Multiple pathways governing Cdx1 expression during murine development.
Cdx1 encodes a mammalian homeobox gene involved in vertebral patterning. Retinoic acid (RA) is likewise implicated in vertebral patterning. We have previously shown that Cdx1 is a direct retinoid target gene, suggesting that Cdx1 may convey some of the effects of retinoid signaling. However, RA appears to be essential for only early stages of Cdx1 expression, and therefore other factors must be involved in maintaining later stages of expression. Based on function and pattern of expression, Wnt family members, in particular Wnt3a, are candidates for regulation of expression of Cdx1. Consistent with this, we confirm prior results which demonstrated that Cdx1 can be directly regulated by Wnt signaling, and identify functional LEF/TCF response motifs essential for this response. We also find that Cdx1 expression is markedly attenuated in a stage- and tissue-specific fashion in the Wnt3a hypomorph vestigial tail, and present data demonstrating that Wnt3a and RA synergize strongly to activate Cdx1. Finally, we show that Cdx1 positively regulates its own expression. These data prompt a model whereby retinoid and Wnt signaling function directly and synergistically to initiate Cdx1 expression in the caudal embryo. Expression is then maintained, at least in part, by an autoregulatory mechanism at later stages.
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Institut de Recherches Cliniques de Montréal, 110 ave des Pins, ouest, Montréal, Québec, Canada H2W 1R7.
Joseph
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Meyer
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Gruss
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Lohnes
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D000818:Animals; D001483:Base Sequence; D000071616:CDX2 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics*; D017403:In Situ Hybridization; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D014981:Xenopus; D029867:Xenopus Proteins; D029961:Zebrafish Proteins
D000071616:CDX2 Transcription Factor; C491272:Cdx1 protein, mouse; D018398:Homeodomain Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; C555506:WNT3A protein, Xenopus; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C000605378:cdx2 protein, Xenopus; D014212:Tretinoin