Runx1 regulates zebrafish neutrophil maturation via synergistic interaction with c-Myb

Abstract

Neutrophils play an essential role in the innate immune defense system in vertebrates. During hematopoiesis, the full function of neutrophils involves maturation of granules and related enzymes. Yet, transcription regulators that promote neutrophil maturation remain largely undefined. Here, two hematopoiesis-defective zebrafish mutants, runx1w84x and c-mybhkz3, were used to investigate the in vivo roles of Runx1 in cooperation with c-Myb in regulating neutrophil maturation. Loss of runx1 impairs primitive neutrophil development. Additional regulation of c-myb+/− and c-myb−/− induces a more severe phenotypes suggesting a synergistic genetic interaction between c-myb and runx1 in neutrophil maturation. Further studies revealed that the two transcription factors act cooperatively to control neutrophil maturation processes via transactivating a series of neutrophil maturation-related genes. These data reveal the in vivo roles of Runx1 in regulating primitive neutrophil maturation while also indicating a novel genetic and molecular orchestration of Runx1 and c-Myb in myeloid cell development. The study will provide new evidence on the regulation of neutrophil maturation during hematopoiesis. Neutrophils play an essential role in the innate immune defense system in vertebrates. During hematopoiesis, the full function of neutrophils involves maturation of granules and related enzymes. Yet, transcription regulators that promote neutrophil maturation remain largely undefined. Here, two hematopoiesis-defective zebrafish mutants, runx1w84x and c-mybhkz3, were used to investigate the in vivo roles of Runx1 in cooperation with c-Myb in regulating neutrophil maturation. Loss of runx1 impairs primitive neutrophil development. Additional regulation of c-myb+/− and c-myb−/− induces a more severe phenotypes suggesting a synergistic genetic interaction between c-myb and runx1 in neutrophil maturation. Further studies revealed that the two transcription factors act cooperatively to control neutrophil maturation processes via transactivating a series of neutrophil maturation-related genes. These data reveal the in vivo roles of Runx1 in regulating primitive neutrophil maturation while also indicating a novel genetic and molecular orchestration of Runx1 and c-Myb in myeloid cell development. The study will provide new evidence on the regulation of neutrophil maturation during hematopoiesis. Neutrophils are the most abundant phagocytes essential for the first line of defense in the innate immune system. Mature neutrophils play an important role in pathogen clearance, response to tissue injury, and in mediating the inflammatory response (1Kruger P. Saffarzadeh M. Weber A.N. Rieber N. Radsak M. von Bernuth H. Benarafa C. Roos D. Skokowa J. Hartl D. Neutrophils: Between host defence, immune modulation, and tissue injury.PLoS Pathog. 2015; 11e1004651Crossref PubMed Scopus (335) Google Scholar). Dysregulation of granulopoiesis can cause neutropenia, myeloid leukemia, or neutrophil function disorders (2Borregaard N. Neutrophils, from marrow to microbes.Immunity. 2010; 33: 657-670Abstract Full Text Full Text PDF PubMed Scopus (839) Google Scholar, 3Galli S.J. Borregaard N. Wynn T.A. Phenotypic and functional plasticity of cells of innate immunity: Macrophages, mast cells and neutrophils.Nat. Immunol. 2011; 12: 1035Crossref PubMed Scopus (637) Google Scholar, 4Mantovani A. Cassatella M.A. Costantini C. Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity.Nat. Rev. Immunol. 2011; 11: 519-531Crossref PubMed Scopus (1675) Google Scholar, 5Amulic B. Cazalet C. Hayes G.L. Metzler K.D. Zychlinsky A. Neutrophil function: From mechanisms to disease.Annu. Rev. Immunol. 2012; 30: 459Crossref PubMed Scopus (942) Google Scholar, 6Bellissimo D.C. Speck N.A. RUNX1 mutations in inherited and sporadic leukemia.Front. Cell Dev. Biol. 2017; 5: 111Crossref PubMed Scopus (31) Google Scholar, 7Mangan J.K. Speck N.A. RUNX1 mutations in clonal myeloid disorders: From conventional cytogenetics to next generation sequencing, a story 40 years in the making.Crit. Rev. Oncog. 2011; 16: 77-91Crossref PubMed Scopus (64) Google Scholar). Thus, understanding how neutrophils differentiate into functional mature cells might facilitate the development of new therapeutic strategies for the treatment of neutrophil-related disorders. The function of mature neutrophils requires the development of characteristic neutrophil granules along with stored enzymes. These neutrophil-specific elements are formed at different stages during neutrophil maturation. Mammalian neutrophils contain four types of granules: azurophil granules, specific granules, gelatinase granules, and secretory granules. Each subtype of granule contains highly specific storage proteins that carry out different immune functions (8Pham C.T. Neutrophil serine proteases: Specific regulators of inflammation.Nat. Rev. Immunol. 2006; 6: 541-550Crossref PubMed Scopus (685) Google Scholar). Neutrophil granule subtypes are released in order to lyse and eradicate microbes when neutrophils are activated during infections (2Borregaard N. Neutrophils, from marrow to microbes.Immunity. 2010; 33: 657-670Abstract Full Text Full Text PDF PubMed Scopus (839) Google Scholar). Digestive enzymes are key components in neutrophil granules. For example, lysozyme C (Lyz), is a key bactericidal enzyme found in all types of neutrophil granules, and myeloperoxidase (Mpx) is an abundant peroxidase stored in neutrophil azurophilic granules (2Borregaard N. Neutrophils, from marrow to microbes.Immunity. 2010; 33: 657-670Abstract Full Text Full Text PDF PubMed Scopus (839) Google Scholar). Sorting and packing neutrophil granule proteins by proteoglycans, such as serglycin (Srgn), are essential for neutrophil differentiation (9Niemann C.U. Cowland J.B. Klausen P. Askaa J. Calafat J. Borregaard N. Localization of serglycin in human neutrophil granulocytes and their precursors.J. Leukoc. Biol. 2004; 76: 406-415Crossref PubMed Scopus (39) Google Scholar, 10Niemann C.U. Abrink M. Pejler G. Fischer R.L. Christensen E.I. Knight S.D. Borregaard N. Neutrophil elastase depends on serglycin proteoglycan for localization in granules.Blood. 2007; 109: 4478-4486Crossref PubMed Scopus (77) Google Scholar). Neutrophil maturation requires that these granule-related proteins are properly produced, yet the molecular basis controlling the process remains largely unknown. Several hematopoietic-specific transcription factors are reported to control neutrophil granule-related protein expression. RUNX1 has been described as a pivotal transcription factor during definitive hematopoiesis (11Ezoe S. Matsumura I. Satoh Y. Tanaka H. Kanakura Y. Cell cycle regulation in hematopoietic stem/progenitor cells.Cell Cycle. 2004; 3: 314-318Crossref PubMed Google Scholar, 12Okuda T. Deursen J.V. Hiebert S.W. Grosveld G. Downing R J. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.Cell. 1996; 84: 321Abstract Full Text Full Text PDF PubMed Scopus (1552) Google Scholar, 13Veldhoen M. Ferreira C. Influence of nutrient-derived metabolites on lymphocyte immunity.Nat. Med. 2015; 21: 709-718Crossref PubMed Scopus (41) Google Scholar). In neutrophil development, Runx1 is reported to promote granulocytic over monocytic lineage fate choice in zebrafish (14Jin H. Li L. Xu J. Zhen F. Zhu L. Liu P.P. Zhang M. Zhang W. Wen Z. Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression.Blood. 2012; 119: 5239-5249Crossref PubMed Scopus (61) Google Scholar). Yet, the function of RUNX1 in neutrophil differentiation and maturation is still debatable. It has been reported that RUNX1 could regulate Mpx and Elane transcription in myeloid cell lines (15Nuchprayoon I. Meyers S. Scott L.M. Suzow J. Hiebert S. Friedman A.D. PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells.Mol. Cell. Biol. 1994; 14: 5558-5568Crossref PubMed Google Scholar, 16Austin G.E. Zhao W.G. Regmi A. Lu J.P. Braun J. Identification of an upstream enhancer containing an AML1 site in the human myeloperoxidase (MPO) gene.Leuk. Res. 1998; 22: 1037-1048Crossref PubMed Scopus (19) Google Scholar, 17Brightman D.S. Grant R.L. Ruzycki P.A. Suzuki R. Hennig A.K. Chen S. MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity.Sci. Rep. 2018; 8: 11902Crossref PubMed Scopus (6) Google Scholar). Similarly, recent mouse data demonstrated that RUNX1-haploinsufficient hematopoietic progenitors impaired in vitro differentiation in neutrophils by repressing Cebpe expression (18Ng K.P. Hu Z. Ebrahem Q. Negrotto S. Lausen J. Saunthararajah Y. Runx1 deficiency permits granulocyte lineage commitment but impairs subsequent maturation.Oncogenesis. 2013; 2: e78Crossref PubMed Scopus (14) Google Scholar). However, another study found that conditional ablation of the Runx1 gene in adult mice paradoxically expands myeloid pools to an extent without incurring any discernible differentiation blockage (19Growney J.D. Shigematsu H. Li Z. Lee B.H. Adelsperger J. Rowan R. Curley D.P. Kutok J.L. Akashi K. Williams I.R. Speck N.A. Gilliland D.G. Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype.Blood. 2005; 106: 494-504Crossref PubMed Scopus (347) Google Scholar). Therefore, whether RUNX1 plays roles in granulocyte differentiation and maturation in vivo is still unclear, especially in early developmental stages. We previously showed that lyz is a direct target of c-Myb in regulating neutrophil maturation (20Jin H. Huang Z. Chi Y. Wu M. Zhou R. Zhao L. Xu J. Zhen F. Lan Y. Li L. Zhang W. Wen Z. Zhang Y. c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.Blood. 2016; 128: 415-426Crossref PubMed Scopus (15) Google Scholar). Interestingly, lyz is also a transcriptional target of Runx1 (21Kitaguchi T. Kawakami K. Kawahara A. Transcriptional regulation of a myeloid-lineage specific gene lysozyme C during zebrafish myelopoiesis.Mech. Dev. 2009; 126: 314-323Crossref PubMed Scopus (34) Google Scholar); however, whether RUNX1 participates in neutrophil differentiation and maturation lacks sufficient in vivo evidence. Furthermore, whether the neutrophil maturation process is achieved by the orchestration of these two transcription factors requires genetic verification. Here, we used two hematopoietic-defective zebrafish mutants, runx1w84x (22Jin H. Sood R. Xu J. Zhen F. English M.A. Liu P.P. Wen Z. Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI.Development. 2009; 136: 647-654Crossref PubMed Scopus (70) Google Scholar) and c-mybhkz3 (23Zhang Y. Jin H. Li L. Qin F.X. Wen Z. cMyb regulates hematopoietic stem/progenitor cell mobilization during zebrafish hematopoiesis.Blood. 2011; 118: 4093-4101Crossref PubMed Scopus (55) Google Scholar) to determine the role of Runx1 during neutrophil maturation. These mutants were used to elucidate the genetic interaction of the two transcription factors through genetic epistasis and biochemical analysis. It was found that Runx1 cooperates with c-Myb to control neutrophil maturation in zebrafish embryonic myelopoiesis. This study elucidates the genetic networks that orchestrate primitive myeloid cell development, improving understanding of the of neutrophil-related Mature neutrophils are by abundant granules in the can by (14Jin H. Li L. Xu J. Zhen F. Zhu L. Liu P.P. Zhang M. Zhang W. Wen Z. Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression.Blood. 2012; 119: 5239-5249Crossref PubMed Scopus (61) Google Scholar, K. A. H. P. and of neutrophils in zebrafish.Blood. PubMed Scopus Google Scholar). to the of c-myb−/− mutants in primitive (20Jin H. Huang Z. Chi Y. Wu M. Zhou R. Zhao L. Xu J. Zhen F. Lan Y. Li L. Zhang W. Wen Z. Zhang Y. c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.Blood. 2016; 128: 415-426Crossref PubMed Scopus (15) Google mutants the of neutrophils at (14Jin H. Li L. Xu J. Zhen F. Zhu L. Liu P.P. Zhang M. Zhang W. Wen Z. Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression.Blood. 2012; 119: 5239-5249Crossref PubMed Scopus (61) Google Scholar) the for of the neutrophils was in mutants with that in and suggesting that Runx1 is in neutrophil maturation. mature neutrophils abundant granules in their P. B. C. and of early in the zebrafish 126: PubMed Google Scholar) was used to neutrophil granule and in at in was in neutrophils the control of the neutrophil-specific S. zebrafish of 2006; PubMed Scopus Google Scholar). cell were and the expression was in the mutants, we could still the neutrophils the mutants mature neutrophils in and Mature neutrophils were also by and (20Jin H. Huang Z. Chi Y. Wu M. Zhou R. Zhao L. Xu J. Zhen F. Lan Y. Li L. Zhang W. Wen Z. Zhang Y. c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.Blood. 2016; 128: 415-426Crossref PubMed Scopus (15) Google Scholar, and functional of granulocytes and in embryonic and adult zebrafish.Blood. PubMed Scopus (347) Google Scholar). Therefore, mature and immature neutrophils were by with These studies showed a in mature neutrophils in mutants with and The data that primitive neutrophils were by the runx1 in determine the role of runx1 in with c-myb in neutrophil a genetic was used to the neutrophil phenotypes of runx1 or c-myb mutants with mutants from c-myb+/− were from in the of cells at (20Jin H. Huang Z. Chi Y. Wu M. Zhou R. Zhao L. Xu J. Zhen F. Lan Y. Li L. Zhang W. Wen Z. Zhang Y. c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.Blood. 2016; 128: 415-426Crossref PubMed Scopus (15) Google we on the of mutants and c-myb+/− and mutants to determine whether c-myb+/− more severe of c-myb+/− was into the of cells was the cells Furthermore, the of and showed that the neutrophils in and more immature with granules expression when with and or mutants and determine whether the synergistic regulation by c-Myb and Runx1 has on neutrophil we the of by neutrophils in c-myb+/− the as mutants the with mutants The data that runx1 could with c-myb to neutrophil maturation. to zebrafish neutrophil maturation also neutrophil granule-related components and such as and to properly (2Borregaard N. Neutrophils, from marrow to microbes.Immunity. 2010; 33: 657-670Abstract Full Text Full Text PDF PubMed Scopus (839) Google Scholar, S. G. Y. S. I. I. D. H. of gene expression to hematopoietic and Immunol. 2018; PubMed Scopus Google Scholar). It has been reported that zebrafish lyz is by c-Myb (20Jin H. Huang Z. Chi Y. Wu M. Zhou R. Zhao L. Xu J. Zhen F. Lan Y. Li L. Zhang W. Wen Z. Zhang Y. c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.Blood. 2016; 128: 415-426Crossref PubMed Scopus (15) Google Scholar) and by Runx1 (21Kitaguchi T. Kawakami K. Kawahara A. Transcriptional regulation of a myeloid-lineage specific gene lysozyme C during zebrafish myelopoiesis.Mech. Dev. 2009; 126: 314-323Crossref PubMed Scopus (34) Google but whether lyz could by c-Myb and Runx1 in vivo is the in was to lyz between previously showed that c-myb−/− cells (20Jin H. Huang Z. Chi Y. Wu M. Zhou R. Zhao L. Xu J. Zhen F. Lan Y. Li L. Zhang W. Wen Z. Zhang Y. c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.Blood. 2016; 128: 415-426Crossref PubMed Scopus (15) Google Scholar) and that the between and were and These that c-myb deficiency when the runx1 gene is In the cells to of in the cells in mutants were when of c-myb+/− was as the cell was from in to in and The data a synergistic regulation of the two transcription factors on the expression of neutrophil maturation requires expression of was that the synergistic of c-myb and runx1 are for as as for related genes. Mpx and are neutrophil-specific used for host of infections S. G. Y. S. I. I. D. H. of gene expression to hematopoietic and Immunol. 2018; PubMed Scopus Google Scholar, K. N. Q. Huang Z. Liu W. Xu M. Chen Zhang W. Zhang Y. zebrafish an inflammatory response to with Immunol. 2015; PubMed Scopus (15) Google Scholar). Similarly, and cells were when or two of the c-myb were in mutants and and the was in c-myb zebrafish mutants (20Jin H. Huang Z. Chi Y. Wu M. Zhou R. Zhao L. Xu J. Zhen F. Lan Y. Li L. Zhang W. Wen Z. Zhang Y. c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.Blood. 2016; 128: 415-426Crossref PubMed Scopus (15) Google suggesting is also by in mutants, cells showed a with c-myb+/− or mutants and and the mutants showed the of expression of genes and The data that is a synergistic regulation of c-myb and runx1 on neutrophil maturation-related genes. these that cooperatively with is essential for neutrophil maturation by regulating neutrophil maturation-related genes. determine whether the four genes and are by c-Myb and the of these genes were It was found that these genes c-Myb and Runx1 were to whether the two transcription factors can to the in were with c-myb or runx1 to c-Myb and Runx1 for in The showed that all of the target genes were an This that these neutrophil-specific genes are all by c-Myb and Runx1 the the in vivo was by neutrophil-specific with c-myb or runx1 in zebrafish by the zebrafish c-Myb lyz transcription (20Jin H. Huang Z. Chi Y. Wu M. Zhou R. Zhao L. Xu J. Zhen F. Lan Y. Li L. Zhang W. Wen Z. Zhang Y. c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.Blood. 2016; 128: 415-426Crossref PubMed Scopus (15) Google Scholar). In the was also found that c-Myb and transcription with c-Myb transcription activation of the four target genes were all by Runx1 This a cooperation of c-Myb and Runx1 on genes. was whether c-Myb and Runx1 in these molecular were in cells with and Cell were an by and in of This cooperation between zebrafish Runx1 and In the was in zebrafish The was with that in the cells the of c-Myb and Runx1 that are for their zebrafish c-Myb and Runx1 proteins were for the The showed that the of c-Myb and of Runx1 are for the interaction and However, the for c-Myb or Runx1 proteins were into c-mybhkz3 and runx1w84x mutants but the could the neutrophil in these two mutants These data that the proteins also the essential functions of these such as The was to whether a on c-myb and runx1 expression in early neutrophil were at a in when zebrafish from the K. A. H. P. and of neutrophils in zebrafish.Blood. PubMed Scopus Google Scholar, B.H. M.A. a site of myeloid development of primitive for Biol. PubMed Scopus Google Scholar). In the c-myb expression was found to in and and runx1 expression was also in c-myb−/− C and These expression data that c-myb and runx1 are of during early neutrophil development. From the genetic epistasis and biochemical can that Runx1 functions as a for neutrophil maturation in early development. In and cooperates with c-Myb to a of neutrophil maturation-related genes In by the zebrafish the in vivo roles of Runx1 were in neutrophil maturation. The demonstrated a genetic and molecular interaction between Runx1 and c-Myb in regulating neutrophil development. These data into the genetic and molecular orchestration in neutrophil maturation. In hematopoiesis, RUNX1 is to function in the of hematopoietic cells T. Deursen J.V. Hiebert S.W. Grosveld G. Downing R J. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.Cell. 1996; 84: 321Abstract Full Text Full Text PDF PubMed Scopus (1552) Google Scholar, Q. T. M. M. Speck N.A. of the gene and in the system and definitive S. A. 1996; PubMed Scopus Google the fate of (14Jin H. Li L. Xu J. Zhen F. Zhu L. Liu P.P. Zhang M. Zhang W. Wen Z. Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression.Blood. 2012; 119: 5239-5249Crossref PubMed Scopus (61) Google and the maturation of and (19Growney J.D. Shigematsu H. Li Z. Lee B.H. Adelsperger J. Rowan R. Curley D.P. Kutok J.L. Akashi K. Williams I.R. Speck N.A. Gilliland D.G. Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype.Blood. 2005; 106: 494-504Crossref PubMed Scopus (347) Google Scholar, M. T. T. S. I. T. K. S. S. M. is for maturation and but for of hematopoietic cells in adult Med. 2004; PubMed Scopus Google Scholar, Y. Huang Z. Chen Q. Chen K. Xu J. Zhang Y. Zhang W. Loss of runx1 function in cell but cell in adult Biol. 2018; 8: PubMed Scopus Google Scholar). RUNX1 is of the most genes in a of such as myeloid and and the new 2015; PubMed Scopus Google Scholar, M. N. K. H. T. H. K. T. K. Y. and mutations in the of the gene associated with PubMed Google Scholar). The of RUNX1 mutations in multiple types of evidence for essential function in lineage development. more translocations that RUNX1 function been most of cause maturation of myeloid cells and N. F. C. M. RUNX1 translocations and genes in 2011; 77-91Crossref PubMed Scopus (64) Google Scholar). studies that RUNX1 is of a transcriptional that regulates important target genes in myelopoiesis. The key that remain to are mechanisms and target genes and and how can used for for these From mouse the role of RUNX1 in primitive is still unknown. The study direct evidence of a novel function of Runx1 and in the primitive neutrophil maturation The of in vivo roles of Runx1 in early myeloid cell development will new on a understanding of Neutrophil maturation requires a of neutrophil granule-related that are while granules are properly The of granule will to immature or neutrophils and In c-myb and runx1 mutants, neutrophil granule was In genes were as as an of the granule and proteoglycan These the of c-Myb and Runx1 cooperatively controlling neutrophil development by transactivating a of neutrophil maturation-related genes. It was also reported that the and of transcription factors all function in genetic networks in A.D. Transcriptional control of granulocyte and 2007; PubMed Scopus Google Scholar, A.D. of immature myeloid cell differentiation by PEBP2/CBF, and Immunol. 1996; Google Scholar, A.D. in normal and J. 2015; PubMed Scopus Google Scholar, S. Chen D.G. of and AML1 in early of multiple myeloid Immunol. 1996; Google Scholar). Thus, how genes are by different transcription factors is of for In these transcription factor function in neutrophils remains to It is that during neutrophil development, transcription factors might in different of neutrophils might activated by the It will important to a target gene of c-Myb and In is to upstream factors and proteins to elucidate the regulation of the neutrophil maturation study has demonstrated the in vivo role of Runx1 in neutrophil maturation during early myelopoiesis. Furthermore, a genetic interaction between the two transcription Runx1 and was to regulate neutrophil maturation through a molecular interaction that functions to regulate genes expression in a This study understanding of the genetic networks that orchestrate primitive myeloid cell development and revealed the molecular basis of neutrophil-related runx1 and c-myb were used in the The were S. zebrafish of 2006; PubMed Scopus Google runx1w84x (22Jin H. Sood R. Xu J. Zhen F. English M.A. Liu P.P. Wen Z. Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI.Development. 2009; 136: 647-654Crossref PubMed Scopus (70) Google and c-mybhkz3 (23Zhang Y. Jin H. Li L. Qin F.X. Wen Z. cMyb regulates hematopoietic stem/progenitor cell mobilization during zebrafish hematopoiesis.Blood. 2011; 118: 4093-4101Crossref PubMed Scopus (55) Google Scholar). runx1w84x a to a in the of the Runx1 This most of the important in Runx1 such as and and localization c-mybhkz3 a that in the of a c-Myb protein were in with the from the and of of were by the of and of of were in containing cells were by and by at for a The were and to to the Each was from and were at to K. A. H. P. and of neutrophils in zebrafish.Blood. PubMed Scopus Google Scholar, M. The for the of of as primitive neutrophils were for of was by and were by and into the the control of the protein with were at for treatment at cells were in with Cell cell and been described M. F. Hu Y. C. Li Z. Wen Z. factor a of Cell Biol. PubMed Scopus Google Scholar). with zebrafish c-myb and zebrafish runx1 were into Cell were with and the were by and of cell used for and were from and was with on to previously described P. B. C. and of early in the zebrafish 126: PubMed Google Scholar). In the neutrophil granule is to with the neutrophil granules are abundant and neutrophils are to by the transcriptional were by were with or at were at for was with or to the described by T. R M. of zebrafish by the factor 2007; PubMed Scopus (64) Google Scholar). The were to could found in The zebrafish were at with and in the with were with and in for in neutrophils was were by the for between two and of with multiple was when are as of the a data or during study are in The or We Kawakami for Liu for and P. Liu for runx1w84x Y. Z. and Z. H. the Z. H. most of the K. C. and Y. C. to the H. J. and L. L. generation and Z. H. and Y. Z. the W. Z. and J. and on the This was by the of and the of and and the for the

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