Lineage restriction of the RARalpha 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 RARalpha (primarily the RARalpha1 isoform). Following induction of myelomonocytic differentiation with granulocyte and granulocyte-macrophage colony-stimulating factors, a dramatic increase in RARalpha expression (particularly the RARalpha2 isoform) was seen. In contrast, expression of both RARalpha isoforms was rapidly extinguished upon induction of erythroid differentiation with erythropoeitin (EPO). A modest induction of RXRalpha expression was seen, particularly during differentiation in the myelomonocytic lineage. Low expression levels of RARgamma2 and RXRbeta remained unchanged, irrespective of differentiation pathway. Consistent with the gene expression patterns, RARalpha 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 RARalpha 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 RARalpha2 expression, can exert inhibitory effects on erythroid differentiation.
Zhu
J
J
Leukaemia Research Fund Centre and Section of Gene Function and Regulation at the Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom.
Heyworth
C M
CM
Glasow
A
A
Huang
Q H
QH
Petrie
K
K
Lanotte
M
M
Benoit
G
G
Gallagher
R
R
Waxman
S
S
Enver
T
T
Zelent
A
A
D001853:Bone Marrow / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers; D004921:Erythropoietin / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007938:Leukemia; D008954:Models, Biological; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D017931:DNA Primers; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor