|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online July 25, 2008
doi: 10.1242/10.1242/dev.021188
Jeem Classic |
Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
* Author for correspondence (e-mail: tabin{at}genetics.med.harvard.edu)
SUMMARY
Dennis Summerbell was a leading contributor to our understanding of limb patterning prior to the advent of molecular biology. He published several groundbreaking papers, including one that developed a key model for patterning the limb from the shoulder to the fingertips and another that presented the co-discovery of the effect of retinoids on limb morphogenesis. He brought detailed quantitative analyses to bear on these studies, as highlighted in two of his insightful papers published in the Journal of Embryology and Experimental Morphology, in which he provided elegant models that, today, remain relevant to limb patterning, as well as to many disciplines of developmental biology.
Introduction
Because the developing limb bud is easily accessible to manipulation and is not required for the survival of the embryo, it has long served as an ideal system in which to study patterning mechanisms. It begins as a relatively undifferentiated mass of cells that becomes sculpted into an adult limb, which contains asymmetries along the three axes: proximodistal (PD), anteroposterior (AP) and dorsoventral. When Dennis Summerbell's two papers were first published in the Journal of Embryology and Experimental Morphology (JEEM), separate signaling centers were known to be present in the limb and to influence each of these axes. In particular, the apical ectodermal ridge (AER) was known to be essential for proper PD outgrowth and the zone of polarizing activity (ZPA) had been identified as being important for AP patterning. Although the molecular identity of the signals that emanate from these centers was unknown at the time, based on the effects of experimental manipulations, Summerbell and others proposed elegant models that conceptualized limb-patterning ideas. These models shaped our thinking about developmental patterning, not just in the limb but throughout the embryo.
Limb development in the pre-molecular era
The AER is a thickened ectoderm that is located at the distal end of the
limb (see Fig. 1). It overlies
the early limb bud mesenchyme and is essential for the outgrowth of all three
PD limb segments: the stylopod (humerus/upper arm), the zeugopod (radius and
ulna/forearm) and the autopod (digits/hand). AER extirpation experiments,
which were published by John Saunders in 1948
(Saunders, 1948
), were the
first to show that chick limbs in which the AER was removed at early stages
completely lacked distal structures, whereas the removal of the AER at later
stages resulted in limbs that had increasingly more intact distal structures,
At this time, it had already been established that there was a progressive
proximal-to-distal order of limb skeletal differentiation. It was also
recognized that there was no change in the influence of the AER on PD axis
specification over time, suggesting that the AER provided only a permissive
signal that allowed for limb outgrowth. This conclusion was based on
transplant studies in which older and younger AERs were transplanted onto
differently aged chick limb mesenchyme, and in which no effect on PD
patterning was observed (Rubin and
Saunders, 1972).
Based on these findings, Summerbell, Julian Lewis and Lewis Wolpert
proposed the progress zone model to explain patterning along the PD axis of
the limb in a landmark paper in 1973
(Summerbell et al., 1973)
(Fig. 1A). This model stated
that the PD positional identity of a cell is intrinsically determined by the
amount of time it spends in the progress zone, an area of mesenchymal cells
approximately 300 µm thick that is located just beneath the AER. This model
provided a twist on other types of limb patterning models that previously had
been proposed by adding a new dimension, time, as having an influence on limb
patterning. Central to this hypothesis was the idea that progress zone cells
possess an autonomous clock that records the time they spend in the labile
region. The authors rejected a morphogen-based model system because of
experiments that had shown that grafts of limb bud pieces transplanted to
hosts retained their presumptive fates.
By contrast, the idea of a morphogen was central to the way in which
Summerbell and others conceptualized the establishment of the AP axis of the
limb. Saunders and Mary Gasseling were the first to show that cells located at
the posterior lateral edge of a chick limb bud had the unique ability to cause
mirror-image duplications when transplanted to an anterior location
(Saunders and Gasseling,
1968). Because of its potency in re-patterning the limb along the
AP axis, this region was termed the zone of polarizing activity (ZPA). Based
on this result, the idea that different cell fates could be specified at
different concentration thresholds of a diffusible signal, or morphogen
gradient, was first proposed by Lewis Wolpert in 1969
(Wolpert, 1969). In the
context of the developing AP limb axis, Wolpert hypothesized that tissue
closest to the ZPA would experience the highest levels of a morphogen and
would develop into posterior structures (ulna, digit 4), whereas anterior
tissues would receive lower levels of morphogen and would develop into
anterior skeletal elements (radius, digit 2). This model was strongly
supported by two experiments by Cheryll Tickle. The first experiment showed
that a direct relationship exists between the number of ZPA cells that are
grafted into a chick limb and the identity of the digit(s) induced by the
graft (Tickle, 1981). The
second showed that grafting ZPA tissue to different locations in the limb bud
gave rise to digit patterns that were consistent with the transplanted ZPAs
releasing a diffusible morphogen that was capable of re-patterning the host
tissue (Tickle et al.,
1975).
A potential candidate for the ZPA morphogen came out of studies of limb
regeneration. Iqbal Niazi and Saroj Saxena first demonstrated that ectopically
provided vitamin A (retinoic acid, RA) would result in the reorganization of
the PD axis of regenerating amphibian limbs
(Niazi and Saxena, 1978).
Building on this work, both Cheryll Tickle and Dennis Summerbell independently
showed that, in the context of developing chick limb buds, ectopic RA served
to mimic the ZPA-induced mirror-image duplications
(Summerbell and Harvey, 1983;
Tickle et al., 1982).
The removal of the AER and its effect on PD patterning, and the application of RA and its effect on AP patterning, were important results that provided assays for exploring and understanding limb patterning in the pre-molecular era of developmental biology. In the two extremely influential papers published by Summerbell in JEEM, each of these findings was readdressed on a quantitative level, providing new insights and, indeed, new ways of looking at these problems.
|
The progress zone model (see Fig. 1A) stated that PD identity is continuously changing in the distal limb bud and does not become specified until cells are displaced away from the distal domain. In particular, the positional identity of a cell is determined by the amount of time it spends in the progress zone, which lies beneath the AER. When the AER is removed, the cells of the progress zone cease to alter their PD fate, just as if they had exited the distal progress zone in an unaltered limb bud. Thus, distal-most fates are never specified following AER removal, resulting in the observed truncations in distal limb pattern.
To gain further insight into this phenomenon, Summerbell took a careful,
quantitative approach to the AER removal experiments
(Summerbell, 1974), in which
he removed the AER from chick embryo right forelimb buds at Hamburger Hamilton
(HH) stages 18-28. At 10 days of development, the embryos were harvested and
stained with Alcian Green to visualize the cartilage elements. The length of
each element (humerus, ulna, radius and digit III) was measured and compared
between control and operated limbs. Similar to the previous studies, he found
that AER removal at later stages resulted in truncations that were
progressively more distal. Moreover, he found that elements could be partially
lost: skeletal elements were normal on the proximal end, but truncated at the
distal end. This led to the important suggestion that limb segments did not
undergo regulative patterning (which would have led to the formation of a
whole segment of smaller size). Thus, rather than being patterned
segment-by-segment, the limb bud appeared to be patterned continuously along
the PD axis. Perhaps the key insight in this paper is that, if the progress
zone model is correct, the pattern that forms after AER removal directly
reflects the extent of PD specification present in the distal limb at the time
of AER extirpation (Fig. 1A,C).
Thus, by comparing the pattern of the limb that results from the removal of
the AER at different time points, one can assay the rate of change of a cell's
positional value within the progress zone.
We now have an improved molecular understanding of the signals that emanate
from the AER and of the cellular events that occur following its removal.
Fibroblast growth factors (FGFs) are known to be the key signals generated by
the AER that promote limb outgrowth (Fallon
et al., 1994; Niswander et
al., 1993). In addition, the AER FGFs are now known to be crucial
for the survival of the limb progenitors located within the progress zone
(Dudley et al., 2002;
Rowe et al., 1982). This
knowledge has brought about a reinterpretation of the AER extirpation
experiments. If the resultant truncations were due to distal cells being
frozen in an inappropriately proximal positional identity, they should
contribute to proximal structures. Instead, as highlighted by cell labeling
experiments, distal cells fail to be maintained in any skeletal elements
following AER removal, owing to cell death
(Dudley et al., 2002). Thus,
the AER extirpation experiments do not give a reliable estimate of when PD
segments are specified in the progress zone during limb development.
Nonetheless, the logic presented by Summerbell
(Summerbell, 1974) still
holds, although the parameter being assessed is not the rate of change of
positional value in the progress zone, but rather the process of
differentiation at the proximal edge of the progress zone, where cells cease
to require the AER for survival (Fig.
1B,C).
Interestingly, Summerbell considered but then discounted cell death. This
is because an earlier study of cell death following AER removal had
erroneously reported that the wave of cell loss extends from the distal tip to
the base of the limb bud (Janners and
Searls, 1971). Summerbell correctly reasoned that, were this to be
true, and if its effect was indeed significant, cell death would result in the
loss of proximal, as well as distal, structures (which was not observed). It
was not until eight years after Summerbell published his analysis that it was
realized that the cell death that follows AER removal is actually confined to
the distal 200-300 µm of the limb bud
(Rowe et al., 1982).
As AER extirpation causes distal cell death, the timing of PD specification
in the distal limb at the time of AER removal is, therefore, not a valid test
of the progress zone model. In the decades following Summerbell's work, other
models have been proposed to explain limb PD patterning. Based on the analysis
of cell death following AER removal and other experiments, it has been
proposed that cell fates for all three segments, stylopod, zeugopod and
autopod, are established within the early limb bud and are subsequently
expanded before differentiation into particular skeletal elements
(Dudley et al., 2002). However,
the current lack of molecular expression data supporting either the early
specification model or the progress zone model has forced a re-examination of
both models (Tabin and Wolpert,
2007). Instead, molecular evidence suggests that PD specification
may be based on a system that involves two opposing signals, which operate
distally and proximally to coordinate gene expression along the PD axis. In
particular, the distal signaling molecule is thought to be FGF, while the
proximal signal has been suggested to be RA
(Fig. 1B)
(Capdevila et al., 1999;
Mercader et al., 1999;
Mercader et al., 2000).
Studies in mice have supported this two-signal model, and have proposed that
FGFs from the AER have dual functions: specifying the initial progenitor size
of each segment, and maintaining and expanding proper progenitor cell numbers
prior to condensation (Mariani,
2008; Sun et al.,
2002). Integrating the dynamic changes in target gene expression
that occur in response to these signals as the limb bud grows out with the
proximal-to-distal wave of differentiation
(Tabin and Wolpert, 2007) can
in principle provide a context for understanding, in modern terms, the process
of PD specification that was so elegantly analyzed by Summerbell in his 1974
JEEM paper.
The ZPA and the role of RA
At the time of Summerbell's 1983 paper, many in the field believed that a
morphogen gradient produced by the ZPA specified positional information along
the AP axis of the limb. The finding that RA could, like the ZPA, induce
mirror-image duplications (Summerbell and
Harvey, 1983; Tickle,
1983; Tickle et al.,
1982) raised the intriguing possibility that a retinoid might, in
fact, be the endogenous morphogen released by the ZPA. Summerbell undertook a
quantitative analysis of this paradigm, by placing newspaper soaked in various
concentrations of RA into slits cut into chick limb buds from HH stages 17-22.
Summerbell discovered that the addition of RA at intermediate stages of chick
development (HH19-HH20) gave mirror-image duplications similar to those caused
by the ZPA grafts. He also found that the extent of mirror-image duplications
was dependent upon the concentration of RA and the stage at which it was
applied. This provided important additional evidence that AP patterning is
laid down as a series of threshold responses. However, the introduction of
very high doses of RA at early stages of limb development caused severe
reductions in all skeletal elements. As such truncations are never seen in
grafts that contain large numbers of ZPA cells when they are transplanted at
early stages, Summerbell was led to re-evaluate the presumption that
ectopically applied RA reflects the activity of an endogenous retinoid
morphogen.
In his paper, Summerbell very thoughtfully describes the possible models that could explain all of his results, particularly the reduction in skeletal elements. He first considered RA to be the ZPA morphogen. For this to be the case, the reduction in digits that occurs in response to high doses of RA would result from an enhancement of the signal, such that the concentration of morphogen was too high to specify the most anterior digits and only the most posterior digits would form. However, this does not easily explain the complete loss of skeletal elements at some doses. Alternatively, Summerbell proposed that RA might have dual functions in instructing patterning, as well as in causing cell death. Still, this explanation seemed unsatisfactory as Summerbell found it difficult to generate dose-response curves that incorporated both duplication and reduction phenotypes. Ultimately, Summerbell proposed that the phenotypical effect of RA could be more fully explained in terms of RA being an ectopic agent that acts on an endogenous patterning system, which he put in the context of a reaction-diffusion model for generating a concentration gradient of a morphogen in the limb bud.
The general reaction-diffusion model was proposed by Alan Turing in 1952 to
describe how patterns could form from two interacting substances with
different diffusion rates (Turing,
1952). Alfred Gierer and Hans Meinhardt added to this model by
demonstrating that an important aspect of pattern formation is self-activation
and long-range inhibition (Gierer and
Meinhardt, 1972). In this model, an activator is produced that
diffuses slowly promoting its own production and that of a more rapidly
diffusing inhibitor. In effect, the concentration ratio of activator to
inhibitor near the source is higher than the ratio far from the source. Based
on this model, Summerbell proposed that rather than being the ZPA morphogen,
RA alters the activator to inhibitor ratio, thereby causing the activator to
be released from inhibition. At low to moderate RA concentrations, a stable
anterior peak of activator forms, resulting in mirror-image duplications of
the skeletal elements. This model also explains the loss of structures that is
observed when high RA concentrations are applied to the limb as resulting from
there being an increased amount of activator across the whole of the limb
field. Anterior skeletal elements that are normally specified at lower
activator concentrations are progressively lost at increasing doses of RA.
Summerbell was correct in interpreting the effect of RA as a
pharmacological influence on an unrelated endogenous morphogen released by the
ZPA. We now know that morphogen to be sonic hedegehog (SHH)
(Riddle et al., 1993). In
causing limb duplications, RA does not exactly mimic the ZPA, but instead acts
to convert anterior cells into ZPA cells, causing SHH to be expressed in the
anterior limb bud (Fig. 2A)
(Noji et al., 1991;
Riddle et al., 1993;
Wanek et al., 1991).
Although the spatial gradient of SHH activity across the limb bud is not
established by a true reaction-diffusion mechanism, many elements incorporated
into Summerbell's model have held true. Intrinsic to the reaction-diffusion
mechanism is an activator that positively influences its own activity and that
also induces the formation of an inhibitor. Indeed, through an FGF-feedback
loop, SHH indirectly promotes its own expression
(Fig. 2B)
(Laufer et al., 1994;
Niswander et al., 1994), and
it also activates the expression of inhibitors, such as patched
(Chen and Struhl, 1998;
Goodrich et al., 1996;
Marigo et al., 1996) and
hedgehog-interacting protein (HIP) that act to limit SHH activity
(Chuang and McMahon, 1999).
Currently, SHH is believed to control digit identity by acting as a morphogen
both spatially and temporally. From studies in mice that have examined the
fate of SHH descendants and SHH-responsive cells, and from experiments in
chick in which the time period over which the limb bud is exposed to SHH has
been altered, it is thought that the digits are differentially patterned by
the length of time and the concentration of SHH
(Fig. 2D)
(Scherz, 2007;
Ahn and Joyner, 2004;
Harfe et al., 2004).
|
). Based on
mouse knockout data, it is thought that SHH signaling in the limb alters the
activator-to-repressor ratio of GLI3, which ultimately determines digit number
and identity (Fig. 2C)
(Litingtung et al., 2002;
te Welscher et al., 2002).
Although Summerbell could not have known these molecular details at the time,
his quantitative analysis provided profound insights into the mechanisms
patterning the developing limb. Conclusions
The two papers by Dennis Summerbell that we have discussed in this essay
illustrate how early conceptual models of patterning events can shape our
thinking about developmental processes for decades. Although the progress zone
model is still contested today in the limb field, its implications - that time
can be an important factor in patterning mechanisms - has been broadly felt.
The concept of a cell-autonomous clock has been validated in other processes,
such as somitogenesis (Hirata et al.,
2002; Jouve et al.,
2000; Palmeirim et al.,
1997). Moreover, the reaction-diffusion mechanism that Summerbell
applied to AP patterning in the limb can be found in other developmental
contexts, such as in the initial stages of left-right body axis determination
and in skin pattern formation (Asai et al.,
1999; Jung et al.,
1998; Nakamura et al.,
2006). The fact that Summerbell pushed beyond the initial
conclusion that RA is the ZPA morphogen and drew upon a model that, to him,
better satisfied all the data is a testament to his commitment towards gaining
a fuller understanding of limb patterning. Ultimately, what Summerbell's work
truly exemplifies is how a careful and thorough approach to generating,
interpreting and modeling the data can have a profound impact on our
understanding of developmental patterning mechanisms.
ACKNOWLEDGMENTS
We thank Edwina McGlinn and Jose Rivera-Feliciano for their critical reading of the manuscript and help with the figures. J.L.G. is supported by the National Institute of Child Health and Human Development. The Tabin laboratory is supported by the NIH.
REFERENCES
Ahn, S. and Joyner, A. L. (2004). Dynamic
changes in the response of cells to positive hedgehog signaling during mouse
limb patterning. Cell
118,505
-516.[CrossRef][Medline]
Asai, R., Taguchi, E., Kume, Y., Saito, M. and Kondo, S.
(1999). Zebrafish leopard gene as a component of the putative
reaction-diffusion system. Mech. Dev.
89, 87-92.[CrossRef][Medline]
Capdevila, J., Tsukui, T., Rodriquez Esteban, C., Zappavigna, V.
and Izpisua Belmonte, J. C. (1999). Control of vertebrate
limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by
Gremlin. Mol. Cell 4,839
-849.[CrossRef][Medline]
Charite, J., de Graaff, W., Shen, S. and Deschamps, J.
(1994). Ectopic expression of Hoxb-8 causes duplication of the
ZPA in the forelimb and homeotic transformation of axial structures.
Cell 78,589
-601.[CrossRef][Medline]
Chen, Y. and Struhl, G. (1998). In vivo
evidence that Patched and Smoothened constitute distinct binding and
transducing components of a Hedgehog receptor complex.
Development 125,4943
-4948.[Abstract]
Chuang, P. T. and McMahon, A. P. (1999).
Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding
protein. Nature 397,617
-621.[CrossRef][Medline]
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]
Fallon, J. F., Lopez, A., Ros, M. A., Savage, M. P., Olwin, B.
B. and Simandl, B. K. (1994). FGF-2: apical ectodermal ridge
growth signal for chick limb development. Science
264,104
-107.
Gierer, A. and Meinhardt, H. (1972). A theory
of biological pattern formation. Kybernetik
12, 30-39.[CrossRef][Medline]
Goodrich, L. V., Johnson, R. L., Milenkovic, L., McMahon, J. A.
and Scott, M. P. (1996). Conservation of the hedgehog/patched
signaling pathway from flies to mice: induction of a mouse patched gene by
Hedgehog. Genes Dev. 10,301
-312.
Harfe, B. D., Scherz, P. J., Nissim, S., Tian, H., McMahon, A.
P. and Tabin, C. J. (2004). Evidence for an expansion-based
temporal Shh gradient in specifying vertebrate digit identities.
Cell 118,517
-528.[CrossRef][Medline]
Hirata, H., Yoshiura, S., Ohtsuka, T., Bessho, Y., Harada, T.,
Yoshikawa, K. and Kageyama, R. (2002). Oscillatory expression
of the bHLH factor Hes1 regulated by a negative feedback loop.
Science 298,840
-843.
Janners, M. Y. and Searls, R. L. (1971). Effect
of removal of the apical ectodermal ridge on the rate of cell division in the
subridge mesenchyme of the embryonic chick wing. Dev.
Biol. 24,465
-476.[CrossRef][Medline]
Jouve, C., Palmeirim, I., Henrique, D., Beckers, J., Gossler,
A., Ish-Horowicz, D. and Pourquie, O. (2000). Notch
signalling is required for cyclic expression of the hairy-like gene HES1 in
the presomitic mesoderm. Development
127,1421
-1429.[Abstract]
Jung, H. S., Francis-West, P. H., Widelitz, R. B., Jiang, T. X.,
Ting-Berreth, S., Tickle, C., Wolpert, L. and Chuong, C. M.
(1998). Local inhibitory action of BMPs and their relationships
with activators in feather formation: implications for periodic patterning.
Dev. Biol. 196,11
-23.[CrossRef][Medline]
Laufer, E., Nelson, C. E., Johnson, R. L., Morgan, B. A. and
Tabin, C. (1994). Sonic hedgehog and Fgf-4 act through a
signaling cascade and feedback loop to integrate growth and patterning of the
developing limb bud. Cell
79,993
-1003.[CrossRef][Medline]
Litingtung, Y., Dahn, R. D., Li, Y., Fallon, J. F. and Chiang,
C. (2002). Shh and Gli3 are dispensable for limb skeleton
formation but regulate digit number and identity.
Nature 418,979
-983.[CrossRef][Medline]
Lu, H. C., Revelli, J. P., Goering, L., Thaller, C. and Eichele,
G. (1997). Retinoid signaling is required for the
establishment of a ZPA and for the expression of Hoxb-8, a mediator of ZPA
formation. Development
124,1643
-1651.[Abstract]
Mariani, F. V., Ahn, C. P. and Martin, G. R.
(2008). Genetic evidence that FGFs have an instructive role in
limb proximal-distal patterning. Nature
453,401
-405.[CrossRef][Medline]
Marigo, V., Davey, R. A., Zuo, Y., Cunningham, J. M. and Tabin,
C. J. (1996). Biochemical evidence that patched is the
Hedgehog receptor. Nature
384,176
-179.[CrossRef][Medline]
Mercader, N., Leonardo, E., Azpiazu, N., Serrano, A., Morata,
G., Martinez, C. and Torres, M. (1999). Conserved regulation
of proximodistal limb axis development by Meis1/Hth.
Nature 402,425
-429.[CrossRef][Medline]
Mercader, N., Leonardo, E., Piedra, M. E., Martinez, A. C., Ros,
M. A. and Torres, M. (2000). Opposing RA and FGF signals
control proximodistal vertebrate limb development through regulation of Meis
genes. Development 127,3961
-3970.[Abstract]
Nakamura, T., Mine, N., Nakaguchi, E., Mochizuki, A., Yamamoto,
M., Yashiro, K., Meno, C. and Hamada, H. (2006). Generation
of robust left-right asymmetry in the mouse embryo requires a self-enhancement
and lateral-inhibition system. Dev. Cell
11,495
-504.[CrossRef][Medline]
Niazi, I. A. and Saxena, S. (1978). Abnormal
hind limb regeneration in tadpoles of the toad, Bufo andersoni, exposed to
excess vitamin A. Folia Biol. (Krakow)
26, 3-8.[Medline]
Niswander, L., Tickle, C., Vogel, A., Booth, I. and Martin, G.
R. (1993). FGF-4 replaces the apical ectodermal ridge and
directs outgrowth and patterning of the limb. Cell
75,579
-587.[CrossRef][Medline]
Niswander, L., Jeffrey, S., Martin, G. R. and Tickle, C.
(1994). A positive feedback loop coordinates growth and
patterning in the vertebrate limb. Nature
371,609
-612.[CrossRef][Medline]
Noji, S., Nohno, T., Koyama, E., Muto, K., Ohyama, K., Aoki, Y.,
Tamura, K., Ohsugi, K., Ide, H., Taniguchi, S. et al. (1991).
Retinoic acid induces polarizing activity but is unlikely to be a morphogen in
the chick limb bud. Nature
350, 83-86.[CrossRef][Medline]
Palmeirim, I., Henrique, D., Ish-Horowicz, D. and Pourquie,
O. (1997). Avian hairy gene expression identifies a molecular
clock linked to vertebrate segmentation and somitogenesis.
Cell 91,639
-648.[CrossRef][Medline]
Riddle, R. D., Johnson, R. L., Laufer, E. and Tabin, C.
(1993). Sonic hedgehog mediates the polarizing activity of the
ZPA. Cell 75,1401
-1416.[CrossRef][Medline]
Rowe, D. A., Cairns, J. M. and Fallon, J. F.
(1982). Spatial and temporal patterns of cell death in limb bud
mesoderm after apical ectodermal ridge removal. Dev.
Biol. 93,83
-91.[CrossRef][Medline]
Rubin, L. and Saunders, J. W., Jr (1972).
Ectodermal-mesodermal interactions in the growth of limb buds in the chick
embryo: constancy and temporal limits of the ectodermal induction.
Dev. Biol. 28,94
-112.[CrossRef][Medline]
Saunders, J. W. (1948). The proximo-distal
sequence of origin of the parts of the chick wing and the role of the
ectoderm. J. Exp. Zool.
108,363
-403.[CrossRef][Medline]
Saunders, J. W., Jr and Gasseling, M. T.
(1968). Ectoderm-mesenchymal interactions in the origin of wing
symmetry. In Epithelial-Mesenchymal Interactions (ed.
R. Fleischmajer and R. E. Billingham), pp. 78-97.
Baltimore, MD: Williams and Wilkins.
Scherz, P. J., McGlinn, E., Nissim, S. and Tabin, C. J.
(2007). Extended exposure to Sonic hedgehog is required for
patterning the posterior digits of the vertebrate limb. Dev.
Biol. 308,343
-354.[CrossRef][Medline]
Stratford, T. H., Kostakopoulou, K. and Maden, M.
(1997). Hoxb-8 has a role in establishing early
anterior-posterior polarity in chick forelimb but not hindlimb.
Development 124,4225
-4234.[Abstract]
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. (1983). The effect of local
application of retinoic acid to the anterior margin of the developing chick
limb. J. Embryol. Exp. Morphol.
78,269
-289.[Medline]
Summerbell, D. and Harvey, F. (1983). Vitamin A
and the control of pattern in developing limbs. Prog. Clin. Biol.
Res. 110,109
-118.[Medline]
Summerbell, D., Lewis, J. H. and Wolpert, L.
(1973). Positional information in chick limb morphogenesis.
Nature 244,492
-496.[CrossRef][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]
Tabin, C. and Wolpert, L. (2007). Rethinking
the proximodistal axis of the vertebrate limb in the molecular era.
Genes Dev. 21,1433
-1442.
te Welscher, P., Zuniga, A., Kuijper, S., Drenth, T., Goedemans,
H. J., Meijlink, F. and Zeller, R. (2002). Progression of
vertebrate limb development through SHH-mediated counteraction of GLI3.
Science 298,827
-830.
Tickle, C. (1981). The number of polarizing
region cells required to specify additional digits in the developing chick
wing. Nature 289,295
-298.[CrossRef][Medline]
Tickle, C. (1983). Positional signalling by
retinoic acid in the developing chick wing. Prog. Clin. Biol.
Res. 110,89
-98.[Medline]
Tickle, C., Summerbell, D. and Wolpert, L.
(1975). Positional signalling and specification of digits in
chick limb morphogenesis. Nature
254,199
-202.[CrossRef][Medline]
Tickle, C., Alberts, B., Wolpert, L. and Lee, J.
(1982). Local application of retinoic acid to the limb bond
mimics the action of the polarizing region. Nature
296,564
-566.[CrossRef][Medline]
Turing, A. M. (1952). The chemical basis of
morphogenesis. Philos. Trans. R. Soc. Lond. Ser. B
237, 37-72.
van den Akker, E., Reijnen, M., Korving, J., Brouwer, A.,
Meijlink, F. and Deschamps, J. (1999). Targeted inactivation
of Hoxb8 affects survival of a spinal ganglion and causes aberrant limb
reflexes. Mech. Dev. 89,103
-114.[CrossRef][Medline]
Wanek, N., Gardiner, D. M., Muneoka, K. and Bryant, S. V.
(1991). Conversion by retinoic acid of anterior cells into ZPA
cells in the chick wing bud. Nature
350, 81-83.[CrossRef][Medline]
Wang, B., Fallon, J. F. and Beachy, P. A.
(2000). Hedgehog-regulated processing of Gli3 produces an
anterior/posterior repressor gradient in the developing vertebrate limb.
Cell 100,423
-434.[CrossRef][Medline]
Wolpert, L. (1969). Positional information and
the spatial pattern of cellular differentiation. J. Theor.
Biol. 25,1
-47.[CrossRef][Medline]
Zuniga, A., Haramis, A. P., McMahon, A. P. and Zeller, R.
(1999). Signal relay by BMP antagonism controls the SHH/FGF4
feedback loop in vertebrate limb buds. Nature
401,598
-602.[CrossRef][Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
