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Molecular and Cellular Biology, July 2007, p. 5201-5213, Vol. 27, No. 14
0270-7306/07/$08.00+0     doi:10.1128/MCB.02237-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Transcriptional Repressor Erf Determines Extraembryonic Ectoderm Differentiation ^,

Medical School, University of Crete and IMBB, FORTH, Heraklion, Crete 710 03, Greece,¹ Institute of Immunology, BSRC Alexander Fleming, Vari 166 72, Greece,² The Burnham Institute for Medical Research, La Jolla, California 92037,³ Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB T2N 4N1, Canada⁴

Received 29 November 2006/ Returned for modification 13 February 2007/ Accepted 2 May 2007

Extraembryonic ectoderm differentiation and chorioallantoic attachment are fibroblast growth factor (FGF)- and transforming growth factor ß-regulated processes that are the first steps in the development of the placenta labyrinth and the establishment of the fetal-maternal circulation in the developing embryo. Only a small number of genes have been demonstrated to be important in trophoblast stem cell differentiation. Erf is a ubiquitously expressed Erk-regulated, ets domain transcriptional repressor expressed throughout embryonic development and adulthood. However, in the developing placenta, after 7.5 days postcoitum (dpc) its expression is restricted to the extraembryonic ectoderm, and its expression is restricted after 9.5 dpc in a subpopulation of labyrinth cells. Homozygous deletion of Erf in mice leads to a block of chorionic cell differentiation before chorioallantoic attachment, resulting in a persisting chorion layer, a persisting ectoplacental cone cavity, failure of chorioallantoic attachment, and absence of labyrinth. These defects result in embryo death by 10.5 dpc. Trophoblast stem cell lines derived from Erf^dl1/dl1 knockout blastocysts exhibit delayed differentiation and decreased expression of spongiotrophoblast markers, consistent with the persisting chorion layer, the expanded giant cell layer, and the diminished spongiotrophoblast layer observed in vivo. Our data suggest that attenuation of FGF/Erk signaling and consecutive Erf nuclear localization and function is required for extraembryonic ectoderm differentiation, ectoplacental cone cavity closure, and chorioallantoic attachment.

Published ahead of print on 14 May 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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