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J. Biol. Chem., Vol. 280, Issue 9, 7909-7916, March 4, 2005

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Essential Role of Synoviolin in Embryogenesis^*

Naoko Yagishita, Kinuko Ohneda, Tetsuya Amano, Satoshi Yamasaki, Akiko Sugiura, Kaneyuki Tsuchimochi, Hiroshi Shin¶, Ko-ichi Kawahara||, Osamu Ohneda, Tomohiko Ohta**, Sakae Tanaka, Masayuki Yamamoto, Ikuro Maruyama||, Kusuki Nishioka, Akiyoshi Fukamizu¶, and Toshihiro Nakajima

From the Department of Genome Science, Institute of Medical Science, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku, Kawasaki, Kanagawa 216-8512, the Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, the ^¶Institute of Applied Biochemistry and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, the ^||Department of Dermatology and Laboratory of Molecular Medicine, Kagoshima University, Faculty of Medicine, Kagoshima 890-8520, the ^**Department of Surgery and Laboratory of Surgical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8512, and the Department of Orthopaedic Surgery, Facility of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

We recently reported the importance of Synoviolin in quality control of proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) system and its involvement in the pathogenesis of arthropathy through its anti-apoptotic effect. For further understanding of the role of Synoviolin in vivo, we generated in this study synoviolin-deficient (syno^–/–) mice by genetargeted disruption. Strikingly, all fetuses lacking syno died in utero around embryonic day 13.5, although Hrd1p, a yeast orthologue of Synoviolin, is non-essential for survival. Histologically, hypocellularity and aberrant apoptosis were noted in the syno^–/– fetal liver. Moreover, definitive erythropoiesis was affected in non-cell autonomous manner in syno^–/– embryos, causing death in utero. Cultured embryonic fibroblasts derived from syno^–/– mice were more susceptible to endoplasmic reticulum stress-induced apoptosis than those from syno^+/+ mice, but the susceptibility was rescued by overexpression of synoviolin. Our findings emphasized the indispensable role of the Synoviolin in embryogenesis.

Received for publication, September 21, 2004 , and in revised form, December 15, 2004.

^* This work was partially supported financially by LocomoGene Inc., by the Japanese Ministry of Education, Science Culture and Sports, by the Japanese Ministry of Health and Welfare, Japan Science and Technology Corporation, by the Human Health Science Foundation, by funds from the Memorial Yamanouchi Foundation, by the Kato Memorial Trust for Nanbyo Research, by Kanagawa Academy of Science and Technology Research Grants, by the Japan Medical Association, by the Nagao Memorial Fund, by the Kanae Foundation for Life & Socio-Medical Science, by the Japan Research Foundation for Clinical Pharmacology, by the Kanagawa Nanbyo Foundation, by Japan College of Rheumatology, by the Nakajima Foundation, by the Mitsubishi Pharma Research Foundation, by New Energy and Industrial Technology Development Organization, by Mochida Pharmaceutical Co., Ltd., by the Pharmaceuticals and Medical Devices Agency, by the Kanagawa High-Technology Foundation, by Kanagawa Academy of Science and Technology Research Grants, by the Ministry of Education, Culture, Sports and Technology, by the Japan Society for Promotion of Science, by the Ministry of Health, Labor and Welfare, and by the Kanto Bureau of Economy, Trade and Industry. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-44-977-8111 (ext. 4113); Fax: 81-44-977-9772; E-mail: nakashit{at}marianna-u.ac.jp.

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