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Molecular and Cellular Biology, January 2004, p. 228-244, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.228-244.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cited1 Is Required in Trophoblasts for Placental Development and for Embryo Growth and Survival

Tristan A. Rodriguez,^1, Duncan B. Sparrow,² Annabelle N. Scott,² Sarah L. Withington,² Jost I. Preis,² Jan Michalicek,³ Melanie Clements,¹ Tania E. Tsang,² Toshi Shioda,⁴ Rosa S. P. Beddington,^1, and Sally L. Dunwoodie^1,2,5*

Mammalian Development Division, National Institute for Medical Research, London, United Kingdom,¹ Developmental Biology Program,² Molecular Cardiology Program, Victor Chang Cardiac Research Institute,³ Department of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia,⁵ Laboratory of Tumor Biology, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts⁴

Received 4 November 2002/ Returned for modification 13 December 2002/ Accepted 18 September 2003

Cited1 is a transcriptional cofactor that interacts with Smad4, estrogen receptors and ß, TFAP2, and CBP/p300. It is expressed in a restricted manner in the embryo as well as in extraembryonic tissues during embryonic development. In this study we report the engineering of a loss-of-function Cited1 mutation in the mouse. Cited1 null mutants show growth restriction at 18.5 days postcoitum, and most of them die shortly after birth. Half the heterozygous females, i.e., those that carry a paternally inherited wild-type Cited1 allele, are similarly affected. Cited1 is normally expressed in trophectoderm-derived cells of the placenta; however, in these heterozygous females, Cited1 is not expressed in these cells. This occurs because Cited1 is located on the X chromosome, and thus the wild-type Cited1 allele is not expressed because the paternal X chromosome is preferentially inactivated. Loss of Cited1 resulted in abnormal placental development. In mutants, the spongiotrophoblast layer is irregular in shape and enlarged while the labyrinthine layer is reduced in size. In addition, the blood spaces within the labyrinthine layer are disrupted; the maternal sinusoids are considerably larger in mutants, leading to a reduction in the surface area available for nutrient exchange. We conclude that Cited1 is required in trophoblasts for normal placental development and subsequently for embryo viability.

Dedicated to the memory of Rosa Beddington (23 March 1956 to 18 May 2001).

Present address: MRC Clinical Sciences Centre, Imperial College, London, United Kingdom.

Deceased.

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