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© The Rockefeller University Press, 0021-9525/1997//735 $5.00
The Journal of Cell Biology, Volume 139, Number 3, , 1997 735-747

Article

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 compared their 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 induction of primitive and parietal endodermal differentiation, as well as for antiproliferative and apoptotic responses, whereas they could differentiate into visceral endodermlike cells, as previously observed 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, indicating that RXR{alpha} and RAR{gamma} represent an essential receptor pair for these responses. Taken together with results obtained by treatment of WT and mutant F9 cells with RAR isotype– and panRXR-selective retinoids, our observations support the conclusion that RXR/ RAR heterodimers are the functional units mediating the retinoid signal in vivo. Our results also indicate that the various heterodimers can exert both specific and redundant functions in differentiation, proliferation, and apoptosis. We also show that the functional redundancy exhibited between RXR isotypes and between RAR isotypes in cellular processes can be artifactually generated by gene knockouts. The present approach for multiple gene targeting should allow inactivation of any set of genes in a given cell.

Abbreviations used in this paper: AFP, {alpha}-fetoprotein; E2, estradiol; EC, embryonal carcinoma; EMSA, electrophoretic mobility shift assays; HR, homologous recombination; PGK, phosphoglycerate kinase; RAR, retinoic acid receptor; RXR, retinoid X receptor; RARE, retinoic acid response element; RT, reverse transcription; tRA, all-trans retinoic acid; VE, visceral endoderm; WT, wild-type.

Address all correspondence to P. 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, BP 163, 67404 Illkirch-Cedex, France. Tel.: (33) 388-65-32-13. Fax: (33) 388-65-32-03. E-mail: IGBMC@ IGBMC.U-STRASBG.FR

H. Chiba's present address is Department of Pathology, Sapporo Medical University, School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060, Japan.

J. Clifford's present address is M.D. Anderson Cancer Center, Department of Clinical Cancer Center, Department of Clinical Cancer Prevention, Box 236, 1515 Holcombe Boulevard, Houston, TX 77030.


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