sanz-Ezquerro, J. J., Farrell, E. R., Mathers, J., Keyse, S. M., Storey,
K. and Tickle, C. (2003). Negative feedback regulation of FGF
signaling levels by Pyst1/MKP3 in chick embryos. Curr.
Biol. 13,1009
-1018.[CrossRef][Medline]
Hamburger, V. and Hamilton, H. L. (1951). A
series of normal stages in the development of the chick embryo.
Dev. Dyn. 195,231
-272.
Hashimoto, K., Yokouchi, Y., Yamamoto, M. and Kuroiwa, A.
(1999). Distinct signaling molecules control Hoxa-11 and Hoxa-13
expression in the muscle precursor and mesenchyme of the chick limb bud.
Development 126,2771
-2783.[Abstract]
Hinchliffe, J. R. (1977). The chondrogenic
pattern in chick limb morphogenesis: a problem of development and evolution.
In Vertebrate Limb and Somite Morphogenesis (ed. D. A.
Ede, J. R. Hinchliffe and M. J. Balls), pp. 293-310.
Cambridge: Cambridge University Press.
Kawakami, Y., Rodriguez-Leon, J., Koth, C. M., Buscher, D.,
Itoh, T., Raya, A., Ng, J. K., Esteban, C. R., Takahashi, S., Henrique, D. et
al. (2003). MKP3 mediates the cellular response to FGF8
signalling in the vertebrate limb. Nat. Cell Biol.
5, 513-519.[CrossRef][Medline]
Kimura, W., Yasugi, S., Stern, C. D. and Fukuda, K.
(2006). Fate and plasticity of the endoderm in the early chick
embryo. Dev. Biol. 289,283
-295.[CrossRef][Medline]
Lewis, J. H. (1975). Fate maps and the pattern
of cell division: a calculation for the chick wing-bud. J. Embryol.
Exp. Morphol. 33,419
-434.[Medline]
Li, S. and Muneoka, K. (1999). Cell migration
and chick limb development: chemotactic action of FGF-4 and the AER.
Dev. Biol. 211,335
-347.[CrossRef][Medline]
Mallein-Gerin, F., Kosher, R. A., Upholt, W. B. and Tanzer, M.
L. (1988). Temporal and spatial analysis of cartilage
proteoglycan core protein gene expression during limb development by in situ
hybridization. Dev. Biol.
126,337
-345.[CrossRef][Medline]
Minowada, G., Jarvis, L. A., Chi, C. L., Neubuser, A., Sun, X.,
Hacohen, N., Krasnow, M. A. and Martin, G. R. (1999).
Vertebrate Sprouty genes are induced by FGF signaling and can cause
chondrodysplasia when overexpressed. Development
126,4465
-4475.[Abstract]
Nelson, C. E., Morgan, B. A., Burke, A. C., Laufer, E.,
DiMambro, E., Murtaugh, L. C., Gonzales, E., Tessarollo, L., Parada, L. F. and
Tabin, C. (1996). Analysis of Hox gene expression in the
chick limb bud. Development
122,1449
-1466.[Abstract]
Richardson, M. K., Jeffery, J. E. and Tabin, C. J.
(2004). Proximodistal patterning of the limb: insights from
evolutionary morphology. Evol. Dev.
6, 1-5.[CrossRef][Medline]
Saunders, J. W., Jr (1948). The proximo-distal
sequence of origin of the parts of the chick wing and the role of the
ectoderm. J. Exp. Zool.
282,628
-668.
Saunders, J. W., Jr (2002). Is the progress
zone model a victim of progress? Cell
110,541
-543.[CrossRef][Medline]
Stark, R. J. and Searls, R. L. (1973). A
description of chick wing bud development and a model of limb morphogenesis.
Dev. Biol. 33,138
-153.[CrossRef][Medline]
Stocum, D. L. (1975). Outgrowth and pattern
formation during limb ontogeny and regeneration.
Differentiation 3,167
-182.[CrossRef][Medline]
Summerbell, D. (1974). A quantitative analysis
of the effect of excision of the AER from the chick limb-bud. J.
Embryol. Exp. Morphol. 32,651
-660.[Medline]
Summerbell, D. (1976). A descriptive study of
the rate of elongation and differentiation of the skeleton of the developing
chick wing. J. Embryol. Exp. Morphol.
35,241
-260.[Medline]
Summerbell, D. and Lewis, J. H. (1975). Time,
place and positional value in the chick limb-bud. J. Embryol. Exp.
Morphol. 33,621
-643.[Medline]
Sun, X., Mariani, F. V. and Martin, G. R.
(2002). Functions of FGF signalling from the apical ectodermal
ridge in limb development. Nature
418,501
-508.[CrossRef][Medline]
Suzuki, M. and Kuroiwa, A. (2002). Transition
of Hox expression during limb cartilage development. Mech.
Dev. 118,241
-245.[CrossRef][Medline]
Tickle, C. and Wolpert, L. (2002). The progress
zone - alive or dead? Nat. Cell Biol.
4,E216
-E217.[CrossRef][Medline]
Vargesson, N., Clarke, J. D., Vincent, K., Coles, C., Wolpert,
L. and Tickle, C. (1997). Cell fate in the chick limb bud and
relationship to gene expression. Development
124,1909
-1918.[Abstract]
Wolpert, L. (1969). Positional information and
the spatial pattern of cellular differentiation. J. Theor.
Biol. 25,1
-47.[CrossRef][Medline]
Wolpert, L. (2002). Limb patterning: reports of
model's death exaggerated. Curr. Biol.
12,R628
-R630.[CrossRef][Medline]
Wolpert, L., Lewis, J. and Summerbell, D.
(1975). Morphogenesis of the vertebrate limb. Ciba
Found. Symp. 0,95
-130.
Yajima, H., Yoneitamura, S., Watanabe, N., Tamura, K. and Ide,
H. (1999). Role of N-cadherin in the sorting-out of
mesenchymal cells and in the positional identity along the proximodistal axis
of the chick limb bud. Dev. Dyn.
216,274
-284.[CrossRef][Medline]
Yajima, H., Hara, K., Ide, H. and Tamura, K.
(2002). Cell adhesiveness and affinity for limb pattern
formation. Int. J. Dev. Biol.
46,897
-904.[Medline]
Yamamoto, M., Gotoh, Y., Tamura, K., Tanaka, M., Kawakami, A.,
Ide, H. and Kuroiwa, A. (1998). Coordinated expression of
Hoxa-11 and Hoxa-13 during limb muscle patterning.
Development 125,1325
-1335.[Abstract]
Yokouchi, Y., Sasaki, H. and Kuroiwa, A.
(1991). Homeobox gene expression correlated with the bifurcation
process of limb cartilage development. Nature
353,443
-445.[CrossRef][Medline]
Yonei, S., Tamura, K., Ohsugi, K. and Ide, H.
(1995). MRC-5 cells induce the AER prior to the duplicated
pattern formation in chick limb bud. Dev. Biol.
170,542
-552.[CrossRef][Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
Related articles in Development:
This article has been cited by other articles:
|
|
 |
|
  I. Tzchori, T. F. Day, P. J. Carolan, Y. Zhao, C. A. Wassif, L. Li, M. Lewandoski, M. Gorivodsky, P. E. Love, F. D. Porter, et al. LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth Development, April 15, 2009; 136(8): 1375 - 1385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Towers and C. Tickle Growing models of vertebrate limb development Development, January 15, 2009; 136(2): 179 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Wolff and G. Scholtz The clonal composition of biramous and uniramous arthropod limbs Proc R Soc B, May 7, 2008; 275(1638): 1023 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lu, Y. Yu, Y. Perdue, and Z. Werb The apical ectodermal ridge is a timer for generating distal limb progenitors Development, April 15, 2008; 135(8): 1395 - 1405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. G. Arques, R. Doohan, J. Sharpe, and M. Torres Cell tracing reveals a dorsoventral lineage restriction plane in the mouse limb bud mesenchyme Development, October 15, 2007; 134(20): 3713 - 3722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Tabin and L. Wolpert Rethinking the proximodistal axis of the vertebrate limb in the molecular era Genes & Dev., June 15, 2007; 21(12): 1433 - 1442. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
