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Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis.

Bayha E, Jørgensen MC, Serup P, Grapin-Botton A - PLoS ONE (2009)

Bottom Line: Conversely reducing RA signaling shifts Hox genes posteriorly in endoderm.These results imply that RA acts as a caudalizing factor in a graded manner in pharyngeal endoderm.Our results show that the induction of CdxA, a midgut marker, and pancreas induction require direct RA signaling in endoderm.

View Article: PubMed Central - PubMed

Affiliation: Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

ABSTRACT

Background: Endoderm organ primordia become specified between gastrulation and gut tube folding in Amniotes. Although the requirement for RA signaling for the development of a few individual endoderm organs has been established a systematic assessment of its activity along the entire antero-posterior axis has not been performed in this germ layer.

Methodology/principal findings: RA is synthesized from gastrulation to somitogenesis in the mesoderm that is close to the developing gut tube. In the branchial arch region specific levels of RA signaling control organ boundaries. The most anterior endoderm forming the thyroid gland is specified in the absence of RA signaling. Increasing RA in anterior branchial arches results in thyroid primordium repression and the induction of more posterior markers such as branchial arch Hox genes. Conversely reducing RA signaling shifts Hox genes posteriorly in endoderm. These results imply that RA acts as a caudalizing factor in a graded manner in pharyngeal endoderm. Posterior foregut and midgut organ primordia also require RA, but exposing endoderm to additional RA is not sufficient to expand these primordia anteriorly. We show that in chick, in contrast to non-Amniotes, RA signaling is not only necessary during gastrulation, but also throughout gut tube folding during somitogenesis. Our results show that the induction of CdxA, a midgut marker, and pancreas induction require direct RA signaling in endoderm. Moreover, communication between CdxA(+) cells is necessary to maintain CdxA expression, therefore synchronizing the cells of the midgut primordium. We further show that the RA pathway acts synergistically with FGF4 in endoderm patterning rather than mediating FGF4 activity.

Conclusions/significance: Our work establishes that retinoic acid (RA) signaling coordinates the position of different endoderm organs along the antero-posterior axis in chick embryos and could serve as a basis for the differentiation of specific endodermal organs from ES cells.

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Model for AP patterning of RA and FGFs in endoderm.At gastrulation and early somitogenesis RA is synthesized in the posterior part of the embryo with its anterior limit around the junction between prospective fore- and hindgut. RA degrading enzyme Cyp26A1 is expressed anteriorly and functions as intracellular sink for RA molecules (upper panel to the left). A RA gradient may be formed in the intermediate region. At the same time FGFs are expressed in the node and in the posterior streak acting in a graded manner along the entire AP axis (upper panel to the right). At stage HH 10 graded activation of RA signaling may be maintained in the dorsal (axial) endoderm anterior to the 6th somite and in the foregut, while LPE is constantly exposured to RA (lower panel). FGFs are produced caudally in the tail bud (lower panel to the left), again acting in a graded manner along the AP axis. Posteriorly, RA may form a contra-gradient to FGFs antagonizing each other as it was shown in pre-somitic mesoderm. Different levels of signaling gradients induce different gene transcription. Whether FGFs also induce genes at the level of the posterior BAs, is not known (lower panel to the right). Color code is explained in the legend beside. Dotted orange lines represent presumptive neural plate. LPE, lateral plate endoderm; LPM, lateral plate mesoderm.
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pone-0005845-g007: Model for AP patterning of RA and FGFs in endoderm.At gastrulation and early somitogenesis RA is synthesized in the posterior part of the embryo with its anterior limit around the junction between prospective fore- and hindgut. RA degrading enzyme Cyp26A1 is expressed anteriorly and functions as intracellular sink for RA molecules (upper panel to the left). A RA gradient may be formed in the intermediate region. At the same time FGFs are expressed in the node and in the posterior streak acting in a graded manner along the entire AP axis (upper panel to the right). At stage HH 10 graded activation of RA signaling may be maintained in the dorsal (axial) endoderm anterior to the 6th somite and in the foregut, while LPE is constantly exposured to RA (lower panel). FGFs are produced caudally in the tail bud (lower panel to the left), again acting in a graded manner along the AP axis. Posteriorly, RA may form a contra-gradient to FGFs antagonizing each other as it was shown in pre-somitic mesoderm. Different levels of signaling gradients induce different gene transcription. Whether FGFs also induce genes at the level of the posterior BAs, is not known (lower panel to the right). Color code is explained in the legend beside. Dotted orange lines represent presumptive neural plate. LPE, lateral plate endoderm; LPM, lateral plate mesoderm.

Mentions: Although the roles of RA in a subset of the organ primordia investigated here have been reported in different species, our study uniquely provides a general overview of its activity coordinating the position of different endoderm organs along the AP axis, as schematized in Fig. 7. In spite of being largely consistent with previous observations in other species, we uncover important differences in the timing of RA activity as compared to non-Amniotes. Moreover, our work shows that RA is generally needed to generate all endoderm organs posterior to the branchial arches rather than a few.


Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis.

Bayha E, Jørgensen MC, Serup P, Grapin-Botton A - PLoS ONE (2009)

Model for AP patterning of RA and FGFs in endoderm.At gastrulation and early somitogenesis RA is synthesized in the posterior part of the embryo with its anterior limit around the junction between prospective fore- and hindgut. RA degrading enzyme Cyp26A1 is expressed anteriorly and functions as intracellular sink for RA molecules (upper panel to the left). A RA gradient may be formed in the intermediate region. At the same time FGFs are expressed in the node and in the posterior streak acting in a graded manner along the entire AP axis (upper panel to the right). At stage HH 10 graded activation of RA signaling may be maintained in the dorsal (axial) endoderm anterior to the 6th somite and in the foregut, while LPE is constantly exposured to RA (lower panel). FGFs are produced caudally in the tail bud (lower panel to the left), again acting in a graded manner along the AP axis. Posteriorly, RA may form a contra-gradient to FGFs antagonizing each other as it was shown in pre-somitic mesoderm. Different levels of signaling gradients induce different gene transcription. Whether FGFs also induce genes at the level of the posterior BAs, is not known (lower panel to the right). Color code is explained in the legend beside. Dotted orange lines represent presumptive neural plate. LPE, lateral plate endoderm; LPM, lateral plate mesoderm.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2690404&req=5

pone-0005845-g007: Model for AP patterning of RA and FGFs in endoderm.At gastrulation and early somitogenesis RA is synthesized in the posterior part of the embryo with its anterior limit around the junction between prospective fore- and hindgut. RA degrading enzyme Cyp26A1 is expressed anteriorly and functions as intracellular sink for RA molecules (upper panel to the left). A RA gradient may be formed in the intermediate region. At the same time FGFs are expressed in the node and in the posterior streak acting in a graded manner along the entire AP axis (upper panel to the right). At stage HH 10 graded activation of RA signaling may be maintained in the dorsal (axial) endoderm anterior to the 6th somite and in the foregut, while LPE is constantly exposured to RA (lower panel). FGFs are produced caudally in the tail bud (lower panel to the left), again acting in a graded manner along the AP axis. Posteriorly, RA may form a contra-gradient to FGFs antagonizing each other as it was shown in pre-somitic mesoderm. Different levels of signaling gradients induce different gene transcription. Whether FGFs also induce genes at the level of the posterior BAs, is not known (lower panel to the right). Color code is explained in the legend beside. Dotted orange lines represent presumptive neural plate. LPE, lateral plate endoderm; LPM, lateral plate mesoderm.
Mentions: Although the roles of RA in a subset of the organ primordia investigated here have been reported in different species, our study uniquely provides a general overview of its activity coordinating the position of different endoderm organs along the AP axis, as schematized in Fig. 7. In spite of being largely consistent with previous observations in other species, we uncover important differences in the timing of RA activity as compared to non-Amniotes. Moreover, our work shows that RA is generally needed to generate all endoderm organs posterior to the branchial arches rather than a few.

Bottom Line: Conversely reducing RA signaling shifts Hox genes posteriorly in endoderm.These results imply that RA acts as a caudalizing factor in a graded manner in pharyngeal endoderm.Our results show that the induction of CdxA, a midgut marker, and pancreas induction require direct RA signaling in endoderm.

View Article: PubMed Central - PubMed

Affiliation: Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

ABSTRACT

Background: Endoderm organ primordia become specified between gastrulation and gut tube folding in Amniotes. Although the requirement for RA signaling for the development of a few individual endoderm organs has been established a systematic assessment of its activity along the entire antero-posterior axis has not been performed in this germ layer.

Methodology/principal findings: RA is synthesized from gastrulation to somitogenesis in the mesoderm that is close to the developing gut tube. In the branchial arch region specific levels of RA signaling control organ boundaries. The most anterior endoderm forming the thyroid gland is specified in the absence of RA signaling. Increasing RA in anterior branchial arches results in thyroid primordium repression and the induction of more posterior markers such as branchial arch Hox genes. Conversely reducing RA signaling shifts Hox genes posteriorly in endoderm. These results imply that RA acts as a caudalizing factor in a graded manner in pharyngeal endoderm. Posterior foregut and midgut organ primordia also require RA, but exposing endoderm to additional RA is not sufficient to expand these primordia anteriorly. We show that in chick, in contrast to non-Amniotes, RA signaling is not only necessary during gastrulation, but also throughout gut tube folding during somitogenesis. Our results show that the induction of CdxA, a midgut marker, and pancreas induction require direct RA signaling in endoderm. Moreover, communication between CdxA(+) cells is necessary to maintain CdxA expression, therefore synchronizing the cells of the midgut primordium. We further show that the RA pathway acts synergistically with FGF4 in endoderm patterning rather than mediating FGF4 activity.

Conclusions/significance: Our work establishes that retinoic acid (RA) signaling coordinates the position of different endoderm organs along the antero-posterior axis in chick embryos and could serve as a basis for the differentiation of specific endodermal organs from ES cells.

Show MeSH
Related in: MedlinePlus