Specific and Redundant Functions of Retinoid X Receptor/Retinoic Acid Receptor Heterodimers in Differentiation, Proliferation, and Apoptosis of F9 Embryonal Carcinoma Cells

doi:10.1083/jcb.139.3.735

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J. Cell Biol., Volume 139, Number 3, November 3, 1997 735-747

Specific and Redundant Functions of Retinoid X Receptor/Retinoic Acid Receptor Heterodimers in Differentiation, Proliferation, and Apoptosis of F9 Embryonal Carcinoma Cells

Hideki Chiba, John Clifford, Daniel Metzger, and Pierre Chambon

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, Collège de France, 67404 Illkirch-Cedex, France

We have generated F9 murine embryonal carcinoma cells in which either the retinoid X receptor (RXR) $alpha$ and retinoic acid receptor(RAR) $alpha$ genes or the RXR $alpha$ and RAR $gamma$ genes are knocked out, and comparedtheir phenotypes with those of wild-type (WT), RXR $alpha$ ^/, RAR $alpha$ ^/, and RAR $gamma$ ^/ cells. RXR $alpha$ ^// RAR $alpha$ ^/ cells were resistant to retinoic acid treatment for the inductionof primitive and parietal endodermal differentiation, as wellas for antiproliferative and apoptotic responses, whereas theycould differentiate into visceral endodermlike cells, as previouslyobserved for RXR $alpha$ ^/ cells. In contrast, RXR $alpha$ ^//RAR $gamma$ ^/ cells were defective for all three types of differentiation,as well as antiproliferative and apoptotic responses, indicatingthat RXR $alpha$ and RAR $gamma$ represent an essential receptor pair for theseresponses. Taken together with results obtained by treatment ofWT and mutant F9 cells with RAR isotype- and panRXR-selectiveretinoids, our observations support the conclusion that RXR/ RARheterodimers are the functional units mediating the retinoid signalin vivo. Our results also indicate that the various heterodimerscan exert both specific and redundant functions in differentiation,proliferation, and apoptosis. We also show that the functionalredundancy exhibited between RXR isotypes and between RAR isotypesin cellular processes can be artifactually generated by gene knockouts.The present approach for multiple gene targeting should allowinactivation of any set of genes in a given cell.

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