FGF-2: apical ectodermal ridge growth signal for chick limb development

During early limb development, distal tip ectoderm is induced by the underlying mesenchyme to form the apical ectodermal ridge. Subsequent limb growth and patterning depend on reciprocal signaling between the mesenchyme and ridge. Mice that are homozygous for mutations at the limb deformity (ld) locus do not form a proper ridge and the anteroposterior axis of the limb is shortened. Skeletal analyses reveal shortened limbs that involve loss and fusion of distal bones and digits, defects in both anteroposterior and proximodistal patterning. Using molecular markers and mouse-chick chimeras we examined the ridge-mesenchymal interactions to determine the origin of the ld patterning defects. In the ld ridge, fibroblast growth factor 8 (Fgf8) RNA is decreased and Fgf4 RNA is not detected. In the ld mesenchyme, Sonic hedgehog (Shh), Evx1 and Wnt5a expression is decreased. In chimeras between ld ectoderm and wild-type mesenchyme, a ridge of normal morphology and function is restored, Fgf8 and Shh are expressed normally, Fgf4 is induced and a normal skeletal pattern arises. These results suggest that the ld mesenchyme is unable to induce the formation of a completely functional ridge. This primary defect causes a disruption of ridge function and subsequently leads to the patterning defects observed in ld limbs. We propose a model in which ridge induction requires at least two phases: an early competence phase, which includes induction of Fgf8 expression, and a later differentiation phase in which Fgf4 is induced and a morphological ridge is formed. Ld proteins appear to act during the differentiation phase.

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Retinoic acid signaling is required during early chick limb development

Development ◽

10.1242/dev.122.5.1385 ◽

1996 ◽

Vol 122 (5) ◽

pp. 1385-1394 ◽

Cited By ~ 10

Author(s):

J.A. Helms ◽

C.H. Kim ◽

G. Eichele ◽

C. Thaller

Keyword(s):

Retinoic Acid ◽

Limb Development ◽

Acid Synthesis ◽

Apical Ectodermal Ridge ◽

Limb Bud ◽

Retinoid Receptor ◽

Limb Morphogenesis ◽

Wing Bud ◽

Zone Of Polarizing Activity

In the chick limb bud, the zone of polarizing activity controls limb patterning along the anteroposterior and proximodistal axes. Since retinoic acid can induce ectopic polarizing activity, we examined whether this molecule plays a role in the establishment of the endogenous zone of polarizing activity. Grafts of wing bud mesenchyme treated with physiologic doses of retinoic acid had weak polarizing activity but inclusion of a retinoic acid-exposed apical ectodermal ridge or of prospective wing bud ectoderm evoked strong polarizing activity. Likewise, polarizing activity of prospective wing mesenchyme was markedly enhanced by co-grafting either a retinoic acid-exposed apical ectodermal ridge or ectoderm from the wing region. This equivalence of ectoderm-mesenchyme interactions required for the establishment of polarizing activity in retinoic acid-treated wing buds and in prospective wing tissue, suggests a role of retinoic acid in the establishment of the zone of polarizing activity. We found that prospective wing bud tissue is a high-point of retinoic acid synthesis. Furthermore, retinoid receptor-specific antagonists blocked limb morphogenesis and down-regulated a polarizing signal, sonic hedgehog. Limb agenesis was reversed when antagonist-exposed wing buds were treated with retinoic acid. Our results demonstrate a role of retinoic acid in the establishment of the endogenous zone of polarizing activity.

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Faculty Opinions recommendation of Functions of FGF signalling from the apical ectodermal ridge in limb development.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1008383.111562 ◽

2002 ◽

Author(s):

Harukazu Nakamura

Keyword(s):

Limb Development ◽

Apical Ectodermal Ridge ◽

Fgf Signalling

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BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb

Development ◽

10.1242/dev.128.22.4449 ◽

2001 ◽

Vol 128 (22) ◽

pp. 4449-4461 ◽

Cited By ~ 7

Author(s):

Kyung Ahn ◽

Yuji Mishina ◽

Mark C. Hanks ◽

Richard R. Behringer ◽

E. Bryan Crenshaw

Keyword(s):

Limb Development ◽

Apical Ectodermal Ridge ◽

Bmp Signaling ◽

Conditional Knockout ◽

Limb Bud ◽

Gene Encoding ◽

Bone Morphogenetic Protein Receptor ◽

Protein Receptor ◽

Morphogenetic Protein ◽

Embryonic Limb

We demonstrate that signaling via the bone morphogenetic protein receptor IA (BMPR-IA) is required to establish two of the three cardinal axes of the limb: the proximal-distal axis and the dorsal-ventral axis. We generated a conditional knockout of the gene encoding BMPR-IA (Bmpr) that disrupted BMP signaling in the limb ectoderm. In the most severely affected embryos, this conditional mutation resulted in gross malformations of the limbs with complete agenesis of the hindlimbs. The proximal-distal axis is specified by the apical ectodermal ridge (AER), which forms from limb ectoderm at the distal tip of the embryonic limb bud. Analyses of the expression of molecular markers, such as Fgf8, demonstrate that formation of the AER was disrupted in the Bmpr mutants. Along the dorsal/ventral axis, loss of engrailed 1 (En1) expression in the non-ridge ectoderm of the mutants resulted in a dorsal transformation of the ventral limb structures. The expression pattern of Bmp4 and Bmp7 suggest that these growth factors play an instructive role in specifying dorsoventral pattern in the limb. This study demonstrates that BMPR-IA signaling plays a crucial role in AER formation and in the establishment of the dorsal/ventral patterning during limb development.

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Functions of FGF signalling from the apical ectodermal ridge in limb development

Nature ◽

10.1038/nature00902 ◽

2002 ◽

Vol 418 (6897) ◽

pp. 501-508 ◽

Cited By ~ 336

Author(s):

Xin Sun ◽

Francesca V. Mariani ◽

Gail R. Martin

Keyword(s):

Limb Development ◽

Apical Ectodermal Ridge ◽

Fgf Signalling

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Bhlha9 regulates apical ectodermal ridge formation during limb development

Journal of Bone and Mineral Metabolism ◽

10.1007/s00774-017-0820-0 ◽

2017 ◽

Vol 36 (1) ◽

pp. 64-72 ◽

Cited By ~ 5

Author(s):

Kensuke Kataoka ◽

Takahide Matsushima ◽

Yoshiaki Ito ◽

Tempei Sato ◽

Shigetoshi Yokoyama ◽

...

Keyword(s):

Limb Development ◽

Apical Ectodermal Ridge

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Retinoids reprogramme pre-bud mesenchyme to give changes in limb pattern

Development ◽

10.1242/dev.100.4.723 ◽

1987 ◽

Vol 100 (4) ◽

pp. 723-733 ◽

Cited By ~ 2

Author(s):

S.M. Wilde ◽

S.E. Wedden ◽

C. Tickle

Keyword(s):

Retinoic Acid ◽

Effective Treatment ◽

Limb Development ◽

Apical Ectodermal Ridge ◽

Limb Bud ◽

Chick Embryos ◽

Early Stages ◽

Limb Pattern

Retinoic acid was locally applied to presumptive limb regions of chick embryos to find out the earliest time at which the limb pattern can be reprogrammed. When beads soaked in retinoic acid were placed in the appropriate positions in embryos at stage 10 or older, duplicated or reduced leg patterns resulted. To pin point the time at which the cells in the limb rudiment respond to the retinoid, beads were removed at various times and the lengths of exposure required to reprogramme limb development found. The early limb rudiments require longer exposures to give duplications than late rudiments. The effective treatment periods last at least until stage 17 when the limb bud and apical ectodermal ridge develop. In contrast, the length of exposure to reduce the limb is constant at early stages. Retinoids first start acting to produce duplicated structures between stages 10 and 13. Therefore, retinoids appear to begin to reprogramme the cells as soon as they are determined to give rise to a limb.

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Apical ridge dependent and independent mesodermal domains of GHox-7 and GHox-8 expression in chick limb buds

Development ◽

10.1242/dev.116.3.811 ◽

1992 ◽

Vol 116 (3) ◽

pp. 811-818 ◽

Cited By ~ 11

Author(s):

M.A. Ros ◽

G. Lyons ◽

R.A. Kosher ◽

W.B. Upholt ◽

C.N. Coelho ◽

...

Keyword(s):

Pattern Formation ◽

Limb Development ◽

Apical Ectodermal Ridge ◽

Limb Bud ◽

Rapid Decline ◽

Limb Buds ◽

Limb Outgrowth ◽

Removal Experiments ◽

The Relationship

The homeobox-containing genes GHox-7 and GHox-8 have been proposed to play fundamental roles in limb development. The expression of GHox-8, by the apical ridge cells, and GHox-7, in the subridge mesoderm, suggests the involvement of these two genes in limb outgrowth and proximo-distal pattern formation. A straightforward way to test this is to remove the apical ridge. Here we report the relationship between the mesodermal expression of GHox-7 and GHox-8 and the apical ectodermal ridge in the chick limb bud. The data from ridge removal experiments indicate that there are at least two domains of GHox-7 expression in the apical limb bud mesoderm. The posterior subridge GHox-7 domain in the progress zone requires the influence of the apical ridge for continued expression, while the anterior GHox-7 domain continues expression after ridge removal. Posterior subridge mesoderm is exquisitely sensitive to the loss of the ridge in that GHox-7 expression by these cells is reduced in only two hours and undetectable by three hours after ridge removal. It would appear that one of the ways progress zone cells respond to the apical ridge signal is by expressing GHox-7. The loss of ridge influence whether by growth at the apex or by ridge removal is followed by an unusually rapid decline in detectable GHox-7 transcripts. Maintenance of GHox-8 expression by the anterior mesoderm appears to be independent of the presence of the apical ridge.(ABSTRACT TRUNCATED AT 250 WORDS)

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