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Molecular and Cellular Biology, June 2009, p. 3186-3203, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01970-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Pluripotency-Associated Gene Dppa4 Is Dispensable for Embryonic Stem Cell Identity and Germ Cell Development but Essential for Embryogenesis{triangledown} ,{dagger}

Babita Madan,1 Vikas Madan,1 Odile Weber,1 Philippe Tropel,2,3 Carmen Blum,1 Emmanuelle Kieffer,2 Stéphane Viville,2 and Hans Jörg Fehling1*

Institute of Immunology, University Clinics Ulm, Albert Einstein Allee 11, D-89081 Ulm, Germany,1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, B.P. 10142, F-67404 Strasbourg-Illkirch,2 I-STEM, INSERM/UEVE UMR 861, Genopole Campus 1, 5 rue Henrie Desbruères, 91030 Evry cedex, France3

Received 31 December 2008/ Returned for modification 4 March 2009/ Accepted 19 March 2009

Dppa4 (developmental pluripotency-associated 4) has been identified in several high-profile screens as a gene that is expressed exclusively in pluripotent cells. It encodes a nuclear protein with an SAP-like domain and appears to be associated preferentially with transcriptionally active chromatin. Its exquisite expression pattern and results of RNA interference experiments have led to speculation that Dppa4, as well as its nearby homolog Dppa2, might play essential roles in embryonic stem (ES) cell function and/or germ cell development. To rigorously assess suggested roles, we have generated Dppa4-deficient and Dppa4/Dppa2 doubly deficient ES cells, as well as mice lacking Dppa4. Contrary to predictions, we find that Dppa4 is completely dispensable for ES cell identity and germ cell development. Instead, loss of Dppa4 in mice results in late embryonic/perinatal death and striking skeletal defects with partial penetrance. Thus, surprisingly, Dppa4-deficiency affects tissues that apparently never transcribed the gene, and at least some loss-of-function defects manifest phenotypically at an embryonic stage long after physiologic Dppa4 expression has ceased. Concomitant with targeted gene inactivation, we have introduced into the Dppa4 locus a red fluorescent marker (tandem-dimer red fluorescent protein) that is compatible with green fluorescent proteins and allows noninvasive visualization of pluripotent cells and reprogramming events.

* Corresponding author. Mailing address: Albert Einstein Allee 11, D-89081 Ulm, Germany. Phone: 49 731 5006 5210. Fax: 49 731 5006 5211. E-mail: joerg.fehling{at}uni-ulm.de

{triangledown} Published ahead of print on 30 March 2009.

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

Molecular and Cellular Biology, June 2009, p. 3186-3203, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01970-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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