期刊
DIFFERENTIATION
卷 83, 期 5, 页码 282-292出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.diff.2012.02.010
关键词
Mesendoderm; Wnt/beta-catenin signaling; P19 embryonal carcinoma cell; Brachyury; Primitive streak; Transcription factor
资金
- George F. Straub Trust of the Hawaii Community Foundation [20060374, 11ADVC-49271]
- National Institutes of Health Centers of Biomedical Research Excellence [P20RR024206]
Activation of Wnt/beta-catenin signaling is crucial for the differentiation of pluripotent stem cells, namely the epiblast, embryonic stem, and embryonal carcinoma cells, into mesendoderm. However, downstream events of Wnt/beta-catenin signaling that control the formation of mesendoderm are still unclear. In the present study, we used mouse P19 embryonal carcinoma cells as a model, and identified a homeodomain protein Nkx1-2 as a key regulator of mesendoderm formation. In the mouse embryo, Nkx1-2 was expressed in the primitive streak, in which the nascent mesendoderm emerges. In P19 cells, the expression of Nkx1-2 was activated by Wnt/beta-catenin signaling independently of Brachyury, an evolutionary conserved early mesendoderm gene. In contrast, the expression of Nkx1-2 was both necessary and sufficient for the activation of Brachyury. Nkx1-2 acted as a transcriptional repressor to mediate the action of Wnt/beta-catenin signaling to activate the Brachyury expression. We found Tcf3 as a potential target of gene repression by Nkx1-2, and the down-regulation of Tcf3 was partly required for effective activation of Brachyury by Wnt/beta-catenin signaling. These results suggest that Nkx1-2 is a critical component of the gene regulatory network that operates downstream of Wnt/beta-catenin signaling to regulate the formation of mesendoderm. (C) 2012 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.
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