The Neural Crest as the First Production Site of the Erythroid Growth Factor Erythropoietin

Abstract

While the neural crest is considered the fourth germ layer that originates a variety of tissues during mammalian development, we recently discovered that some neural crest cells and neuroepithelial cells play a unique role in secreting a vital hematopoietic hormone, erythropoietin (EPO), in mouse embryos. EPO production by the neural crest is transient in mid-stage embryos but essential for the first erythropoiesis in the yolk sac and for sufficient oxygen supply in the whole embryo growing in utero. The site of EPO production shifts from the neural crest to the liver in late embryonic stages, followed by interstitial fibroblasts of the kidneys in adults. Interestingly, the transition of EPO production sites synchronizes with the transition of erythropoietic sites during mouse development from the yolk sac and the fetal liver to the bone marrow. EPO produced by the neural crest and the neuroepithelium is first stored around the production sites and delivered to the yolk sac as an endocrine hormone for erythropoiesis after heartbeat activation. The fact that EPO is produced by some human cell lines derived from neuroblastoma, which mainly originates from the neural crest, provides evidence that the neural crest secretes EPO for primitive erythropoiesis not only in mouse but also in human embryos. Here, we introduce and discuss recent progress in studies on the mechanism of EPO production by the neural crest and its roles in erythropoietic development and in the fate of EPO-producing neural crest cells.

Keywords: REP cell; erythropoiesis; erythropoietin; hypoxia; reporter mice.

FIGURE 1

The EPO-producing cells and the erythropoietic sites in mouse development. The sites of EPO production (green) and erythropoiesis (red) during mouse development between E7.5 and E12.0. Circulation (yellow) is gradually activated around E9.0. Arrows and arrowheads indicate EPO secretion and cell migration, respectively. Note that the primitive erythroid cells are generated in the yolk sac in an EPO-independent manner until the initiation of active circulation.

FIGURE 2

NEP cells and their derivatives in mouse embryos. (A) EpoGFP transgene expression (green) around the neural fold of an E8.5 embryo. Fluorescent (left) and bright-field (right) images are shown. (B) Epo mRNA expression (brown) in the neural tube of an E9.5 embryo. Hematoxylin was used to counterstain the section applied for in situ hybridization. (C,D) Cre transgenes expressed under the Wnt1- (C) and Mpz- (D) gene regulation label the neural crest cells with tdTomato reporter expression (red) in mouse embryos at E9.5 (C) and E10.5 (D). EpoGFP transgene expression (green) is detected in tdTomato-positive neural crest cells (arrowheads) migrating from dorsal (upper) to ventral (lower) regions in the intersomatic spaces. (E) Tracing the cell fate of NEP cells in mouse embryos. EpoCre transgene-mediated tdTomato expression (red) traces the cell fate of NEP cells in an E15.5 embryo. Fluorescent (left) and bright-field (right) images are shown. (F) The Neplic cell line established from the tdTomato-positive brain cells of the embryo shown in E.