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Molecular and Cellular Biology, August 2008, p. 4999-5013, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.00695-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

L-Sox5 and Sox6 Drive Expression of the Aggrecan Gene in Cartilage by Securing Binding of Sox9 to a Far-Upstream Enhancer {triangledown}

Yu Han and Véronique Lefebvre*

Department of Cell Biology and Orthopaedic Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195

Received 28 April 2008/ Returned for modification 27 May 2008/ Accepted 30 May 2008

The Sry-related high-mobility-group box transcription factor Sox9 recruits the redundant L-Sox5 and Sox6 proteins to effect chondrogenesis, but the mode of action of the trio remains unclear. We identify here a highly conserved 359-bp sequence 10 kb upstream of the Agc1 gene for aggrecan, a most essential cartilage proteoglycan and key marker of chondrocyte differentiation. This sequence directs expression of a minimal promoter in both embryonic and adult cartilage in transgenic mice, in a manner that matches Agc1 expression. The chondrogenic trio is required and sufficient to mediate the activity of this enhancer. It acts directly, Sox9 binding to a critical cis-acting element and L-Sox5/Sox6 binding to three additional elements, which are cooperatively needed. Upon binding to their specific sites, L-Sox5/Sox6 increases the efficiency of Sox9 binding to its own recognition site and thereby robustly potentiates the ability of Sox9 to activate the enhancer. L-Sox5/Sox6 similarly secures Sox9 binding to Col2a1 (encoding collagen-2) and other cartilage-specific enhancers. This study thus uncovers critical cis-acting elements and transcription factors driving Agc1 expression in cartilage and increases understanding of the mode of action of the chondrogenic Sox trio.

* Corresponding author. Mailing address: Department of Cell Biology, Cleveland Clinic, 9500 Euclid Avenue (NC-10), Cleveland, OH 44195. Phone: (216) 445-0762. Fax: (216) 444-9404. E-mail: lefebvv{at}ccf.org

{triangledown} Published ahead of print on 16 June 2008.

Molecular and Cellular Biology, August 2008, p. 4999-5013, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.00695-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yin, W., Park, J.-I., Loeser, R. F. (2009). Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways. J. Biol. Chem. 284: 31972-31981 [Abstract] [Full Text]  


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