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Blood, 1 July 2004, Vol. 104, No. 1, pp. 1-2. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chasis, J. A. Search for Related Content PubMed Articles by Chasis, J. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  PLENARY PAPER Mammalian primitive erythrocytes: neither fish nor fowl Joel Anne Chasis UNIVERSITY OF CALIFORNIA, LAWRENCE BERKELEY NATIONAL LABORATORY Mammalian primitive erythroblasts undergo enucleation in the circulation, thus refuting the long-standing perception that primitive erythroblasts remain nucleated and are more similar to nucleated avian, fish, and reptile red cells than to definitive red cells of mammals. During mammalian embryogenesis, erythropoiesis progresses through distinct phases, each phase producing cells with dramatically different characteristics. When cardiac contractions begin in mice embryos at embryonic day 8.25 (E8.25), "primitive" erythroblasts, developed in yolk sac blood islands, enter the circulation.1,2 However, by E12.5 "definitive" erythrocytes, produced in the fetal liver, begin to circulate and quickly prevail as the dominant erythroid phenotype.3 While definitive erythroblasts synthesize adult hemoglobins and enucleate, primitive red cells are larger, contain embryonic and adult hemoglobins, and have been thought not to undergo enucleation during their life span. Although several earlier observations hinted that in mouse embryos a population of large, enucleated cells might be circulating,4 the longstanding perception has been that primitive mammalian erythrocytes retain their nuclei and are thus more similar to nucleated avian, fish, and reptile red cells5 than to definitive red cells of mammals. However, in this issue, Kingsley and colleagues (page 19) report quantitative data showing that between E12.5 and E16.5 primitive erythroblasts progressively enucleate in circulation. Further, they observed that enucleated, primitive cells can be detected up to 5 days after birth. Using antibodies to specific regions of murine embryonic H1-globin and adult major-globin, they were able to differentiate yolk sac–derived primitive red cells. These antibodies, in combination with nuclear staining, identified 3 distinct peripheral blood cell populations in E13.5 and E15.5 fetuses: a nucleated population expressing embryonic H1-globin, an enucleated population lacking H1-globin, and surprisingly, an enucleated population expressing H1-globin. Small numbers of enucleated H1-globin–expressing cells were initially detected at E12.5. By E16.5, all of the H1-globin–expressing cells were enucleated. Morphometric analysis of cell area revealed that both nucleated and enucleated H1-globin–expressing cells were 100 µm2 in size and about 3-fold larger than definitive erythrocytes. Importantly, the disappearance of circulating nucleated primitive cells was due to their progressive enucleation and not loss from the bloodstream. Immunohistochemistry with antiglobin antibodies. See the complete figure in the article beginning on page 19.   These findings provide a persuasive argument refuting the currently held view that primitive mammalian erythropoiesis resembles avian and reptilian erythropoiesis more than definitive mammalian erythropoiesis. Indeed, the authors delineate a number of important similarities between murine primitive and definitive erythropoiesis. Both differentiation programs exhibit maturation with enucleation. Additionally, prior to extrusion, nuclei condense and move to the plasma membrane, coincident with loss of intermediate filaments.6 Yet one striking difference in the differentiation programs is that primitive erythroblasts appear to undergo terminal differentiation in circulation, while definitive erythroblasts mature extravascularly within 3-dimensional erythroblastic islands, closely associated with macrophages and extracellular matrix proteins. A number of new questions can now be asked. Do circulating primitive erythroblasts require contact with macrophages of the reticuloendothelial system for enucleation? What is the trigger for enucleation? Are molecular mechanisms of chromatin condensation, cytoskeletal remodeling, and nuclear extrusion similar or different in primitive and definitive erythroblasts? Do membrane mechanical properties of enucleated primitive cells differ from those of definitive cells, suggesting unique interactions among transmembrane and cytoskeletal components? The findings of Kingsley and colleagues open up many new avenues for exploration. References McGrath KE, Koniski AD, Malik J, Palis J. Circulation is established in a step-wise pattern in the mammalian embryo. Blood. 2003;101: 1669-1676.[Abstract/Free Full Text] Ji RP, Phoon CKL, Aristizábal O, McGrath KE, Palis J, Turnbull DH. Onset of cardiac function during early mouse embryogenesis coincides with entry of primitive erythroblasts into the embryo proper. Circ Res. 2003;92: 133-135.[Abstract/Free Full Text] Brotherton TW, Chui DHK, Gauldie J, Patterson M. Hemoglobin ontogeny during normal mouse fetal development. Proc Natl Acad Sci U S A. 1979;76: 2853-2857.[Abstract/Free Full Text] Bethlenfalvay NC, Block M. Fetal erythropoiesis. Maturation in megaloblastic (yolk sac) erythropoiesis in the C57Bl/6J mouse. Acta Haemat. 1970;44: 240-245.[Medline] [Order article via Infotrieve] Lazarides E. From genes to structural morphogenesis: the genesis and epigenesis. Cell. 1987;51: 345-356.[CrossRef][Medline] [Order article via Infotrieve] Sangiorgi F, Woods CM, Lazarides E. Vimentin down-regulation is an inherent feature of murine erythropoiesis and occurs independently of lineage. Development. 1990;110: 85-96.[Abstract] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Yolk sac–derived primitive erythroblasts enucleate during mammalian embryogenesis Paul D. Kingsley, Jeffrey Malik, Katherine A. Fantauzzo, and James Palis Blood 2004 104: 19-25. [Abstract] [Full Text] [PDF] This article has been cited by other articles: A. Serrels, I. R.J. Macpherson, T.R. J. Evans, F. Y. Lee, E. A. Clark, O. J. Sansom, G. H. Ashton, M. C. Frame, and V. G. Brunton Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib Mol. Cancer Ther., December 1, 2006; 5(12): 3014 - 3022. [Abstract] [Full Text] [PDF] F. M. Johnson, B. Saigal, M. Talpaz, and N. J. Donato Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non-Small Cell Lung Cancer Cells Clin. Cancer Res., October 1, 2005; 11(19): 6924 - 6932. [Abstract] [Full Text] [PDF] K. N. Bhalla Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies J. Clin. Oncol., June 10, 2005; 23(17): 3971 - 3993. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chasis, J. A. Search for Related Content PubMed Articles by Chasis, J. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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