The Krü ppel-like factors (KLFs) are a family of C2/H2 zinc finger DNA-binding proteins that are important in controlling developmental programs. Erythroid Krü ppel-like factor (EKLF or KLF1) positively regulates the ␤-globin gene in definitive erythroid cells. KLF2 (LKLF) is closely related to EKLF and is expressed in erythroid cells. KLF2 ؊/؊ mice die between embryonic day 12.5 (E12.5) and E14.5, because of severe intraembryonic hemorrhaging. They also display growth retardation and anemia. We investigated the expression of the ␤-like globin genes in KLF2 knockout mice. Our results show that KLF2 ؊/؊ mice have a significant reduction of murine embryonic Ey-and ␤h1-globin but not -globin gene expression in the E10.5 yolk sac, compared with wild-type mice. The expression of the adult ␤ maj -and ␤ min -globin genes is unaffected in the fetal livers of E12.5 embryos. In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic ⑀-globin gene but not the adult ␤-globin gene, suggesting that this developmentalstage-specific role is evolutionarily conserved. KLF2 also plays a role in the maturation and/or stability of erythroid cells in the yolk sac. KLF2 ؊ IntroductionHematopoiesis represents a complex differentiation pathway involving many transcription factors and growth factors that interact in a concerted fashion during mammalian development. 1 Transcription factors often exist as multigene families of structurally and functionally related members that are involved in the different stages of development of a particular cell lineage. For example, members of the GATA family of transcription factors are involved in both primitive and definitive erythropoiesis. 2-4 Different phenotypic features seen after ablation of either the GATA1 or the GATA2 gene in mice clearly demonstrate that these factors have different but overlapping functions. The Krüppel-like factors (KLFs) are a family of DNA-binding proteins named after the Drosophila Krüppel protein. KLFs have 3 C2/H2 zinc finger domains and share conserved residues located primarily within these zinc fingers. 5,6 Several of the KLFs are expressed in erythroid cells starting early in development. Erythroid Krüppel-like factor (EKLF or KLF1) was the first of 16 KLFs to be identified. EKLF Ϫ/Ϫ mice develop fatal anemia during fetal liver erythropoiesis. 7,8 EKLF is responsible for positively regulating the adult ␤-globin gene, but it is not required for embryonic/fetal globin gene expression. [9][10][11] Other KLF family members may be involved in the developmental control of the embryonic and fetal globin genes. A few of the KLFs, namely KLF2 and KLF5, 12 and KLF11 and KLF13,13,14 have been shown to activate the fetal ␥-globin gene in transient transfection assays in human erythroleukemia cell lines. So far none of these studies have been replicated in vivo. In a recent study, KLF11 (fetal Krüppel like factor, FKLF1)-null mice were found to be fertile, with normal hematopoiesis at all stages of development. There was no effe...

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