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Molecular and Cellular Biology, May 2005, p. 4105-4116, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.4105-4116.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Docking Protein FRS2 Is an Essential Component of Multiple Fibroblast Growth Factor Responses during Early Mouse Development

N. Gotoh,^1,2 K. Manova,³ S. Tanaka,⁴ M. Murohashi,² Y. Hadari,¹ A. Lee,¹ Y. Hamada,⁵ T. Hiroe,⁶ M. Ito,⁷ T. Kurihara,⁸ H. Nakazato,^8, M. Shibuya,² I. Lax,¹ E. Lacy,⁹ and J. Schlessinger^1*

Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven Connecticut 06520,¹ Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan,² Molecular Cytology Core Facility,³ Developmental Biology Program, Memorial Sloan-Kettering Cancer-Center, 1275 York Avenue, New York, New York 10021,⁹ Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical School, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan,⁴ National Institute for Basic Biology,⁵ Physiological Science, 38 Myodaizi-machi, Okazaki, Nagoya 444-8585, Japan,⁶ Department of Anatomy, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan,⁷ Daiichi Suntory Biomedical Research Co., Ltd., 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8513, Japan⁸

Received 4 October 2004/ Returned for modification 23 November 2004/ Accepted 28 December 2004

The docking protein FRS2 is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2 in vivo remains unknown. In this report, we show that Frs2-null mouse embryos have a defect in anterior-posterior (A-P) axis formation and are developmentally retarded, resulting in embryonic lethality by embryonic day 8. We demonstrate that FRS2 is essential for the maintenance of self-renewing trophoblast stem (TS) cells in response to FGF4 in the extraembryonic ectoderm (ExE) that gives rise to tissues of the placenta. By analyzing chimeric embryos, we found that FRS2 also plays a role in cell movement through the primitive streak during gastrulation. In addition, experiments are presented demonstrating that Bmp4 expression in TS cells is controlled by mitogen-activated protein kinase-dependent FGF4 stimulation. Moreover, both the expression of Bmp4 in ExE and activation of Smad1/5 in epiblasts are reduced in Frs2-null embryos. These experiments underscore the critical role of FRS2 in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.

Present address: NoviTech Metagenome Research Institute, Ho372-3, Yachimata-shi, 289-1115, Japan.

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