Review
Formation of mammalian erythrocytes: chromatin condensation and enucleation

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In all vertebrates, the cell nucleus becomes highly condensed and transcriptionally inactive during the final stages of red cell biogenesis. Enucleation, the process by which the nucleus is extruded by budding off from the erythroblast, is unique to mammals. Enucleation has critical physiological and evolutionary significance in that it allows an elevation of hemoglobin levels in the blood and also gives red cells their flexible biconcave shape. Recent experiments reveal that enucleation involves multiple molecular and cellular pathways that include histone deacetylation, actin polymerization, cytokinesis, cell–matrix interactions, specific microRNAs and vesicle trafficking; many evolutionarily conserved proteins and genes have been recruited to participate in this uniquely mammalian process. In this review, we discuss recent advances in mammalian erythroblast chromatin condensation and enucleation, and conclude with our perspectives on future studies.

Section snippets

Mammalian erythroblast enucleation

Red blood cells are continuously replenished; in humans their half-life is around 120 days. Erythropoietin (Epo), a cytokine produced by the kidney in response to low oxygen pressure, is the principal regulator of red blood cell production. Epo binds to cognate receptors on Colony Forming Unit Erythroid (CFU-E) progenitor cells and activates the JAK2 protein tyrosine kinase and several downstream signal transduction pathways. These prevent CFU-E apoptosis and stimulate its terminal

Chromatin condensation and apoptosis

During mammalian erythropoiesis, the chromatin gradually undergoes condensation; nuclear and chromatin condensation are thought to be critical for enucleation. Chromatin condensation occurs during other cellular processes such as apoptosis, and apoptotic mechanisms are known to play important roles in erythropoiesis (reviewed in [12]). Apoptotic mechanisms have been implicated in the loss of the nucleus in mammalian lens epithelia and keratinocytes 13, 14, although these processes are

Membrane and cytoskeletal proteins that mediate enucleation and asymmetrical cell division

Early studies indicated that enucleation involves a process of cytokinesis involving several membrane and cytoskeleton proteins 9, 10, 22, 23. Mature red cells possess a unique submembrane cytoskeleton that maintains the stability and flexibility characteristic of these cells. Essentially, the heterodimeric α- and β-spectrins self-associate into α2β2 tetramers, which are connected by actins to form pentagonal or hexagonal lattices [24]. Ankyrin–protein 4.2 and protein 4.1–adducin complexes

Erythropoietic microenvironment and enucleation

Studies in the 1970s showed that the extruded nucleus is enveloped by a portion of the plasma membrane with distinctive cell surface proteins different from those on the reticulocyte 29, 42. The exoplasmic leaflet of the membrane enveloping the nucleus contains high levels of phosphatidylserine, which serves as a signal for macrophage engulfment; masking phosphatidylserine on the nucleus prevents macrophage phagocytosis of the extruded nuclei [17]. Correspondingly, the cell surface of mature

MicroRNAs in enucleation

MicroRNAs are a class of small RNAs that downregulate expression of specific target genes post-transcriptionally [55]. They play a wide variety of roles in hematopoiesis 56, 57, specifically in erythropoiesis [58]. Among these microRNAs, the miR-144/451 cluster is directly activated by the erythroid-important GATA1 transcription factor and is required for erythropoiesis [59]. Specifically, in Zebrafish miR-144 directly suppresses the levels of Klfd, an erythroid specific Kruppel-like

Concluding remarks

Enucleation of mammalian erythroblasts is a complex process that involves a series of morphological and structural changes. In this review, we summarized current progress in understanding mammalian erythroid cell enucleation. Most of these studies utilized in vitro erythroblast culture systems because the extruded nucleus is released into the culture medium and not immediately engulfed by macrophages. The Emp-deficient mouse might provide an intriguing system to study enucleation in vivo.

Acknowledgments

This study was supported by NIH grant P01 HL 32262, a research grant from Amgen (to H.F.L.) and by intramural funds from the Temasek Life Sciences Laboratory to M.M.-H. P.J. is the recipient of a Leukemia and Lymphoma Society fellowship and a National Institutes of Health (NIH) Pathway to Independence Award (K99/R00).

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