Lineage restriction of the RARα gene expression in myeloid differentiation

To better understand the role of retinoids in myelopoiesis, expression of the retinoid receptor genes (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) were examined during differentiation of factor-dependent cell-Paterson (FDCP)–mixA4 murine progenitor cells. The major receptor expressed in undifferentiated A4 cells was RARα (primarily the RARα1 isoform). Following induction of myelomonocytic differentiation with granulocyte and granulocyte-macrophage colony-stimulating factors, a dramatic increase in RARα expression (particularly the RARα2 isoform) was seen. In contrast, expression of both RARα isoforms was rapidly extinguished upon induction of erythroid differentiation with erythropoeitin (EPO). A modest induction of RXRα expression was seen, particularly during differentiation in the myelomonocytic lineage. Low expression levels of RARγ2 and RXRβ remained unchanged, irrespective of differentiation pathway. Consistent with the gene expression patterns, RARα agonists and antagonists stimulated myelomonocytic and erythroid differentiation of FDCP-mixA4 cells, respectively. Taken together, these results suggest that erythropoiesis and granulopoiesis require diminished and enhanced RARα activities, respectively, which at physiological all-trans-retinoic acid (RA) concentrations may be accomplished by reciprocal effects of EPO and myelomonocytic growth factors on its expression. This hypothesis is corroborated by data showing that RA, which positively regulates RARα2 expression, can exert inhibitory effects on erythroid differentiation.