The Krü ppel-like C2/H2 zinc finger transcription factors (KLFs) control development and differentiation. Erythroid Krü ppel-like factor (EKLF or KLF1) regulates adult -globin gene expression and is necessary for normal definitive erythropoiesis. KLF2 is required for normal embryonic Ey-and h1-, but not adult -globin, gene expression in mice. Both EKLF and KLF2 play roles in primitive erythroid cell development. To investigate potential interactions between these genes, EKLF/KLF2 double-mutant embryos were analyzed. EKLF ؊/؊ KLF2 ؊/؊ mice appear anemic at embryonic day 10.5 (E10.5) and die before E11.5, whereas single-knockout EKLF ؊/؊ or KLF2 ؊/؊ embryos are grossly normal at E10.5 and die later than EKLF ؊/؊ KLF2 ؊/؊ embryos. At E10.5, Ey-and h1-globin mRNA is greatly reduced in EKLF ؊/؊ KLF2 ؊/؊ , compared with EKLF ؊/؊ or KLF2 ؊/؊ embryos, consistent with the observed anemia. Light and electron microscopic analyses of E9.5 EKLF ؊/؊ KLF2 ؊/؊ yolk sacs, and cytospins, indicate that erythroid and endothelial cells are morphologically more abnormal than in either single knockout.
EKLF
IntroductionKrüppel-Like factors (KLFs) are a family of DNA-binding proteins with sequence homology to the Drosophila transcription factor, Krüppel. KLFs have 3 C2/H2 zinc finger domains and share conserved residues located primarily within these domains. 1,2 Erythroid Krüppel-Like factor (EKLF or KLF1) was the first of 17 KLFs to be identified in mouse and man. 3 It is expressed specifically in erythroid cells and positively regulates the adult -globin gene. 3,4 EKLF Ϫ/Ϫ mice develop fatal anemia during definitive (fetal liver) erythropoiesis, due to a defect in the maturation of red blood cells, and die by embryonic day 16 (E16). [5][6][7] Several other members of the KLF family, including KLF2 (lung Krüppel-like factor, LKLF), also are expressed in erythroid cells. [8][9][10][11] Based on phylogenetic analyses, the zinc finger domains of KLF2 and EKLF are very similar. 1,2,12,13 KLF2 Ϫ/Ϫ mice die between E12.5 and E14.5 due to heart failure and severe hemorrhaging, caused by defects in vascular endothelial cells and in stabilization of immature vessels by recruited smooth muscle cells. 14,15 Prior to E12.5, KLF2 Ϫ/Ϫ embryos have normal vasculogenesis and angiogenesis. 14,15 KLF2 also plays an important role in hematopoietic cell biology. We reported that KLF2 is essential for primitive (embryonic yolk sac) erythropoiesis and positively regulates the embryonic -like globin genes in vivo. E10.5 KLF2 Ϫ/Ϫ primitive erythroid cells have abnormal morphology. 9 KLF2 also regulates T-cell activation. Deficiency of KLF2 leads to a decrease in the peripheral T-cell pool 16 due to defective thymocyte emigration. 17 Overexpression of KLF2 in mice inhibits proinflammatory activation of peripheral blood monocytes. 18 It was initially reported that EKLF does not affect embryonic/ fetal globin gene expression. Interestingly, however, EKLF is expressed very early in mouse and chicken development, as early as the primitive streak stage, fo...
