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).

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.

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.

Transient establishment of anteroposterior polarity in the zebrafish pectoral fin bud in the absence of sonic hedgehog activity

Development ◽  
1999 ◽  
Vol 126 (21) ◽  
pp. 4817-4826 ◽  
Author(s):  
C.J. Neumann ◽  
H. Grandel ◽  
W. Gaffield ◽  
S. Schulte-Merker ◽  
C. Nusslein-Volhard
Keyword(s):  
Retinoic Acid ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Normal Development ◽  
Limb Bud ◽  
Pectoral Fin ◽  
Anteroposterior Patterning ◽  
Vertebrate Limb ◽  
Anteroposterior Polarity

Sonic hedgehog (Shh) is expressed in the posterior vertebrate limb bud mesenchyme and directs anteroposterior patterning and growth during limb development. Here we report an analysis of the pectoral fin phenotype of zebrafish sonic you mutants, which disrupt the shh gene. We show that Shh is required for the establishment of some aspects of anteroposterior polarity, while other aspects of anteroposterior polarity are established independently of Shh, and only later come to depend on Shh for their maintenance. We also demonstrate that Shh is required for the activation of posterior HoxD genes by retinoic acid. Finally, we show that Shh is required for normal development of the apical ectodermal fold, for growth of the fin bud, and for formation of the fin endoskeleton.

The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor

Development ◽  
1997 ◽  
Vol 124 (11) ◽  
pp. 2235-2244 ◽  
Author(s):  
H. Ohuchi ◽  
T. Nakagawa ◽  
A. Yamamoto ◽  
A. Araga ◽  
T. Ohata ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Limb Bud ◽  
Fibroblast Growth ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Bud Formation ◽  
Limb Mesenchyme ◽  
Vertebrate Limb ◽  
Fgf10 Expression ◽  
Zone Of Polarizing Activity

Vertebrate limb formation has been known to be initiated by a factor(s) secreted from the lateral plate mesoderm. In this report, we provide evidence that a member of the fibroblast growth factor (FGF) family, FGF10, emanates from the prospective limb mesoderm to serve as an endogenous initiator for limb bud formation. Fgf10 expression in the prospective limb mesenchyme precedes Fgf8 expression in the nascent apical ectoderm. Ectopic application of FGF10 to the chick embryonic flank can induce Fgf8 expression in the adjacent ectoderm, resulting in the formation of an additional complete limb. Expression of Fgf10 persists in the mesenchyme of the established limb bud and appears to interact with Fgf8 in the apical ectoderm and Sonic hedgehog in the zone of polarizing activity. These results suggest that FGF10 is a key mesenchymal factor involved in the initial budding as well as the continuous outgrowth of vertebrate limbs.

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).

The zone of polarizing activity: evidence for a role in normal chick limb morphogenesis

Development ◽  
1979 ◽  
Vol 50 (1) ◽  
pp. 217-233
Author(s):  
Dennis Summerbell
Keyword(s):  
Normal Development ◽  
Limb Bud ◽  
Concentration Profiles ◽  
Impermeable Barrier ◽  
Limb Morphogenesis ◽  
Zone Of Polarizing Activity

When an impermeable barrier is placed so as to divide the early chick limb-bud into anterior and posterior parts then development continues only on one side of the barrier. The detailed results are inconsistent with mosaic development. They can readily be explained by supposing that pattern is specified by the concentration of a diffusible morphogen controlled by the zone of polarizing activity. A simulation of appropriate concentration profiles is presented and its relevance to similar experiments published elsewhere is discussed. It seems probable that the zone of polarizing activity is active during normal development.

Evidence that Shh cooperates with a retinoic acid inducible co-factor to establish ZPA-like activity

Development ◽  
1996 ◽  
Vol 122 (2) ◽  
pp. 537-542 ◽  
Author(s):  
T. Ogura ◽  
I.S. Alvarez ◽  
A. Vogel ◽  
C. Rodriguez ◽  
R.M. Evans ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Sonic Hedgehog ◽  
Embryonal Carcinoma ◽  
Carcinoma Cell ◽  
Retinoic Acid Receptor ◽  
Mirror Image ◽  
Limb Bud ◽  
Embryonal Carcinoma Cell ◽  
Embryonal Carcinoma Cell Line ◽  
Vertebrate Limb

Patterning across the anteroposterior axis of the vertebrate limb bud involves a signal from the polarizing region, a small group of cells at the posterior margin of the bud. Retinoic acid (RA; Tickle, C., Alberts, B., Wolpert, L. and Lee, J. (1982) Nature 296, 554–566) and Sonic hedgehog (Shh; Riddle, R. D. Johnson, R. L., Laufer, E. and Tabin, C. J. (1993) Cell 25, 1401–1416; Chang, D. T., Lopez, A., von Kessler, D. P., Chiang, C., Simandl, B. K., Zhao, R., Seldin, M. F., Fallon, J. F. and Beachy, P. A. (1994 Development 120, 3339–3353) have been independently postulated as such signals because they can mimic the mirror image digit duplication obtained after grafting polarizing cells to the anterior of limb buds. Here we show that a embryonal carcinoma cell line, P19, transfected with a Shh expression vector shows low polarizing activity, but when cultured with retinoic acid, duplications like those induced by the polarizing region (ZPA) arise. Complete duplications are also obtained by cotransfecting P19 Shh cells with a constitutively active human retinoic acid receptor (VP16-hRARalpha). These data suggest that Shh and RA cooperate in generating ZPA activity and that Shh, while essential, may not act alone in this process.

Slug, a zinc finger gene previously implicated in the early patterning of the mesoderm and the neural crest, is also involved in chick limb development

Development ◽  
1997 ◽  
Vol 124 (9) ◽  
pp. 1821-1829
Author(s):  
M.A. Ros ◽  
M. Sefton ◽  
M.A. Nieto
Keyword(s):  
Zinc Finger ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Limb Bud ◽  
Mesenchymal Phenotype ◽  
Signalling Molecules ◽  
Slug Expression ◽  
Snail Family ◽  
Zone Of Polarizing Activity ◽  
Signalling Systems

The great advances made over the last few years in the identification of signalling molecules that pattern the limb bud along the three axes make the limb an excellent model system with which to study developmental mechanisms in vertebrates. The understanding of the signalling networks and their mutual interactions during limb development requires the characterisation of the corresponding downstream genes. In this study we report the expression pattern of Slug, a zinc-finger-containing gene of the snail family, during the development of the limb, and its regulation by distinct axial signalling systems. Slug expression is highly dynamic, and at different stages of limb development can be correlated with the zone of polarizing activity, the progress zone and the interdigital areas. We show that the maintenance of its expression is dependent on signals from the apical ectodermal ridge and independent of Sonic Hedgehog. We also report that, in the interdigit, apoptotic cells lie outside of the domains of Slug expression. The correlation of Slug expression with areas of undifferentiated mesenchyme at stages of tissue differentiation is consistent with its role in early development, in maintaining the mesenchymal phenotype and repressing differentiation processes. We suggest that Slug is involved in the epithelial-mesenchymal interactions that lead to the maintenance of the progress zone.

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