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Molecular and Cellular Biology, June 2002, p. 3794-3802, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3794-3802.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Growth and Early Postimplantation Defects in Mice Deficient for the Bromodomain-Containing Protein Brd4{dagger}

Denis Houzelstein,1* Simon L. Bullock,1,{ddagger} Denise E. Lynch,1 Elena F. Grigorieva,2 Valerie A. Wilson,1,§ and Rosa S. P. Beddington1

Laboratory of Mammalian Development,1 Laboratory of Developmental Neurobiology, Medical Research Council, National Institute for Medical Research, London NW7 1AA, United Kingdom2

Received 20 September 2001/ Returned for modification 31 October 2001/ Accepted 12 February 2002

In a gene trap screen we recovered a mouse mutant line in which an insertion generated a null allele of the Brd4 gene. Brd4 belongs to the Fsh/Brd family, a group of structurally related proteins characterized by the association of two bromodomains and one extraterminal domain. Members of this family include Brd2/Ring3/Fsrg1 in mammals, fs(1)h in Drosophila, and Bdf1 in Saccharomyces cerevisiae. Brd4 heterozygotes display pre- and postnatal growth defects associated with a reduced proliferation rate. These mice also exhibit a variety of anatomical abnormalities: head malformations, absence of subcutaneous fat, cataracts, and abnormal liver cells. In primary cell cultures, heterozygous cells also display reduced proliferation rates and moderate sensitivity to methyl methanesulfonate. Embryos nullizygous for Brd4 die shortly after implantation and are compromised in their ability to maintain an inner cell mass in vitro, suggesting a role in fundamental cellular processes. Finally, sequence comparisons suggest that Brd4 is likely to correspond to the Brd-like element of the mediator of transcriptional regulation isolated by Y. W. Jiang, P. Veschambre, H. Erdjument-Bromage, P. Tempst, J. W. Conaway, R. C. Conaway, and R. D. Kornberg (Proc. Natl. Acad. Sci. USA 95:8538-8543, 1998) and the Brd4 mutant phenotype is discussed in light of this result. Together, our results provide the first genetic evidence for an in vivo role in mammals for a member of the Fsh/Brd family.

* Corresponding author. Present address: Laboratoire de Génétique et Développement, Institut Jacques Monod, 2, place Jussieu, 75251 Paris Cedex 05, France. Phone: 33 1 44 27 40 35. Fax: 33 1 44 27 52 65. E-mail: houzelstein{at}ijm.jussieu.fr.

{dagger} This article is dedicated to the memory of Rosa Beddington.

{ddagger} Present address: Developmental Genetics Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.

§ Present address: Centre for Genome Research, University of Edinburgh, Edinburgh EH9 3JQ, United Kingdom.

Molecular and Cellular Biology, June 2002, p. 3794-3802, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3794-3802.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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