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Blood, 15 September 2005, Vol. 106, No. 6, pp. 1900. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Palis, J. Search for Related Content PubMed Articles by Palis, J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Comment on Krauss et al, page 2200 To condense is not to die James Palis UNIVERSITY OF ROCHESTER MEDICAL CENTER In this issue of Blood, Krauss and colleagues provide evidence that erythropoiesis is indeed a unique process of terminal differentiation that results in nuclear condensation and extrusion without caspase activation of apoptotic machinery. Most cells in the body are nucleated and rely on apoptotic signals to facilitate their demise. Programmed cell death is characterized by the activation of a set of intracellular cysteine proteases, termed caspases, that cleave target proteins to cause characteristic morphologic changes associated with cell death. These changes include nuclear condensation, which is a prominent feature of erythroblast maturation prior to their enucleation (see figure). In fact, red cells are not the only enucleated terminally differentiated cells in mammals. Keratinocytes in the skin and lens epithelial cells in the eye also lose their nuclei during maturation. Limited studies in these 2 cell types indicate that the process of nuclear loss is associated with the activation of caspases, raising the question of whether caspase activation plays a role in terminal maturation of erythroid cells. In this issue of Blood, Krauss and colleagues examine the process of nuclear condensation in murine erythropoiesis using primarily the in vitro differentiation of Friend virus–infected erythroid cells. No evidence was found for caspase-induced cleavage of lamin B, nuclear pore proteins, or components of the spliceosome as the erythroid nucleus condensed. These findings are consistent with the lack of DNA laddering even after erythroid nuclei are extruded.1 Furthermore, immunohistochemical studies revealed that nuclear pores remain intact but redistribute during late stages of erythroblast maturation, supporting the concept that RNA transcripts continue to traffic to the cytoplasm prior to nuclear extrusion. View larger version (33K): [in this window] [in a new window]   Caspases have potential roles at early and possibly late stages of erythroid differentiation, but not as morphologically distinguishable erythroblasts undergo progressive nuclear condensation and enucleation.   Is there a role for programmed cell death in erythropoiesis? Immature erythroid cells, particularly at the erythroid colony-forming unit (CFU-E) and proerythroblast stages, are highly dependent on the hormone erythropoietin for survival and undergo apoptosis upon cytokine withdrawal (see figure). This is thought to be an important mechanism for the regulation of steady-state levels of red cells and in the "stress" response following acute blood loss, and it likely involves caspase cleavage of target proteins, including GATA-1.2 However, caspases may also have nonapoptotic roles in erythropoiesis, since knock-down of caspase-3 transcript levels in erythroid burst-forming unit (BFU-E) leads to a block in erythroid maturation.3 Little is known about the potential nonapoptotic functions of the cell death pathway. Caspases are also expressed in aged erythrocytes, but they do not appear to play a role in the "death" of senescent red cells.4 Thus, paradoxically, caspases appear to function at an early stage of erythroid differentiation but not when erythroblasts undergo the changes in nuclear morphology associated with programmed cell death. It is becoming ever more apparent that the processes of nuclear condensation and enucleation that lead to the mature mammalian erythrocyte are unique in the animal kingdom. References Kelley L, Koury MJ, Bondurant MC, Koury ST, Sawyer ST, Wickrema A. Survival or death of individual proerythroblasts results from differing erythropoietin sensitivities: a mechanism for controlled rates of erythrocyte production. Blood. 1993;82: 2340-2352.[Abstract/Free Full Text] De Maria R, Zeuner A, Eramo A, et al. Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature. 1999;401: 489-493.[CrossRef][Medline] [Order article via Infotrieve] Carlile GW, Smith DH, Wiedmann M. Caspase-3 has a nonapoptotic function in erythroid maturation. Blood. 2004;103: 4310-4316.[Abstract/Free Full Text] Bratosin D, Estaquier J, Petit F, et al. Programmed cell death in mature erythrocytes: a model for investigating death effector pathways operating in the absence of mitochondria. Cell Death Differ. 2001;8: 1143-1156.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Nuclear substructure reorganization during late-stage erythropoiesis is selective and does not involve caspase cleavage of major nuclear substructural proteins Sharon Wald Krauss, Annie J. Lo, Sarah A. Short, Mark J. Koury, Narla Mohandas, and Joel Anne Chasis Blood 2005 106: 2200-2205. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Palis, J. Search for Related Content PubMed Articles by Palis, J. 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