Fig. 5. Migratory and circulatory routes that connect fetal hematopoietic sites. The primitive streak (gray) gives rise to the hemogenic mesoderm/hemangioblasts that migrate into the yolk sac (yellow), paraaortic splanchnopleurae (pSP)/aorta-gonadmesonephros (AGM) region (green) and possibly through the allantois to the placenta (blue). Hematopoietic specification most probably occurs during the migratory process. The two main circulatory routes that connect fetal hematopoietic organs during midgestation are vitelline and umbilical circuits. The vitelline artery connects the upper dorsal aorta to the yolk sac, which connects to the fetal liver (red) via the vitelline vein. The umbilical artery connects the caudal part of dorsal aorta to the placenta, which connects to the liver via the umbilical vein. Although budding into the lumen and seeding through circulation has been hypothesized as the main route by which nascent HSCs seed the fetal liver, direct migration of hematopoietic stem cells (HSCs) from the AGM to the fetal liver has not been formally excluded (indicated by `?'). Broken arrows indicate the migration of HSC precursors and unbroken arrows indicate circulation of HSCs through vasculature. Bone marrow (orange) is seeded by HSCs before birth. Larger black arrows indicate major HSC trafficking. The timing of these events is outlined by the timescale in embryonic days below.