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The v-erbA oncogene, carried by the Avian Erythroblastosis Virus (AEV), is one of the most clear-cut case of an oncogene that acts by blocking a differentiation program. When this oncogene is expressed in an erythrocytic progenitor ceil at the BFU-E stage of differentiation, this ceil progressesalong the differentiationpathwayto the downstream early CFU-Estage where it stops differentiating (Samarut and Gazzola, 1982). Although this effect was first recognised when acting in conjunction with the v-erbB oncogene (Sealy et ai., 1983a, 1983b), the use of a selectable retrovirus carrying the v-erbA oncogene as the sale oncogene has directly demonstrated that the v-ErbA gene product induces by itself a blockade of the erythrocytic differentiation program at the CFU-E stage both in vitro and in vivo (Gandriilon et ai., 1989; Casini and Grat, 1995). The current view of this phenomenon is that during the BFU-E to CFU-E transition, the expression levels of a number of genes wouid have to be modulated by ligand-activated endogenous nuclear hormones receptors of the c-erbA family (belonging to the iarge superfamiiy of structuraily and functionaily related receptors that includes the receptors for thyroid hormone (T3R) and re)inoids (RARs and RXRs) ) thereby committing the ceil from a proliferation to a differentiation program. These genes could either be a smail number of master controilers of the erythrocytic differentiation program or an entire bank of genes each of which playing its own peculiar and discrete role in the combined phenomenon of erythrocytic differentiation. In any case, the vErbA protein would constitutively repress the actions of those endogenous nuclear hormone receptors and thus block the differentiation sequence (see Gandriilon et ai., 1995 for a review). In order to substantiate this view, the isolation and characterization of v-erbA target genes, in its natural target cell, is an absolute necessity. We therefore have screened the expression of a number of genes by RT-PCR in normal early erythrocytic precursor cells treated with various hormones. Most of the tested genes were found to be expressed in those cells and no variation under hormonal influence could be detected in their expression pattern. The expression of some of the tested genes could not be detected in any condition in those progenitor cells (not shown). The RARB gene was found to be strongly induced by retina ids addition (either aI/-trans or 9-cis retinoic acid) starting from undetectable levels in untreated cells. On the other side, no RARB gene expression was detected after all-trans-retinoic acid treatment in AEV-fransformed ceil lines (Sande et aI., 1993). This gene therefore represents a promising putative target gene for the v-erbA oncogene. We therefore have characterized the RARB gene response for both kinetics and dose-response parameters. We first have established that this gene was still activated by aI/trans retinoic acid in the presence of anisomycine, a potent translation inhibitor thereby establishing this response as being a direct phenomenon that does not require ongoing protein synthesis (not shown). Then we established the kinetics of the response, in the absence or presence of cycloheximide. The RARB gene response was found to be a late event requiring at least 4 hours of all-trans retinoic acid addition to start being detected (not shown). We then established the dose-response profile: a sharp increase was noted at 10 nM a/Hrans retinoic acid, thereby estabiishing a molecular basis for differential effects between low and high doses of retinoic acid (not shown). We then investigated the RARB gene response under the influence of isoform-specific synthetic retinoids (Figure 1A). Only the RARa-activating ligands were able to elicit a RARB gene {;,\I'jJI!

Role of the various isoforms of retinoic acid receptors during the final commitment step of the erythrocytic differentiation sequence in the chicken.