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. 1. Historical Backdrop Early in the 1900s, advances in microscopy and histology lead to a golden era of investigation into the processes regulating embryonic blood production. Pioneers such as Maximov, Sabin, and Jordan published a series of monographs describing blood cell production in the vertebrate embryo [1–3]. Much attention was focused on the unusually intimate relationship between developing endothelial cells and hematopoietic cells with the term hemogenic endothelium appearing at this time (reviewed in [4]). A distinct population of erythroid cells was identified and categorized as “megaloblasts”. These nucleated cells appeared to carry hemoglobin but were larger than the conventional anuclear red blood cells observed in the adult. These cells were first detected in the extra-embryonic yolk sac. Due to these characteristics, as well as their similarities to nonmammalian vertebrate erythrocytes, these cells were termed primitive erythroid cells [1] (which is often abbreviated to EryP). The distinctions between EryP and adult-type definitive erythroid cells (EryD) is the main focus of this review. The epithet “primitive” has proven to be somewhat distracting as hematopoietic stem cells with extensive self-renewing potential are also often referred to as being “primitive”. This review is focused on the primitive erythroid lineage originating in the yolk sac. This task however cannot be performed in isolation, and as such other blood cells and hematopoietic tissues will be discussed. 2. The Anatomy of Embryonic Blood
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