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Vol. 18, Issue 4, 1348-1358, April 2007

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Zic3 Is Required for Maintenance of Pluripotency in Embryonic Stem Cells

Linda Shushan Lim^*,, Yuin-Han Loh^,, Weiwei Zhang^,, Yixun Li^||, Xi Chen^,, Yinan Wang^,, Manjiri Bakre^*, Huck-Hui Ng^,, and Lawrence W. Stanton^*,

*Stem Cell and Developmental Biology Group, Gene Regulation Laboratory, and ^||Information and Mathematical Sciences Group, Genome Institute of Singapore, Singapore 138672; and Department of Biological Sciences, National University of Singapore, Singapore 117543

Submitted July 24, 2006; Revised November 9, 2006; Accepted January 22, 2007
Monitoring Editor: Marianne Bronner-Fraser

Embryonic stem (ES) cell pluripotency is dependent upon sustained expression of the key transcriptional regulators Oct4, Nanog, and Sox2. Dissection of the regulatory networks downstream of these transcription factors has provided critical insight into the molecular mechanisms that regulate ES cell pluripotency and early differentiation. Here we describe a role for Zic3, a member of the Gli family of zinc finger transcription factors, in the maintenance of pluripotency in ES cells. We show that Zic3 is expressed in ES cells and that this expression is repressed upon differentiation. The expression of Zic3 in pluripotent ES cells is also directly regulated by Oct4, Sox2, and Nanog. Targeted repression of Zic3 in human and mouse ES cells by RNA interference–induced expression of several markers of the endodermal lineage. Notably, the expression of Nanog, a key pluripotency regulator and repressor of extraembryonic endoderm specification in ES cells, was significantly reduced in Zic3 knockdown cells. This suggests that Zic3 may prevent endodermal marker expression through Nanog-regulated pathways. Thus our results extend the ES cell transcriptional network beyond Oct4, Nanog, and Sox2, and further establish that Zic3 plays an important role in the maintenance of pluripotency by preventing endodermal lineage specification in embryonic stem cells.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Lawrence W. Stanton (stantonl{at}gis.a-star.edu.sg)

Abbreviations used: ES, embryonic stem; RA, retinoic acid; RNAi, RNA interference; ChIP, chromatin immunoprecipitation; AVE, anterior visceral endoderm.

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