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J. Biol. Chem., Vol. 282, Issue 33, 24320-24328, August 17, 2007

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Serum Response Factor Contributes Selectively to Lymphocyte Development^*

Anne Fleige, Siegfried Alberti^¶, Lothar Gröbe^||, Ursula Frischmann, Robert Geffers^||, Werner Müller, Alfred Nordheim^¶, and Angela Schippers¹

From the Department of Experimental Immunology, and the ^||Department of Mucosal Immunity, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany and the ^¶Interfaculty Institute for Cell Biology, Department of Molecular Biology, Tübingen University, 72076 Tübingen, Germany

Serum response factor (SRF), is a crucial transcription factor for murine embryonic development and for the function of muscle cells and neurons. Gene expression data show that SRF and its transcriptional cofactors are also expressed in lymphocyte precursors and mature lymphocytes. However, the role of SRF in lymphocyte development has not been addressed in vivo so far, attributed in part to early embryonic lethality of conventional Srf-null mice. To determine the in vivo role of SRF in developing lymphocytes, we specifically inactivated the murine Srf gene during T or B cell development using lymphocyte-specific Cre transgenic mouse lines. T cell-specific Srf deletion led to a severe block in thymocyte development at the transition from CD4/CD8 double to single positive stage. The few residual T cells detectable in the periphery retained at least one functional Srf allele, thereby demonstrating the importance of SRF in T cell development. In contrast, deletion of Srf in developing B cells did not interfere with the growth and survival of B cells in general, yet led to a complete loss of marginal zone B cells and a marked reduction of the CD5⁺ B cell subset. Our study also revealed a contribution of SRF to the expression of the surface molecules IgM, CD19, and the chemokine receptor 4 in B lymphocytes. We conclude that SRF fulfills essential and distinct functions in the differentiation of different types of lymphocytes.

Received for publication, April 13, 2007 , and in revised form, June 12, 2007.

^* This work was supported by the European Union (HPRN-CT-2002-00255), the Federal Ministry of Education and Research (Hepatosys), the German Research Foundation (NO120/12-2), National Genome Research Network and Integrated Functional Genomics in Mutant Mouse Models as Tools to Investigate the Complexity of Human Immunological Disease. 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.

¹ To whom correspondence should be addressed: Dept. of Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstrae 7, 38124 Braunschweig, Germany. Tel.: 49-531-6181-3036; Fax: 49-531-6181-3099; E-mail: angela.schippers{at}helmholtz-hzi.de.

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