Serum Response Factor Is Required for Immediate-Early Gene Activation yet Is Dispensable for Proliferation of Embryonic Stem Cells

doi:10.1128/MCB.21.8.2933-2943.2001

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Molecular and Cellular Biology, April 2001, p. 2933-2943, Vol. 21, No. 8
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2933-2943.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Serum Response Factor Is Required for Immediate-Early Gene Activation yet Is Dispensable for Proliferation of Embryonic Stem Cells

Gerhard Schratt,¹ Birgit Weinhold,²^, Ante S. Lundberg,³ Sebastian Schuck,¹ Jürgen Berger,⁴ Heinz Schwarz,⁴ Robert A. Weinberg,³ Ulrich Rüther,²^,⁵ and Alfred Nordheim¹^,^*

Interfakultäres Institut für Zellbiologie, Abteilung Molekularbiologie, Universität Tübingen, 72076 Tübingen,¹ Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover,² Max-Planck-Institut für Entwicklungsbiologie, 72074 Tübingen,⁴ and Entwicklungs- und Molekularbiologie der Tiere, Heinrich Heine Universität, 40225 Düsseldorf, Germany,⁵ and Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142-1479³

Received 20 November 2000/Returned for modification 10 January 2001/Accepted 26 January 2001

Addition of serum to mitogen-starved cells activates the cellular immediate-early gene (IEG) response. Serum response factor(SRF) contributes to such mitogen-stimulated transcriptional inductionof many IEGs during the G₀-G₁ cell cycle transition. SRF is alsobelieved to be essential for cell cycle progression, as impairmentof SRF activity by specific antisera or antisense RNA has previouslybeen shown to block mammalian cell proliferation. In contrast,Srf^/ mouse embryos grow and develop up to E6.0. Using the embryonicstem (ES) cell system, we demonstrate here that wild-type ES cellsdo not undergo complete cell cycle arrest upon serum withdrawalbut that they can mount an efficient IEG response. This IEG response,however, is severely impaired in Srf^/ ES cells, providing the first genetic proof that IEG activationis dependent upon SRF. Also, Srf^/ ES cells display altered cellular morphology, reduced corticalactin expression, and an impaired plating efficiency on gelatin.Yet, despite these defects, the proliferation rates of Srf^/ ES cells are not substantially altered, demonstrating that SRFfunction is not required for ES cell cycleprogression.

^* Corresponding author. Mailing address: Interfakultäres Institut für Zellbiologie, Abteilung Molekularbiologie, UniversitätTübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.Phone: 49-7071-297 8898. Fax: 49-7071-295359. E-mail: alfred.nordheim{at}uni-tuebingen.de.

Present address: Institut für Medizinische Mikrobiologie, Medizinische Hochschule Hannover, 30625 Hannover,Germany.

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