Retinoic acid induces a pattern of digits in anterior half wing buds that lack the zone of polarizing activity

Development ◽  
1989 ◽  
Vol 107 (4) ◽  
pp. 863-867 ◽  
Author(s):  
G. Eichele
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Anterior Margin ◽  
Limb Bud ◽  
Posterior Half ◽  
Anterior Half ◽  
Zone Of Polarizing Activity

Wing buds whose posterior half is excised, develop into wings lacking distal structures. However, such experimentally generated preaxial half wing buds can be rescued by implanting a retinoic-acid-releasing bead at their anterior margin. The polarity of the pattern that originates from preaxial half wing buds is reversed. For example, instead of a 234 digit pattern typical for normal wings, the order of digits is 432. This result implies that retinoic acid has the capacity to reprogram anterior limb bud tissue, and that the resulting change in cell fate does not depend on the presence of posterior tissue regions such as the zone of polarizing activity (ZPA).

scholarly journals The effect of the zone of polarizing activity (ZPA) on the anterior half of the chick wing bud

Development ◽  
1987 ◽  
Vol 99 (1) ◽  
pp. 99-108
Author(s):  
D.J. Wilson ◽  
J.R. Hinchliffe
Keyword(s):  
Cell Death ◽  
Limb Bud ◽  
Posterior Half ◽  
Rescue Effect ◽  
Bud Development ◽  
Anterior Half ◽  
Survival And Development ◽  
Wing Bud ◽  
Zone Of Polarizing Activity ◽  
Cut Surface

Removal of the posterior half of the chick wing bud between stages 17–22 results in failure of the anterior distal tissue to survive and differentiate. This observation has been interpreted in terms of a requirement by the anterior half of a factor supplied by the posterior half of the limb containing the zone of polarizing activity (ZPA). This relationship has been tested by grafting ZPA tissue to the posterior surface of the anterior half after posterior half removal. Grafts made proximally on the cut surface did not significantly improve survival and development, nor did the ZPA prevent the expansion of the cell death in the ANZ beyond its normal boundaries into the distal mesenchyme. However, when grafted distally the ZPA inhibited cell death in the apical mesenchyme and caused the anterior mesenchyme to change its normal prospective fate (radius and digit 2). In all these cases, in addition to digit 2, digit 3 and frequently also digit 4 differentiated. The anterior half went on to develop a full set of digits and zeugopod parts in almost 50% of cases, although no skeleton resulting from this regulation of the anterior half had totally size regulated. These results demonstrate a developmental ‘rescue’ effect by the ZPA, and further support the view that the ZPA has a central and unique function in normal limb bud development, controlling survival and differentiation of the mesenchyme along the anteroposterior axis.

Retinoic acid signaling is required during early chick limb development

Development ◽  
1996 ◽  
Vol 122 (5) ◽  
pp. 1385-1394 ◽  
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.

Interaction between the proximo-distal and antero-posterior co-ordinates of positional value during the specification of positional information in the early development of the chick limb-bud

Development ◽  
1974 ◽  
Vol 32 (1) ◽  
pp. 227-237
Author(s):  
Dennis Summerbell
Keyword(s):  
Early Development ◽  
Anterior Margin ◽  
Positional Information ◽  
Apical Ectodermal Ridge ◽  
Limb Bud ◽  
Anteroposterior Axis ◽  
Zone Of Polarizing Activity ◽  
Positional Value ◽  
Special Region

The experiments examine the extent of reduplication of skeletal parts across the anteroposterior axis, following the transplantation of a zone of polarizing activity (ZPA) to the anterior margin of the limb-bud at successively later stages. Previous studies have suggested that the function of the apical ectodermal ridge (AER) is to maintain cells in a special region at the distal tip (the progress zone) labile, with respect to their positional value along the proximo-distal axis. Similarly, the results of these experiments demonstrate that cells in the progress zone are able to change their antero-posterior positional value under the influence of the grafted ZPA, while cells at more proximal levels remain unaffected. In turn, the ZPA may effect the activity of the AER and hence the progress zone.

Relationship between retinoic acid and sonic hedgehog, two polarizing signals in the chick wing bud

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3267-3274 ◽  
Author(s):  
J. Helms ◽  
C. Thaller ◽  
G. Eichele
Keyword(s):  
Retinoic Acid ◽  
Sonic Hedgehog ◽  
Positional Information ◽  
Limb Bud ◽  
Dependent Manner ◽  
All Trans Retinoic Acid ◽  
Wing Bud ◽  
Zone Of Polarizing Activity ◽  
Dose Dependent

Local application of all-trans-retinoic acid (RA) to the anterior margin of chick limb buds results in pattern duplications reminescent of those that develop after grafting cells from the zone of polarizing activity (ZPA). RA may act directly by conferring positional information to limb bud cells, or it may act indirectly by creating a polarizing region in the tissue distal to the RA source. Here we demonstrate that tissue distal to an RA-releasing bead acquires polarizing activity in a dose-dependent manner. Treatments with pharmacological (beads soaked in 330 micrograms/ml) and physiological (beads soaked in 10 micrograms/ml) doses of RA are equally capable of inducing digit pattern duplication. Additionally, both treatments induce sonic hedgehog (shh; also known as vertebrate hedgehog-1, vhh-1), a putative ZPA morphogen and Hoxd-11, a gene induced by the polarizing signal. However, tissue transplantation assays reveal that pharmacological, but not physiological, doses create a polarizing region. This differential response could be explained if physiological doses induced less shh than pharmacological doses. However, our in situ hybridization analyses demonstrate that both treatments result in similar amounts of mRNA encoding this candidate ZPA morphogen. We outline a model describing the apparently disparate effects of pharmacologic and physiological doses RA on limb bud tissue.

Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse

Development ◽  
2002 ◽  
Vol 129 (15) ◽  
pp. 3563-3574 ◽  
Author(s):  
Karen Niederreither ◽  
Julien Vermot ◽  
Brigitte Schuhbaur ◽  
Pierre Chambon ◽  
Pascal Dollé
Keyword(s):  
Retinoic Acid ◽  
Sonic Hedgehog ◽  
Acid Synthesis ◽  
Limb Bud ◽  
Anteroposterior Patterning ◽  
Limb Morphogenesis ◽  
Functional Zone ◽  
Mutant Mouse Embryos ◽  
Bud Growth ◽  
Zone Of Polarizing Activity

Numerous studies, often performed on avian embryos, have implicated retinoic acid (RA) in the control of limb bud growth and patterning. Here we have investigated whether the lack of endogenous RA synthesis affects limb morphogenesis in mutant mouse embryos deficient for the retinaldehyde dehydrogenase 2 (Raldh2/Aldh1a2). These mutants, which have no detectable embryonic RA except in the developing retina, die at E9.5-E10 without any evidence of limb bud formation, but maternal RA supplementation through oral gavage from E7.5 can extend their survival. Such survivors exhibit highly reduced forelimb rudiments, but apparently normal hindlimbs. By providing RA within maternal food, we found both a stage- and dose-dependency for rescue of forelimb growth and patterning. Following RA supplementation from E7.5 to 8.5, mutant forelimbs are markedly hypoplastic and lack anteroposterior (AP) patterning, with a single medial cartilage and 1-2 digit rudiments. RA provided until E9.5 significantly rescues forelimb growth, but cannot restore normal AP patterning. Increasing the RA dose rescues the hypodactyly, but leads to lack of asymmetry of the digit pattern, with abnormally long first digit or symmetrical polydactyly. Mutant forelimb buds are characterized by lack of expression or abnormal distal distribution of Sonic hedgehog (Shh) transcripts, sometimes with highest expression anteriorly. Downregulation or ectopic anterior expression of Fgf4 is also seen. As a result, genes such as Bmp2 or Hoxd genes are expressed symmetrically along the AP axis of the forelimb buds, and/or later, of the autopod. We suggest that RA signaling cooperates with a posteriorly restricted factor such as dHand, to generate a functional zone of polarizing activity (ZPA).

scholarly journals The effect of local application of retinoic acid to the anterior margin of the developing chick limb

Development ◽  
1983 ◽  
Vol 78 (1) ◽  
pp. 269-289
Author(s):  
Dennis Summerbell
Keyword(s):  
Retinoic Acid ◽  
Limb Development ◽  
Anterior Margin ◽  
Mirror Image ◽  
Limb Bud ◽  
Local Application ◽  
Low Doses ◽  
Full Dose ◽  
Early Stages ◽  
High Doses

Local application of retinoic acid to the chick limb bud produces effects that are dose and/or stage dependent. Low doses and/or old stages tend to give normal limbs or perhaps one or two supernumerary digits of a more anterior character. Medium doses and/or intermediate stages tend to give full mirror-image supernumeraries with two or even three extra digits including particularly digits of a posterior character. High doses and/or early stages give limbs in which supernumerary digits fail to form or are lost, and in which even host skeletal elements are missing or reduced. The effects are graded over the full dose and/or stage range. Various explanations are discussed in the context of the current hypotheses of limb development. We conclude that one should not necessarily interpret the results as evidence that retinoids normally play a part in the control of development or regeneration.

scholarly journals Characterization of retinoid metabolism in the developing chick limb bud

Development ◽  
1988 ◽  
Vol 103 (3) ◽  
pp. 473-483 ◽  
Author(s):  
C. Thaller ◽  
G. Eichele
Keyword(s):  
Retinoic Acid ◽  
Pattern Formation ◽  
Local Treatment ◽  
Limb Bud ◽  
Biologically Active ◽  
Retinoid Metabolism ◽  
All Trans Retinoic Acid ◽  
Zone Of Polarizing Activity ◽  
The Right ◽  
Local Metabolism

Retinoids (vitamin A derivatives) have been shown to have striking effects on developing and regenerating vertebrate limbs. In the developing chick limb, retinoic acid is a candidate morphogen that may coordinate the pattern of cellular differentiation along the anteroposterior limb axis. We describe a series of investigations of the metabolic pathway of retinoids in the chick limb bud system. To study retinoid metabolism in the bud, all-trans-[3H]retinol, all-trans-[3H]retinal and all-trans-[3H]retinoic acid were released into the posterior region of the limb anlage, the area that contains the zone of polarizing activity, a tissue possibly involved in limb pattern formation. We found that the locally applied [3H]retinol is primarily converted to [3H]retinal, [3H]retinoic acid and a yet unidentified metabolite. When [3H]retinal is locally applied, it is either oxidized to [3H]retinoic acid or reduced to [3H]retinol. In contrast, local delivery of retinoic acid to the bud yields neither retinal nor retinol nor the unknown metabolite. This flow of metabolites agrees with the biochemical pathway of retinoids that has previously been elucidated in a number of other animal systems. To find out whether metabolism takes place directly in the treated limb bud, we have compared the amount of [3H]retinoid present in each of the four limb anlagen following local treatment of the right wing bud. The data suggest that retinoid metabolism takes place mostly in the treated limb bud. This local metabolism could provide a simple mechanism to generate in a controlled fashion the biologically active all-trans-retinoic acid from its abundant biosynthetic precursor retinol. In addition, local metabolism supports the hypothesis that retinoids are local chemical mediators involved in pattern formation.

scholarly journals Plasticity of proximal–distal cell fate in the mammalian limb bud

2008 ◽  
Vol 313 (1) ◽  
pp. 225-233 ◽  
Author(s):  
Laurie A. Wyngaarden ◽  
Sevan Hopyan
Keyword(s):  
Cell Fate ◽  
Limb Bud ◽  
Distal Cell

scholarly journals Interaction of retinoic acid and scl controls primitive blood development

Blood ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Jill L. O. de Jong ◽  
Alan J. Davidson ◽  
Yuan Wang ◽  
James Palis ◽  
Praise Opara ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retinoic Acid ◽  
Cell Fate ◽  
Embryonic Stem ◽  
Yolk Sac ◽  
Erythroid Progenitors ◽  
Self Renewal ◽  
Hematopoietic Development ◽  
Blood Island ◽  
Primitive Hematopoiesis

Abstract Hematopoietic development during embryogenesis involves the interaction of extrinsic signaling pathways coupled to an intrinsic cell fate that is regulated by cell-specific transcription factors. Retinoic acid (RA) has been linked to stem cell self-renewal in adults and also participates in yolk sac blood island formation. Here, we demonstrate that RA decreases gata1 expression and blocks primitive hematopoiesis in zebrafish (Danio rerio) embryos, while increasing expression of the vascular marker, fli1. Treatment with an inhibitor of RA biosynthesis or a retinoic acid receptor antagonist increases gata1+ erythroid progenitors in the posterior mesoderm of wild-type embryos and anemic cdx4−/− mutants, indicating a link between the cdx-hox signaling pathway and RA. Overexpression of scl, a DNA binding protein necessary for hematopoietic development, rescues the block of hematopoiesis induced by RA. We show that these effects of RA and RA pathway inhibitors are conserved during primitive hematopoiesis in murine yolk sac explant cultures and embryonic stem cell assays. Taken together, these data indicate that RA inhibits the commitment of mesodermal cells to hematopoietic fates, functioning downstream of cdx4 and upstream of scl. Our studies establish a new connection between RA and scl during development that may participate in stem cell self-renewal and hematopoietic differentiation.

FGF-4 maintains polarizing activity of posterior limb bud cells in vivo and in vitro

Development ◽  
1993 ◽  
Vol 119 (1) ◽  
pp. 199-206 ◽  
Author(s):  
A. Vogel ◽  
C. Tickle
Keyword(s):  
Posterior Margin ◽  
Anterior Margin ◽  
Marked Decrease ◽  
Mesenchymal Cells ◽  
Apical Ectodermal Ridge ◽  
Limb Bud ◽  
Posterior Limb ◽  
Vertebrate Limb

The polarizing region is a major signalling tissue involved in patterning the tissues of the vertebrate limb. The polarizing region is located at the posterior margin of the limb bud and can be recognized by its ability to induce additional digits when grafted to the anterior margin of a chick limb bud. The signal from the polarizing region operates at the tip of the bud in the progress zone, a zone of undifferentiated mesenchymal cells, maintained by interactions with the apical ectodermal ridge. A number of observations have pointed to a link between the apical ectodermal ridge and signalling by the polarizing region. To test this possibility, we removed the posterior apical ectodermal ridge of chick wing buds and assayed posterior mesenchyme for polarizing activity. When the apical ectodermal ridge is removed, there is a marked decrease in polarizing activity of posterior cells. The posterior apical ectodermal ridge is known to express FGF-4 and we show that the decrease in polarizing activity of posterior cells of wing buds that normally follows ridge removal can be prevented by implanting a FGF-4-soaked bead. Furthermore, we show that both ectoderm and FGF-4 maintain polarizing activity of limb bud cells in culture.

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