The Modern Primitives: Applying New Technological Approaches to Explore the Biology of the Earliest Red Blood Cells

Abstract

One of the most critical stages in mammalian embryogenesis is the independent production of the embryo's own circulating, functional red blood cells. Correspondingly, erythrocytes are the first cell type to become functionally mature during embryogenesis. Failure to achieve this invariably leads to in utero lethality. The recent application of technologies such as transcriptome analysis, flow cytometry, mutant embryo analysis, and transgenic fluorescent gene expression reporter systems has shed new light on the distinct erythroid lineages that arise early in development. Here, I will describe the similarities and differences between the distinct erythroid populations that must form for the embryo to survive. While much of the focus of this review will be the poorly understood primitive erythroid lineage, a discussion of other erythroid and hematopoietic lineages, as well as the cell types making up the different niches that give rise to these lineages, is essential for presenting an appropriate developmental context of these cells.

Circulating primitive erythroblasts establish a functional, protein 4.1R-dependent cytoskeletal network prior to enucleating

“…However, there are also significant differences between these lineages, including cell size, hemoglobin content, and the predominant expression of embryonic versus adult hemoglobins 10, 11 . Importantly, primitive erythroblasts mature intravascularly, unlike definitive erythroblasts that mature extravascularly before entering the bloodstream as reticulocytes.…”

“…Maturing primitive and definitive erythroblasts share many features, including a progressive decrease in cell size, the accumulation of hemoglobin, nuclear condensation and, ultimately, enucleation to form mature erythrocytes. However, there are also significant differences between these lineages, including cell size, hemoglobin content, and the predominant expression of embryonic versus adult hemoglobins 10 , 11 . Importantly, primitive erythroblasts mature intravascularly, unlike definitive erythroblasts that mature extravascularly before entering the bloodstream as reticulocytes.…”

Gastrokine-2 is transiently expressed in the endodermal and endothelial cells of the maturing mouse yolk sac

“…The YS also serves as a niche for blood cell production from E7.5 in the Mus musculus conceptus (Fraser, 2013;Palis and Yoder, 2001).…”

CD71high population represents primitive erythroblasts derived from mouse embryonic stem cells

“…These data clearly demonstrate that EryPs in the CD71 high population are the dominant blood lineage. As previously reported, EryPs differ significantly from EryDs in size, globin expression, and transcriptional regulation (Baron et al, 2012;Fraser, 2013;Palis et al, 2010). The molecular mechanisms underlying these differences are however only partially described because significant amounts of EryPs are required for such mechanistic investigation.…”

“…They play critical roles in the transport of oxygen and carbon dioxide throughout embryos, as well as in facilitating vascular remodeling. EryPs distinguish from definitive erythroblasts (EryDs) in their larger size, unique globin expression, and oxygen carrying capacity (Baron et al, 2012;Fraser, 2013;Palis et al, 2010). In addition, although both lineages share a number of common regulators such as GATA1 and Klf1, recent transcriptome analyses have demonstrated that several transcriptional regulators are expressed at much higher levels in EryPs than those in EryDs, including Pbx1, Foxh1, Arid3a, Pdlim7, and Cited2 (Isern et al, 2011;Kingsley et al, 2013).…”