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Molecular and Cellular Biology, April 2006, p. 3266-3281, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3266-3281.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Differentiation of Trophoblast Giant Cells and Their Metabolic Functions Are Dependent on Peroxisome Proliferator-Activated Receptor ß/{delta}

Karim Nadra,1 Silvia I. Anghel,1,2 Elisabeth Joye,1 Nguan Soon Tan,1,{dagger} Sharmila Basu-Modak,1,{ddagger} Didier Trono,2,3 Walter Wahli,1,2 and Béatrice Desvergne1,2*

Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland,1 National Research Center "Frontiers in Genetics",§ ,§ School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland3

Received 24 June 2005/ Returned for modification 21 July 2005/ Accepted 24 January 2006

Mutation of the nuclear receptor peroxisome proliferator-activated receptor ß/{delta} (PPARß/{delta}) severely affects placenta development, leading to embryonic death at embryonic day 9.5 (E9.5) to E10.5 of most, but not all, PPARß/{delta}-null mutant embryos. While very little is known at present about the pathway governed by PPARß/{delta} in the developing placenta, this paper demonstrates that the main alteration of the placenta of PPARß/{delta}-null embryos is found in the giant cell layer. PPARß/{delta} activity is in fact essential for the differentiation of the Rcho-1 cells in giant cells, as shown by the severe inhibition of differentiation once PPARß/{delta} is silenced. Conversely, exposure of Rcho-1 cells to a PPARß/{delta} agonist triggers a massive differentiation via increased expression of 3-phosphoinositide-dependent kinase 1 and integrin-linked kinase and subsequent phosphorylation of Akt. The links between PPARß/{delta} activity in giant cells and its role on Akt activity are further strengthened by the remarkable pattern of phospho-Akt expression in vivo at E9.5, specifically in the nucleus of the giant cells. In addition to this phosphatidylinositol 3-kinase/Akt main pathway, PPARß/{delta} also induced giant cell differentiation via increased expression of I-mfa, an inhibitor of Mash-2 activity. Finally, giant cell differentiation at E9.5 is accompanied by a PPARß/{delta}-dependent accumulation of lipid droplets and an increased expression of the adipose differentiation-related protein (also called adipophilin), which may participate to lipid metabolism and/or steroidogenesis. Altogether, this important role of PPARß/{delta} in placenta development and giant cell differentiation should be considered when contemplating the potency of PPARß/{delta} agonist as therapeutic agents of broad application.

* Corresponding author. Mailing address: Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland. Phone: 41 21 6924140. Fax: 41 21 6924115. E-mail: beatrice.desvergne{at}unil.ch.

{dagger} Present address: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.

{ddagger} Present address: Department of Zoology, University of Dehli, Dehli 110007, India.

http://www.frontiers-in-genetics.org/en/index.php.

Molecular and Cellular Biology, April 2006, p. 3266-3281, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3266-3281.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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