Discovery of a new path for red blood cell generation in the mouse embryo

Erythropoiesis occurs through several waves during embryonic development. Although the source of the primitive wave is well characterized, the origin of erythrocytes later in embryogenesis is less clear due to overlaps between the different erythroid waves. Using the miR144/451-GFP mouse model to track cells expressing the erythroid microRNAs miR144/451, we identified cells co-expressing VE-Cadherin and GFP in the yolk sac between E9.5 and E12. This suggested the existence of hemogenic endothelial cells committed to erythropoiesis (Ery-HEC). We showed that these cells were capable of generating erythrocytes ex vivo and we demonstrated that the formation of Ery-HEC was independent of the Runx1 gene expression. Using transcriptome analysis, we demonstrated that these cells co-expressed endothelial and erythroid genes such as Hbb-bh1 and Gata1 but we were surprised to detect the primitive erythroid genes Aqp3 and Aqp8 suggesting the formation of primitive erythrocytes at a much later time point than initially thought. Finally, we showed that enforced expression of Gata1 in endothelial cells was enough to initiate the erythroid transcriptional program.