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Molecular and Cellular Biology, April 2003, p. 2969-2980, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2969-2980.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mammalian Twisted Gastrulation Is Essential for Skeleto-Lymphogenesis

Tetsuya Nosaka,1* Sumiyo Morita,1,{dagger} Hidetomo Kitamura,2 Hideaki Nakajima,3 Fumi Shibata,1 Yoshihiro Morikawa,4 Yuki Kataoka,5 Yasuhiro Ebihara,3 Toshiyuki Kawashima,1 Tsuneo Itoh,2 Katsutoshi Ozaki,1 Emiko Senba,4 Kohichiro Tsuji,3 Fusao Makishima,2 Nobuaki Yoshida,5 and Toshio Kitamura3

Division of Hematopoietic Factors,1 Division of Cellular Therapy, Advanced Clinical Research Center,3 Laboratory of Gene Expression and Regulation, Center for Experimental Medicine, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639,5 Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513,2 Department of Anatomy and Neurobiology, Wakayama Medical School, Wakayama 641-8509, Japan4

Received 27 August 2002/ Returned for modification 4 November 2002/ Accepted 30 January 2003

Dorsoventral patterning depends on the local concentrations of the morphogens. Twisted gastrulation (TSG) regulates the extracellular availability of a mesoderm inducer, bone morphogenetic protein 4 (BMP-4). However, TSG function in vivo is still unclear. We isolated a TSG cDNA as a secreted molecule from the mouse aorta-gonad-mesonephros region. Here we show that TSG-deficient mice were born healthy, but more than half of the neonatal pups showed severe growth retardation shortly after birth and displayed dwarfism with delayed endochondral ossification and lymphopenia, followed by death within a month. TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus. Since BMP-4 promotes skeletogenesis and inhibits thymus development, our findings suggest that TSG acts as both a BMP-4 agonist in skeletogenesis and a BMP-4 antagonist in T-cell development. Although lymphopenia in TSG-deficient mice would partly be ascribed to systemic effects of runtiness and wasting, our findings may also provide a clue for understanding the pathogenesis of human dwarfism with combined immunodeficiency.

* Corresponding author. Mailing address: Division of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5399. Fax: 81-3-5449-5453. E-mail: tenosaka{at}ims.u-tokyo.ac.jp.

{dagger} Present address: Gene Research Center, Gunma University, Maebashi 371-8511, Japan.

Molecular and Cellular Biology, April 2003, p. 2969-2980, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2969-2980.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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