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J. Biol. Chem., Vol. 283, Issue 8, 4905-4911, February 22, 2008

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Isx Participates in the Maintenance of Vitamin A Metabolism by Regulation of β-Carotene 15,15'-Monooxygenase (Bcmo1) Expression^*

Yusuke Seino, Takashi Miki, Hiroshi Kiyonari^¶, Takaya Abe^¶, Wakako Fujimoto^||, Keita Kimura, Ayako Takeuchi¹, Yoshihisa Takahashi, Yutaka Oiso, Toshihiko Iwanaga^||, and Susumu Seino¹

From the Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, the Division of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, the ^¶Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology, RIKEN Kobe 650-0047, Japan, and the ^||Laboratory of Histology and Cytology, Graduate School of Medicisne, Hokkaido University, Sapporo 060-8638, Japan

Isx (intestine specific homeobox) is an intestine-specific transcription factor. To elucidate its physiological function, we generated Isx-deficient mice by knocking in the β-galactosidase gene (LacZ) in the Isx locus (Isx^LacZ/LacZ mice). LacZ staining of heterozygous (Isx^LacZ/+) mice revealed that Isx was expressed abundantly in intestinal epithelial cells from duodenum to proximal colon. Quantitative mRNA expression profiling of duodenum and jejunum showed that β-carotene 15,15'-monooxygenase (EC1.14.99.36 Bcmo1) and the class B type I scavenger receptor, which are involved in vitamin A synthesis and carotenoid uptake, respectively, were drastically increased in Isx^LacZ/LacZ mice. Although mild vitamin A deficiency decreased Isx expression in duodenum of wild-type (Isx^+/+) mice, severe vitamin A deficiency decreased Isx mRNA expression in both duodenum and jejunum of Isx^+/+ mice. On the other hand, vitamin A deficiency increased Bcmo1 expression in both duodenum and jejunum of Isx^+/+ mice. However, Bcmo1 expression was not increased in duodenum of Isx^LacZ/LacZ mice by mild vitamin A deficiency. These data suggest that Isx participates in the maintenance of vitamin A metabolism by regulating Bcmo1 expression in the intestine.

Received for publication, September 21, 2007 , and in revised form, December 18, 2007.

^* This work was supported by a Grant-in-Aid for Specially Promoted Research and for Scientific Research from the Ministry of Education, Science, Sports, Culture, and Technology and by a Grant-in-Aid for CREST (Core Research for Evolutional Science and Technology. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: 7-5-1 Kusunoki-cho, Chuoku, Kobe 650-0017, Japan. Tel.: 81-78-382-5360; Fax: 81-78-382-5370; E-mail: seino{at}med.kobe-u.ac.jp.

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