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Molecular and Cellular Biology, January 2006, p. 654-667, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.654-667.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Deletion of Smad2 in Mouse Liver Reveals Novel Functions in Hepatocyte Growth and Differentiation

Wenjun Ju,1 Atsushi Ogawa,2 Joerg Heyer,3 Dirk Nierhof,2 Liping Yu,1 Raju Kucherlapati,3 David A. Shafritz,2 and Erwin P. Böttinger1*

Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029,1 Marion Bessin Liver Research Center and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461,2 Department of Genetics, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 021153

Received 10 May 2005/ Returned for modification 17 June 2005/ Accepted 23 October 2005

Smad family proteins Smad2 and Smad3 are activated by transforming growth factor ß (TGF-ß)/activin/nodal receptors and mediate transcriptional regulation. Although differential functional roles of Smad2 and Smad3 are apparent in mammalian development, the relative functional roles of Smad2 and Smad3 in postnatal systems remain unclear. We used Cre/loxP-mediated gene targeting for hepatocyte-specific deletion of Smad2 (S2HeKO) in adult mice and generated hepatocyte-selective Smad2/Smad3 double knockouts by intercrossing AlbCre/Smad2f/f (S2HeKO) and Smad3-deficient Smad3ex8/ex8 (S3KO) mice. All strains were viable and had normal adult liver. However, necrogenic CCL4-induced hepatocyte proliferation was significantly increased in S2HeKO compared to Ctrl and S3KO livers, and transplanted S2HeKO hepatocytes repopulated recipient liver at dramatically increased rates compared to Ctrl hepatocytes in vivo. Using primary hepatocytes, we found that TGF-ß-induced G1 arrest, apoptosis, and epithelial-to-mesenchymal transition in Ctrl and S2HeKO but not in S3KO hepatocytes. Interestingly, S2HeKO cells spontaneously acquired mesenchymal features characteristic of epithelial-to-mesenchymal transition (EMT). Collectively, these results demonstrate that Smad2 suppresses hepatocyte growth and dedifferentiation independent of TGF-ß signaling. Smad2 is not required for TGF-ß-stimulated apoptosis, EMT, and growth inhibition in hepatocytes.

* Corresponding author. Mailing address: Mount Sinai School of Medicine, One Gustave L. Levy Pl., Box 1118, New York, NY 10029. Phone: (212) 241-0800. Fax: (212) 849-2643. E-mail: erwin.bottinger{at}mssm.edu.

Molecular and Cellular Biology, January 2006, p. 654-667, Vol. 26, No. 2
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.2.654-667.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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