title: Zebrafish mll gene is essential for hematopoiesis.
abstract: Studies implicate an important role for the mixed lineage leukemia (Mll) gene in hematopoiesis, mainly through maintaining Hox gene expression. However, the mechanisms underlying Mll-mediated hematopoiesis during embryogenesis remain largely unclear. Here, we investigate the role of mll during zebrafish embryogenesis, particularly hematopoiesis. Mll depletion caused severe defects in hematopoiesis as indicated by a lack of blood flow and mature blood cells as well as a significant reduction in expression of hematopoietic progenitor and mature blood cell markers. Furthermore, mll depletion prevented the differentiation of hematopoietic progenitors. In addition, we identified the N-terminal mini-peptide of Mll that acted as a dominant negative form to disrupt normal function of mll during embryogenesis. As expected, mll knockdown altered the expression of a subset of Hox genes. However, overexpression of these down-regulated Hox genes only partially rescued the blood deficiency, suggesting that mll may target additional genes to regulate hematopoiesis. In the mll morphants, microarray analysis revealed a dramatic up-regulation of gadd45αa. Multiple assays indicate that mll inhibited gadd45αa expression and that overexpression of gadd45αa mRNA led to a phenotype similar to the one seen in the mll morphants. Taken together, these findings demonstrate that zebrafish mll plays essential roles in hematopoiesis and that gadd45αa may serve as a potential downstream target for mediating the function of mll in hematopoiesis.
authors.affiliation: Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wan
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Jing-xia
authors.initials: JX
authors.lastname: Liu
authors.forename: Xi
authors.initials: X
authors.lastname: Feng
authors.forename: Wuhan
authors.initials: W
authors.lastname: Xiao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001775:Blood Circulation / Q000187:drug effects; D017124:Conserved Sequence / Q000235:genetics; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000187:drug effects / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D016376:Oligonucleotides, Antisense; D010455:Peptides; D029961:Zebrafish Proteins; D000097642:GADD45 Proteins