F9 embryocarcinoma cells: a cell autonomous model to study the functional selectivity of RARs and RXRs in retinoid signaling

• Rochette-Egly, C. ^[1] ; Chambon, P. ^[1]
  1. [1] Institute of Genetic and Cellular and Molecular Biology, CNRS/INSERM/ULP/Coillege of France, IIlkirch, France
• Localización: Histology and histopathology: cellular and molecular biology, ISSN-e 1699-5848, ISSN 0213-3911, Vol. 16, Nº. 3, 2001, págs. 909-922
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • Mouse F9 embryocarcinoma (EC) cells constitute a well established cell-autonomous model system for investigati ng retinoid signaling in vitro as, depending on culture conditions, retinoic acid (RA) can induce their differentiation into either primitive, parietal or visceral extraembryonic endoderm-like cells. These RA-induced d ifferentiations are accompanied by decreases in pro liferat ion rates, modifications of expression of subsets of RA-target genes, and induction of apoptosis. To elucidate the roles played by the multiple retinoid receptors (RARs and RXRs) in response to RA treatments, F9 EC cells lacking one or several RARs or RXRs were engineered through homologous recombination. Mutated RARs and/or RXRs were then reexpressed in given RAR or RXR null backgrounds. WT and mutant cells were also treated with different combinations of ligands selective for RXRs and/or for each of the three RAR isotypes. These studies lead to the conclusion that most RA-induced events (e.g. primitive and visceral differentiation, growth arrest, apoptosis and activation of expression of a number of genes) are transduced by RARy/RXRa heterodimers, whereas some other events (e.g. parietal differentiation) are mediated by RARa/ RXRa heterodimers. They also demonstrate that both AF-1 and AF-2 activation functions of RARs and RXRs, as well as their phosphorylation, are differentially required in these RA-induced events. In RARy/RXRa heterodimers, the phosphory lation of RA Ry is necessary for triggering primitive differentiation, while that of RXRa is required for growth arrest. On the other hand, phosphorylation of RARa is necessary for parietal differentiat ion. Thus, retinoid receptors are sophisticated signal integrators that transduce not only the effects of their cognate ligands, but also those of ligands that bind to membrane receptors