IntroductionMyeloid cells or phagocytes are a subtype of leukocytes that play essential roles in the host defense, embryogenesis, organogenesis, and tissue regeneration. [1][2][3] In vertebrates, myeloid cells are classified into 2 major lineages: polymorphonuclear and mononuclear lineages, which acquire different morphologies during development and exert overlapping but distinctive biologic functions. Polymorphonuclear phagocytes consist of neutrophils, eosinophils, basophils, and mast cells. They are the key effectors of inflammatory response on pathogen infection and tissue injury. On the other hand, mononuclear phagocytes, which include circulating macrophages, dendritic cells, and tissue-resident macrophages (osteoclasts in the bone, microglia in the brain, and Kupffer cells in the liver), not only play important roles in inflammatory response but also participate in organogenesis and tissue regeneration. 2,3 Despite differences in morphology and biologic function, polymorphonuclear and mononuclear phagocytes are thought to derive from a common myeloid-restricted population termed neutrophil-macrophage progenitors. 4 These multipotent neutrophil-macrophage progenitors then differentiate to macrophage-dendritic cell progenitors, neutrophil-macrophage progenitors, and basophil-mast cell bipotent progenitors, which in turn undergo terminal differentiation to produce mature dentritic cells, macrophages, neutrophils, basophils, and mast cells. 5 This developmental process is tightly controlled, and dysregulation of phagocyte development and function is associated with several human diseases, including cancer, autoimmune disorders, and neurodegenerative disorders.Interferon regulatory factor-8 (IRF8), also known as the interferon consensus sequence-binding protein, was first identified through screening mouse expression libraries with interferon consensus sequence as a probe. 6 It encodes a transcription factor of IRF family, which contains a highly conserved N-terminal DNA-binding domain and a less conserved C-terminal IRF association domain. 7 Among the 9 members of the mammalian IRF family, IRF4 and IRF8 share the highest similarity in protein sequence and they are predominantly expressed in lymphocytes, macrophages, and dendritic cells. 8 The importance of IRF8 in hematopoiesis is first revealed by genetic studies in IRF8 knockout (IRF8-null) 9 and BXH-2 mutant mice, which carry a loss-of-function mutation in the IRF association domain of IRF8 protein. 10 Both IRF8-null and BXH-2 mutant mice have chronic myeloid leukemia with a profound increase of neutrophil number. 9,10 In addition, loss-of-function mutation in IRF8 gene in these animals also causes a severe reduction of macrophages and dendritic cells. [10][11][12][13] These in vivo studies reveal that IRF8 is essential for myeloid progenitor differentiation toward macrophages but is dispensable for neutrophil development during adult murine myelopoiesis. Subsequent study shows that forced expression of IRF8 in IRF8-deficient myeloid progenitor cell line p...

The development of vertebrate definitive hematopoiesis is featured by temporally and spatially dynamic distribution of hematopoietic stem/progenitor cells (HSPCs). It is proposed that the migration of definitive HSPCs, at least in part, accounts for this unique characteristic; however, compelling in vivo lineage evidence is still lacking. Here we present an in vivo analysis to delineate the migration route of definitive HSPCs in the early zebrafish embryo. Cell-marking analysis was able to first map definitive HSPCs to the ventral wall of dorsal aorta (DA). These cells were subsequently found to migrate to a previously unappreciated organ, posterior blood island (PBI), located between the caudal artery and caudal vein, and finally populate the kidney, the adult hematopoietic organ. IntroductionThe ontogeny of vertebrate hematopoietic system is characterized by 2 phases of development: an early transitory primitive wave generating only primitive erythrocytes and some myeloid cells, and a definitive wave that initiates late and produces all the mature blood lineages (erythroid, myeloid, and lymphoid). [1][2][3][4] In vertebrates, the first hematopoietic activity can be identified in an extra-embryonic location: yolk sac in mice and chickens, or ventral blood island (VBI) in amphibians, leading to the hypothesis that yolk sac/VBI is the sole source of hematopoietic cells, which will in turn populate downstream hematopoietic compartments. 5 However, the singular hematopoietic origin from yolk sac/VBI is challenged by substantial evidence from experiments with various species that reveals another evolutionary conserved intraembryonic hematopoietic site: the para-aortic splanchnopleurae (pSP) and later referred as aorta-gonad-mesonephros (AGM). [6][7][8][9][10][11] Hence, it is currently believed that yolk sac/VBI mainly supports primitive hematopoiesis, whereas definitive hematopoiesis is autonomously initiated, at least in part, in the pSP/AGM region.The journey of definitive HSPCs is best characterized both temporally and spatially in mice. 4 Although multipotential hematopoietic progenitor cells revealed by in vitro colony assays, injection into yolk sac cavity, transplantation into fetal liver of newborn mice or reconstitution of immunodeficient mice, can be detected in the pSP/AGM region and yolk sac at earlier developmental stages, 12-15 the first definitive HSPCs, defined as cells fully competent to provide long-term reconstitution of irradiated adult recipients, emerge in the pSP/AGM region at embryonic day (E) 10.5. 6,9,11 Subsequently, at around E11.0, definitive HSPC activity can be found in yolk sac. 6,9,11 Recently, placenta is recognized as another embryonic reservoir from E10.5 for definitive HSPCs operation. 16,17 However, the cellular origin of definitive HSPCs in yolk sac and placenta and their contribution to adult hematopoiesis are not clear. From E11.5, fetal liver begins to be populated by definitive HSPCs and serves as the main site that supports hematopoietic expansion and differentiation dur...

The cytoplasmic domains of UNC5 are responsible for its netrin-mediated signaling events in axonal migrations, blood vessel patterning, and apoptosis, although the molecular mechanisms governing these processes are unknown. To provide a foundation for the elucidation of the UNC5-mediated signaling mechanism, we determined the crystal structure of the cytoplasmic portion of UNC5b. We found that it contains three distinctly folded domains, namely ZU5, UPA, and death domain (DD). These three domains form a structural supramodule, with ZU5 binding to both UPA and DD, thereby locking the ZU5-UPA-DD supramodule in a closed conformation and suppressing its biological activities. Release of the closed conformation of the ZU5-UPA-DD supramodule leads to the activation of the receptor in the promotion of apoptosis and blood vessel patterning. Finally, we provide evidence showing that the supramodular nature of UNC5 ZU5-UPA-DD is likely to be shared by the ankyrin and PIDD families of scaffold proteins.