RETINOID-X-RECEPTOR AND C-ERBA THYROID HORMONE-RECEPTOR REGULATE ERYTHROID CELL-GROWTH AND DIFFERENTIATION/

Nuclear receptors are important regulators of erythroid cell developme nt. Here we investigated the impact of retinoid X receptor (RXR), reti noic acid receptor (RAR), and of the c-erbA/thyroid hormone (T-3) rece ptor (c-erbA/TR) on growth and differentiation of erythroid cells usin g an in vitro culture system of stem cell factor-dependent erythroid p rogenitors. RXR, RAR, and c-erbA/TR-specific ligands were found to ind uce erythroid-specific gene expression and to accelerate erythroid dif ferentiation in culture, with T-3 being most effective. Furthermore, w hile ligand-activated c-erbA/TR accelerated differentiation, unligande d c-erbA/TR effectively blocked differentiation and supported sustaine d progenitor growth in culture. Thus, c-erbA/TR appears to act as a bi nary switch affecting erythroid cell fate: unliganded c-erbA/TR suppor ts growth while ligand-activated c-erbA/TR induces differentiation. Ad ditionally, to determine the impact of RXR for erythroid cell developm ent, dominant interfering mutant RXRs, lacking the transcriptional act ivator functions AF-1 and AF-2, or AF-2 only, or the entire DNA-bindin g domain, were introduced into erythroid progenitor cells via recombin ant retrovirus vectors and analyzed for RXR-specific effects. It was f ound that expression of wild-type RXR and of the RXR mutants devoid of AF-1 and/or AF-2 supported a transient outgrowth of erythroid cells. In marked contrast, expression of the dominant interfering Delta DNA-b inding domain RXR, containing a deletion of the entire DNA-binding dom ain, was incompatible with erythroid cell growth in vitro, suggesting a pivotal role of RXR for erythroid cell development.