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J. Biol. Chem., Vol. 278, Issue 43, 41862-41870, October 24, 2003

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Mouse Snail Family Transcription Repressors Regulate Chondrocyte, Extracellular Matrix, Type II Collagen, and Aggrecan^*

Kenji Seki¶, Toshihiko Fujimori¶, Pierre Savagner||, Akiko Hata**, Tomonao Aikawa, Naoshi Ogata, Yoichi Nabeshima¶, and Lee Kaechoong

From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, the ^¶Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan, ^||INSERM 0229, Montpellier 34000, France, and ^**MCRI, Tufts-New England Medical Center, Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111

Snail family genes are conserved among species during evolution and encode transcription factors expressed at different stages of development in different tissues. These genes are involved in a broad spectrum of biological functions: cell differentiation, cell motility, cell cycle regulation, and apoptosis. However, little is known about the target genes involved in these functions. Here we show that mouse Snail family members, Snail (Sna) and Slug (Slugh), are involved in chondrocyte differentiation by controlling the expression of type II collagen (Col2a1) and aggrecan. In situ hybridization analysis of developing mouse limb demonstrated that Snail and Slug mRNAs were highly expressed in hypertrophic chondrocytes. Inversely, the expression of collagen type II mRNA disappeared during hypertrophic differentiation. Snail and Slug mRNA expression was down-regulated during differentiation of the mouse chondrogenic cell line ATDC5 and overexpression of exogenous Snail or Slug in ATDC5 cells inhibited expression of collagen type II and aggrecan mRNA. Reporter analysis revealed Snail and Slug suppressed the promoter activity of Col2a1, and the E-boxes in the promoter region were the responsible element. Gel shift assay demonstrated the binding of Snail to the E-box. Because type II collagen and aggrecan are major functional components of extracellular matrix in cartilage, these results suggest an important role for Snail-related transcription repressors during chondrocyte differentiation.

Received for publication, July 30, 2003

^* 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: Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Yoshida-Konoe cho, Sakyo-ku, Kyoto 8501, Japan. Tel.: 81-75753-4341; Fax: 81-75-751-7529; E-mail: kseki{at}anat1.med.kyoto-u.ac.jp.

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