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J. Biol. Chem., Vol. 279, Issue 40, 41846-41857, October 1, 2004

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Conserved POU Binding DNA Sites in the Sox2 Upstream Enhancer Regulate Gene Expression in Embryonic and Neural Stem Cells^*

Raffaella Catena, Cecilia Tiveron¶, Antonella Ronchi, Silvia Porta, Anna Ferri, Laura Tatangelo¶, Maurizio Cavallaro, Rebecca Favaro, Sergio Ottolenghi, Rolland Reinbold||, Hans Schöler||, and Silvia K. Nicolis**

From the Department of Biotechnology and Biosciences, University of Milano-Bicocca, piazza della Scienza 2, Milano 20126, Italy, the ^¶Transgenic Mice Service Center, Centro Ricerca Sperimentale, Istituto Regina Elena, via delle Messi d'Oro 156, Roma 00158, Italy, and the ^||Center for Animal Transgenesis and Germ Cell Research, New Bolton Center, Germline Development Group, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania 19348-1692

The Sox2 transcription factor is expressed early in the stem cells of the blastocyst inner cell mass and, later, in neural stem cells. We previously identified a Sox2 5'-regulatory region directing transgene expression to the inner cell mass and, later, to neural stem cells and precursors of the forebrain. Here, we identify a core enhancer element able to specify transgene expression in forebrain neural precursors of mouse embryos, and we show that the same core element efficiently activates transcription in inner cell mass-derived embryonic stem (ES) cells. Mutation of POU factor binding sites, able to recognize the neural factors Brn1 and Brn2, shows that these sites contribute to transgene activity in neural cells. The same sites are also essential for activity in ES cells, where they bind different members of the POU family, including Oct4, as shown by gel shift assays and chromatin immunoprecipitation with anti-Oct4 antibodies. Our findings indicate a role for the same POU binding motifs in Sox2 transgene regulation in both ES and neural precursor cells. Oct4 might play a role in the regulation of Sox2 in ES (inner cell mass) cells and, possibly, at the transition between inner cell mass and neural cells, before recruitment of neural POU factors such as Brn1 and Brn2.

Received for publication, May 18, 2004 , and in revised form, July 6, 2004.

^* This work was supported by Grants D.127 from Telethon, QLG3-CT-01141C00 from the European Community, and a Cofinanziamento Progetti di Ricerca di rilevante interesse nazionale (COFIN 2001) from the Italian Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) (to S. K. N.), and by a Fondo per gli Investimenti della Ricerca di Base (FIRB) (to E. Cattaneo). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 39-02-6448-3315/3339; Fax: 39-02-6448-3565; E-mail: silvia.nicolis{at}unimib.it.

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