Origins of Cdx1 regulatory elements suggest roles in vertebrate evolution

Gaunt, Stephen J.; Paul, Yu-Lee

doi:10.1387/ijdb.103252sg

Cited by 12 publications

(21 citation statements)

References 26 publications

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“…We earlier presented reasons to support our hypothesis that the RAREs in Cdx1 may have played roles in morphological evolution Paul, 2011, Gaunt andPaul, 2012). First, their origins coincide with divisions between major vertebrate groups: the intron RARE at the amphibian/amniote split, and the upstream RARE at the marsupial/eutherian split (Fig.…”

Section: Origins Of Lef/tcf Motifs and Rares During Vertebrate Evolutionmentioning

confidence: 69%

“…7B), as two synergistic components within a new cis-regulatory element. We found the upstream RARE only in eutherian mammals (Gaunt and Paul, 2011) (Fig. 7B).…”

Section: [A/t][a/t][c][a][a][a][g]mentioning

confidence: 70%

“…We earlier showed that the intron Lef/Tcf motif, located near to the intron RARE, is structurally conserved in anole lizard, bird, marsupial and eutherian mammal (Gaunt and Paul, 2011) (Fig. 7B).…”

Section: Evolutionary Origins Of Cdx1 Lef/tcf Motifsmentioning

confidence: 89%

“…Mouse Cdx1 is activated by RA via two retinoic acid response elements (RAREs), one upstream (Houle et al, 2000, Houle et al, 2003, and one in the first intron (Gaunt et al, 2003, Gaunt andPaul, 2011). It has been suggested that these RAREs may have played a part in morphological evolution since their origins coincide with divisions between major vertebrate groups Paul, 2011, Gaunt andPaul, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…It has been suggested that these RAREs may have played a part in morphological evolution since their origins coincide with divisions between major vertebrate groups Paul, 2011, Gaunt andPaul, 2012). Fish and amphibian Cdx1 genes have neither of these RAREs, whereas bird and marsupial Cdx1 genes have only the intron RARE (Gaunt and Paul, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Synergistic action in P19 pluripotential cells of retinoic acid and Wnt3a on Cdx1 enhancer elements

Gaunt¹,

Paul²

2014

Int. J. Dev. Biol.

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Cdx1 encodes a homeodomain protein that regulates expression of some Hox genes. Cdx1 itself is known to be regulated in the primitive streak/tailbud by both retinoic acid (RA) and Wnt3a. Cdx1 in eutherian mammals has two retinoic acid response elements (RAREs), located upstream and in the first intron, and each is adjacent to structural Lef/Tcf motifs. Upstream Lef/Tcf motifs respond to canonical Wnt signalling to activate Cdx1 synergistically with RA. By combined use of reporter assays, immunofluorescence and flow cytometry in mouse P19 embryonal carcinoma cells we show that the Cdx1 intron Lef/Tcf motif also responds to Wnt3a signalling. Synergy between individual Cdx1 RARE and Lef/Tcf motifs can occur whether they are adjacent or distant in the gene. Part, though not all, of the Cdx1 stimulation by RA (in absence of added Wnt3a) likely depends upon Wnt protein produced by the cells themselves, since it is inhibited by mutation of Lef/ Tcf motifs, or by IWP-2, an inhibitor of Wnt production. RA and Wnt3a stimulate Cdx1 by increasing both the proportion of P19 cells that are expressing and also their mean level of expression. The expressing/non-expressing sub-populations do not simply correspond with those that express a marker of pluripotentiality, Nanog. We conclude that RA and Wnt3a activate Cdx1 synergistically by overlapping use of both upstream and intron enhancers, and that mouse embryonal carcinoma cell populations display heterogeneity in their response to these activators.

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Section: Origins Of Lef/tcf Motifs and Rares During Vertebrate Evolutionmentioning

confidence: 69%

“…7B), as two synergistic components within a new cis-regulatory element. We found the upstream RARE only in eutherian mammals (Gaunt and Paul, 2011) (Fig. 7B).…”

Section: [A/t][a/t][c][a][a][a][g]mentioning

confidence: 70%

Section: Evolutionary Origins Of Cdx1 Lef/tcf Motifsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Synergistic action in P19 pluripotential cells of retinoic acid and Wnt3a on Cdx1 enhancer elements

Gaunt¹,

Paul²

2014

Int. J. Dev. Biol.

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Direct activation of a mouse Hoxd11 axial expression enhancer by Gdf11/Smad signalling

Gaunt

George

Paul

2013

Developmental Biology

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A Hoxd11/lacZ reporter, expressed with a Hoxd11-like axial expression pattern in transgenic mouse embryos, is stimulated in tailbud fragments when cultured in presence of Gdf11, a TGF-β growth/differentiation factor. The same construct is also stimulated by Gdf11 when transiently transfected into cultures of HepG2 cells. Stimulation of the reporter in HepG2 cells is enhanced where it contains only the 332 bp Hoxd11 enhancer region VIII upstream or downstream of a luciferase or lacZ reporter. This enhancer contains three elements conserved from fish to mice, one of which has the sequence of a Smad3/4 binding element. Mutation of this motif inhibits the ability of Gdf11 to enhance reporter activity in the HepG2 cell assay. Chromatin immunoprecipitation experiments show direct evidence of Smad2/3 protein binding to the Hoxd11 region VIII enhancer. The action of Gdf11 upon Hoxd11 in HepG2 cells is inhibited, at least in part, by SIS3, a specific inhibitor of Smad3. SIS3 also produces partial inhibition of Hoxd11/lacZ expression in cultured transgenic tailbuds, indicating that Smad3 may play a similar role in the embryonic expression of Hoxd11. Transgenic mouse experiments show that the Smad binding motif is essential for the axial expression of Hoxd11/lacZ reporter in the embryo tailbud, posterior mesoderm and neurectoderm.

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Mechanisms of retinoic acid signalling and its roles in organ and limb development

Cunningham

Duester

2015

Nat Rev Mol Cell Biol

475

474

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Retinoic acid (RA) signalling has a central role during vertebrate development. RA synthesized in specific locations regulates transcription by interacting with nuclear RA receptors (RARs) bound to RA response elements (RAREs) near target genes. RA was first implicated in signalling on the basis of its teratogenic effects on limb development. Genetic studies later revealed that endogenous RA promotes forelimb initiation by repressing fibroblast growth factor 8 (Fgf8). Insights into RA function in the limb serve as a paradigm for understanding how RA regulates other developmental processes. In vivo studies have identified RAREs that control repression of Fgf8 during body axis extension or activation of homeobox (Hox) genes and other key regulators during neuronal differentiation and organogenesis.

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Origins of Cdx1 regulatory elements suggest roles in vertebrate evolution

Cited by 12 publications

References 26 publications

Synergistic action in P19 pluripotential cells of retinoic acid and Wnt3a on Cdx1 enhancer elements

Synergistic action in P19 pluripotential cells of retinoic acid and Wnt3a on Cdx1 enhancer elements

Direct activation of a mouse Hoxd11 axial expression enhancer by Gdf11/Smad signalling

Mechanisms of retinoic acid signalling and its roles in organ and limb development

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