DIFFERENTIAL EXPRESSION AND FUNCTIONAL-ROLE OF GATA-2, NF-E2, AND GATA-1 IN NORMAL ADULT HEMATOPOIESIS

We have explored the expression of the transcription factors GATA-1, G ATA-2, and NF-E2 in purified early hematopoietic progenitor cells (HPC s) induced to gradual unilineage erythroid or granulocytic differentia tion by growth factor stimulus, GATA-2 mRNA and protein, already expre ssed in quiescent HPCs, is rapidly induced as early as 3 h after growt h factor stimulus, but then declines in advanced erythroid and granulo cytic differentiation and maturation, NF-E2 and GATA-1 mRNAs and prote ins, though not detected in quiescent HPCs, are gradually induced at 2 4-48 h in both erythroid and granulocytic culture, Beginning at late d ifferentiation/early maturation stage, both transcription factors are further accumulated in the erythroid pathway, whereas they are suppres sed in the granulopoietic series. Similarly, the erythropoietin recept or (EpR) is induced and sustainedly expressed during erythroid differe ntiation, although beginning at later times (i,e,, day 5), whereas it is barely expressed in the granulopoietic pathway, In the first series of functional studies, HPCs were treated with antisense oligomers tar geted to transcription factor mRNA: inhibition of GATA-2 expression ca used a decreased number of both erythroid and granulocyte-monocytic cl ones, whereas inhibition of NF-E2 or GATA-1 expression induced a selec tive impairment of erythroid colony formation, In a second series of f unctional studies, HPCs treated with retinoic acid were induced to shi ft from erythroid to granulocytic differentiation (Labbaye et al, 1994 , Blood. 83:651-656); this was coupled with abrogation of GATA-1, NF-E 2, and EpR expression and conversely enhanced GATA-2 levels, These res ults indicate the expression and key role of GATA-2 in the early stage s of HPC proliferation/differentiation, Conversely, NF-E2 and GATA-1 e xpression and function are apparently restricted to erythroid differen tiation and maturation: their expression precedes that of the EpR, and their function may be in part mediated via the EpR.