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Molecular and Cellular Biology, April 2004, p. 3505-3513, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3505-3513.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dual Roles for the Notch Target Gene Hes-1 in the Differentiation of 3T3-L1 Preadipocytes

David A. Ross, Prakash K. Rao,{dagger} and Tom Kadesch*

Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145

Received 6 October 2003/ Accepted 17 December 2003

The process of adipogenesis involves a complex program of gene expression that includes down-regulation of the gene encoding Hes-1, a target of the Notch signaling pathway. To determine if Notch signaling affects adipogenesis, we exposed 3T3-L1 preadipocytes to the Notch ligand Jagged1 and found that differentiation was significantly reduced. This effect could be mimicked by constitutive expression of Hes-1. The block was associated with a complete loss of C/EBP{alpha} and peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) induction and could be overcome by retroviral expression of either C/EBP{alpha} or PPAR{gamma}2. Surprisingly, small interfering RNA (siRNA)-mediated reduction of Hes-1 mRNA in 3T3-L1 cells also inhibited differentiation, suggesting an additional, obligatory role for Hes-1 in adipogenesis. This role may be related to our observation that both Notch signaling and Hes-1 down-regulate transcription of the gene encoding DLK/Pref-1, a protein known to inhibit differentiation of 3T3-L1 cells. The results presented in this study establish a new target downstream of the Notch-Hes-1 pathway and suggest a dual role for Hes-1 in adipocyte development.

* Corresponding author. Mailing address: Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19104-6145. Phone: (215) 898-1047. Fax: (215) 898-9750. E-mail: kadesch{at}mail.med.upenn.edu.

{dagger} Present address: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.

Molecular and Cellular Biology, April 2004, p. 3505-3513, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3505-3513.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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