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Molecular and Cellular Biology, December 2005, p. 10953-10964, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.10953-10964.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mammalian E4 Is Required for Cardiac Development and Maintenance of the Nervous System

Chie Kaneko-Oshikawa,^1,2, Tadashi Nakagawa,^1,2, Mitsunori Yamada,³ Hiroo Yoshikawa,⁴ Masaki Matsumoto,^1,2 Masayoshi Yada,^1,2 Shigetsugu Hatakeyama,^1,2 Keiko Nakayama,⁵ and Keiichi I. Nakayama^1,2*

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan,¹ CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan,² Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan,³ Department of Neurology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya 663-8131, Japan,⁴ Department of Developmental Biology, Center for Translational and Advanced Animal Research on Human Disease, Graduate School of Medicine, Tohoku University, 2-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan⁵

Received 20 June 2005/ Returned for modification 21 July 2005/ Accepted 21 September 2005

Ubiquitin conjugation typically requires three classes of enzyme: E1, E2, and E3. A fourth type of enzyme (E4), however, was recently shown to be required for the degradation of certain types of substrate in yeast. We previously identified UFD2a (also known as E4B) as an E4 in mammals. UFD2a is exclusively expressed in cardiac muscle during mouse embryonic development, but it is abundant in neurons of adult mice and is implicated in the pathogenesis of neurodegenerative disease. The precise physiological function of this enzyme has remained largely unknown, however. Here, we show that mice lacking UFD2a die in utero, manifesting marked apoptosis in the developing heart. Polyubiquitylation activity for an E4 substrate was greatly reduced in Ufd2a^–/– mouse embryonic fibroblasts. Furthermore, Ufd2a^+/– mice displayed axonal dystrophy in the nucleus gracilis, as well as degeneration of Purkinje cells accompanied by endoplasmic reticulum stress. These animals also developed a neurological disorder. UFD2a thus appears to be essential for the development of cardiac muscle, as well as for the protection of spinocerebellar neurons from degeneration induced by endoplasmic reticulum stress.

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* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Phone: 81-92-642-6815. Fax: 81-92-642-6819. E-mail: nakayak1{at}bioreg.kyushu-u.ac.jp.

These authors contributed equally to this work.

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Molecular and Cellular Biology, December 2005, p. 10953-10964, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.10953-10964.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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