Globin Composition and Synthesis of Hemoglobins in Developing Fetal Mice Erythroid Cells

Fantoni, A; Bank, Arthur; Marks, Paul A.

doi:10.1126/science.157.3794.1327

Cited by 153 publications

(64 citation statements)

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“…2 indicated that during the early developmental stage there was a switch of the subcellular localization of EKLF in the erythroid cells from the cytosol to the nucleus. This switch coincided with the timing of the switch-on of ␤ maj globin gene transcription (13,26,38,54,57). The nuclear localization of EKLF in the E10.5 yolk sac and E14.5 fetal liver tissues (Fig.…”

Section: Discussionmentioning

confidence: 99%

Subcellular Transport of EKLF and Switch-On of Murine Adult β_maj Globin Gene Transcription

Shyu

Lee

Wen

et al. 2007

Molecular and Cellular Biology

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Erythroid Krüppel-like factor (EKLF) is an essential transcription factor for mammalian ␤-like globin gene switching, and it specifically activates transcription of the adult ␤ globin gene through binding of its zinc fingers to the promoter. It has been a puzzle that in the mouse, despite its expression throughout the erythroid development, EKLF activates the adult ␤ maj globin promoter only in erythroid cells beyond the stage of embryonic day 10.5 (E10.5) but not before. We show here that expression of the mouse ␤ maj globin gene in the aorta-gonad-mesonephros region of E10.5 embryos and in the E14.5 fetal liver is accompanied by predominantly nuclear localization of EKLF. In contrast, EKLF is mainly cytoplasmic in the erythroid cells of E9.5 blood islands in which ␤ maj is silenced. Remarkably, in a cultured mouse adult erythroleukemic (MEL) cell line, the activation of the ␤ maj globin gene by dimethyl sulfoxide (DMSO) or hexamethylene-bis-acetamide (HMBA) induction is also paralleled by a shift of the subcellular location of EKLF from the cytoplasm to the nucleus. Blockage of the nuclear import of EKLF in DMSO-induced MEL cells with a nuclear export inhibitor repressed the transcription of the ␤ maj globin gene. Transient transfection experiments further indicated that the full-sequence context of EKLF was required for the regulation of its subcellular locations in MEL cells during DMSO induction. Finally, in both the E14.5 fetal liver cells and induced MEL cells, the ␤-like globin locus is colocalized the PML oncogene domain nuclear body, and concentrated with EKLF, RNA polymerase II, and the splicing factor SC35. These data together provide the first evidence that developmental stage-and differentiation state-specific regulation of the nuclear transport of EKLF might be one of the steps necessary for the switch-on of the mammalian adult ␤ globin gene transcription.In mammals, the ␤-like and ␣-like families are individually clustered on different chromosomes. Functional members of both gene clusters are arranged in the order of their expression during erythroid development (globin switch). In the mouse, the ␤-like globin locus is arranged as follows: 5Ј-ε y (embryonic)-␤h1 (embryonic)-␤ maj (fetal and adult)-␤ min (fetal and adult, minor species)-3Ј (21, 2a) (top diagram in Fig. 1B). The hematopoietic cells, including the erythroid ones in the embryo, initially arise in the blood island that forms at embryonic day 7.5 (E7.5) (17). Within the primitive erythroblasts derived from the yolk sac are the embryonic genes, including ε y and ␤h1, as transcribed previously (26). The adult ␤ maj globin gene, on the other hand, is silenced in E9.5 yolk sac, but it starts to be expressed on E10.5 in the erythroblasts in the aorta-gonadmesonephros (AGM) region and the fetal liver of the embryo (26,38,54,56). During development, the major site of the erythropoiesis shifts to the fetal liver and then again to the bone marrow at the time of birth. The erythroid cells generated in the latter-named two tissues represent a def...

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Section: Discussionmentioning

confidence: 99%

Subcellular Transport of EKLF and Switch-On of Murine Adult β_maj Globin Gene Transcription

Shyu

Lee

Wen

et al. 2007

Molecular and Cellular Biology

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“…Unlike the adult mouse fi-globin genes, the mouse a-globin genes are expressed during both fetal and adult life (24). In addition, the mature form of the a-globin mRNA appears to be synthesized via a small 850-base precursor, approximately 250 bases larger than the cytoplasmic a-globin mRNA (25,26).…”

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confidence: 99%

Comparison of cloned mouse alpha- and beta-globin genes: conservation of intervening sequence locations and extragenic homology.

Leder¹,

Miller²,

Hamer³

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

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We have cloned and characterized a 9.7-kilobase EcoRI fragment of mouse DNA that contains an a-globin gene. The gene is encoded. in at least three discontinuous segments of DNA interrupted by two small intervening sequences that can be visualize as R-oop structures in the electron microscope. The size of the ene and its small intervening sequences fits well with the Cnown size of the a-globin-mRNA precursor, suggesting that these intervening sequences, like those of f-globin, are transcribed. Partial sequence analysis indicates that the larger intervening sequence interrupts the a-globin gene at a site exactly corresponding to that interrupted by the larger intervening sequences in both the -globin major and minor genes. This observation suggests that these sequences werepresent when the a-and "globin genes diverged in early vertebrate evolution, more than 500 million years ago, Fur-thermore, though a and ,tji genes are encoded on different chromosomes, when their sequences are compared directly by visualization of heteroduplex structures, only one 150-to 200-base-pair segment of homology is recognized. These homologous sequences are located on the 3'-flanking segments of both genes, about 1.5 kilobases from each.Globin production in developing erythroid cells involves the coordinate expression of at least two sets of genes located on different chromosomes: those corresponding to the a-and flglobin polypeptides (see review, ref. 1). By using cloned segments of BALB/c mouse genomic DNA we have shown that the two tightly linked adult fl-globin genes, fjl"i and #rnin, are each interrupted by two intervening sequences of DNA (2-5) and that they share homology with one another in the regions immediately surrounding their coding and intervening sequences (5). Intervening sequences have also been found in rabbit globin genes (6) and in genes corresponding to Drosophila 28S ribosomal RNA (7-9), adenovirus (10-12), simian virus 40 (13), mouse immunoglobulin (14), yeast tRNA (15, 16), and chicken ovalbumin (17)(18)(19)(20) and thus appear to be a common feature of eukaryotic gene organization. Because both mouse f-globin genes are coordinately expressed and direct the synthesis of mRNA precursors that include their intervening sequences (21-23), it is possible that their shared sequences play some critical role in their joint regulation and in the processing of their 15S mRNA transcripts.Unlike the adult mouse fi-globin genes, the mouse a-globin genes are expressed during both fetal and adult life (24). In addition, the mature form of the a-globin mRNA appears to be synthesized via a small 850-base precursor, approximately 250 bases larger than the cytoplasmic a-globin mRNA (25,26). It is likely that certain aspects of the structure and organization of one a-globin gene will allow us to account for its joint expression with other a-globin genes located on the same chro-The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" i...

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“…In the mammalian adult, erythropoietin is a they persist until about day 17 (Craig and Russell, major factor regulating the rate of erythropoiesis 1964 ; Fantoni et al ., 1967) . By the latter part of in response to physiological demand (Gurney, day 10 of gestation, hepatic erythropoiesis begins 1968) .…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin Effects on Fetal Mouse Erythroid Cells

Chui

Djaldetti

Marks

et al. 1971

The Journal of Cell Biology

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The effect of the hormone, erythropoietin, on cultures of erythroblasts derived from the livers of fetal C57BL/6J mice was examined . An increase both in the content and in the rate of synthesis of normal adult mouse globin chains was detected in hormone-treated cultures . The rate of protein synthesis by individual erythroblasts does not increase in response to the hormone, whereas the absolute number of hemoglobin-synthesizing cells does increase and accounts for the observed stimulation of hemoglobin synthesis . The principal effect of erythropoietin appears to be upon the population of immature erythroid precursor cells which persists in the presence of the hormone, the cells maintaining their ability to replicate, and their capacity to differentiate into hemoglobinizing erythroblasts . In the absence of hormone, already committed erythroblasts continue their development, but erythropoiesis is not sustained .

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Globin Composition and Synthesis of Hemoglobins in Developing Fetal Mice Erythroid Cells

Cited by 153 publications

References 14 publications

Subcellular Transport of EKLF and Switch-On of Murine Adult β_maj Globin Gene Transcription

Subcellular Transport of EKLF and Switch-On of Murine Adult β_maj Globin Gene Transcription

Comparison of cloned mouse alpha- and beta-globin genes: conservation of intervening sequence locations and extragenic homology.

Erythropoietin Effects on Fetal Mouse Erythroid Cells

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Globin Composition and Synthesis of Hemoglobins in Developing Fetal Mice Erythroid Cells

Cited by 153 publications

References 14 publications

Subcellular Transport of EKLF and Switch-On of Murine Adult βmaj Globin Gene Transcription

Subcellular Transport of EKLF and Switch-On of Murine Adult βmaj Globin Gene Transcription

Comparison of cloned mouse alpha- and beta-globin genes: conservation of intervening sequence locations and extragenic homology.

Erythropoietin Effects on Fetal Mouse Erythroid Cells

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Subcellular Transport of EKLF and Switch-On of Murine Adult β_maj Globin Gene Transcription

Subcellular Transport of EKLF and Switch-On of Murine Adult β_maj Globin Gene Transcription