Yolk sac–derived primitive erythroblasts enucleate during mammalian embryogenesis

Abstract

The enucleated definitive erythrocytes of mammals are unique in the animal kingdom. The observation that yolk sacderived primitive erythroid cells in mammals circulate as nucleated cells has led to the conjecture that they are related to the red cells of fish, amphibians, and birds that remain nucleated throughout their life span. In mice, primitive red cells express both embryonic and adult hemoglobins, whereas definitive erythroblasts accumulate only adult hemoglobins. We IntroductionIt was recognized more than 125 years ago that the mature red cells of adult vertebrates circulate either in nucleated or enucleated forms. 1 The red cells of all birds, fish, reptiles, and amphibians retain their nucleus and contain 3 filamentous systems: an actinspectrin-based membrane cytoskeleton, intermediate filaments that attach the cytoskeleton to the nuclear membrane, and a group of microtubules organized into a circumferential marginal band. 2,3 In contrast, the red cells of mammals lose intermediate filaments and microtubules during terminal differentiation and enucleate prior to entering the bloodstream. Thus, erythrocytes of adult mammals are enucleated and contain only one filamentous system, a membrane cytoskeleton.Nearly 100 years ago, examination of mammalian embryos revealed the presence of distinct nucleated and enucleated red cells. 4 The continuous circulation of small, enucleated red cells during fetal and postnatal life was termed "definitive" erythropoiesis. Definitive erythropoiesis in the fetus is preceded by a "primitive" erythroid program that is characterized by the transient circulation of large, nucleated red cells that originate extraembryonically in the yolk sac. 4,5 Because primitive erythroblasts in mammals circulate as nucleated cells and are confined to the embryo, they have been thought to share many characteristics with the nucleated red cells of nonmammalian vertebrates when compared with the enucleated definitive red cells of fetal and adult mammals. 6,7 In the mouse embryo, primitive erythroid cells begin to develop in yolk sac blood islands between embryonic days 7 and 8 (E7-8). 8,9 With the onset of cardiac contractions at early somite pair stages (E8.25), primitive erythroblasts enter the embryonic bloodstream 10,11 where they remain until E16.5 when the primitive lineage was thought to be extinguished. 12,13 Definitive erythrocytes begin to emerge from the fetal liver at E12.5 13,14 and rapidly become the predominant cell type in the circulation. Definitive red cells can be distinguished from their primitive counterparts by their smaller size and by their accumulation of adult, but not embryonic, hemoglobins. 6,13,15 In contrast, primitive erythroblasts in the mouse are large cells that accumulate both embryonic and adult hemoglobins. [15][16][17] More than 30 years ago, a population of enucleated red cells with the same hemoglobin content as primitive erythroblasts was described in the embryonic circulation of the mouse. 14 Furthermore, large enucleated red cells have been noted in t...

Maturation and enucleation of primitive erythroblasts during mouse embryogenesis is accompanied by changes in cell-surface antigen expression

“…In the mouse, more than 6 million EryPs are found in the circulation by E14.5. 6 At this stage, active production of definitive erythroid cells from hematopoietic stem cells is in progress in the fetal liver. A major technical hurdle in the analysis of primitive erythropoiesis has been the lack of a method for the rapid and quantifiable segregation of EryPs from EryDs.…”

“…Thus, the maturation of primitive erythroblasts is developmentally synchronized. The final product of the enucleation process 6 is a primitive reticulocyte. Unexpectedly, 1,2 we find that EryPs are not a transient population in the embryo; rather, their For personal use only.…”

“…1 Recently, however, it was discovered that primitive erythroblasts also enucleate, beginning around E12.5 in the mouse embryo and continuing throughout gestation. 6 The developmental origins of EryPs are poorly defined. Yolk sac and fetal liver erythroid cells are derived from distinct populations of mesoderm during gastrulation.…”

Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

“…This shift of erythropoiesis from one tissue to another and the change in globin-gene expression are common features of vertebrate erythropoiesis. Mouse and human definitive erythrocytes in the peripheral blood are enucleated, whereas primitive erythrocytes have a nucleus when they are released from yolk sac and complete their maturation (enucleation) while circulating 9,10 .…”

Hematopoietic stem cells: generation and self-renewal

“…4 Primitive erythroid cells, the first blood cells formed within the blood islands, are large, nucleated red blood cells resembling the erythrocytes of lower vertebrates. These cells, which eventually enucleate after entering the circulation, 5 contain specialized isoforms of hemoglobin that function optimally in the embryonic environment. The erythroid progenitors that give rise to primitive red blood cells can be cultured and will form colonies of erythroid cells in vitro; these primitive erythroid colony-forming cells (CFC) are termed EryP-CFC.…”