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Molecular and Cellular Biology, August 2009, p. 4262-4273, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01779-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Transcriptional Activity of Sox9 in Chondrocytes Is Regulated by RhoA Signaling and Actin Polymerization{triangledown}

Deepak Kumar and Andrew B. Lassar*

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Building C, Room 303, 240 Longwood Avenue, Boston, Massachusetts 02115

Received 20 November 2008/ Returned for modification 9 January 2009/ Accepted 16 May 2009

In this study, we demonstrate that dedifferentiation of round primary chondrocytes into a fibroblast morphology correlates with a profound induction of RhoA protein and stress fibers. Culture of dedifferentiated chondrocytes in alginate gel induces a precipitous loss of RhoA protein and a loss of stress fibers concomitant with the reexpression of the chondrocyte differentiation program. We have found that chondrogenesis in limb bud micromass cultures similarly entails a loss of RhoA protein and that expression of dominant negative RhoA in such cultures can markedly enhance chondrogenesis. Consistent with these results, expression of the Rho antagonist C3 transferase can restore chondrocyte gene expression in dedifferentiated chondrocytes grown on plastic. Transfection of cells with agents that block actin polymerization enhance the ability of either exogenous Sox9 or a Gal4 DBD-Sox9 fusion protein to activate gene expression. Interestingly, the enhancement of Sox9 function by actin depolymerization requires both protein kinase A (PKA) activity and a PKA phosphorylation site in Sox9 (S181) that is known to enhance Sox9 transcriptional activity. Lastly, we demonstrate that RhoA-mediated modulation of actin polymerization regulates the ability of Sox9 to both activate chondrocyte-specific markers and maintain its own expression in chondrocytes via a positive feedback loop.

* Corresponding author. Mailing address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Bldg C, Room 303, 240 Longwood Ave., Boston, MA 02115. Phone: (617) 432-3831. Fax: (617) 738-0516. E-mail: andrew_lassar{at}hms.harvard.edu

{triangledown} Published ahead of print on 26 May 2009.

Molecular and Cellular Biology, August 2009, p. 4262-4273, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01779-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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