ZFIN ID: ZDB-PUB-110803-6
Zebrafish mll is essential for haematopoiesis
Wan, X., Hu, B., Liu, J.X., Feng, X., and Xiao, W.
Date: 2011
Source: The Journal of biological chemistry   286(38): 33345-57 (Journal)
Registered Authors: Feng, Xi, Hu, Bo, Liu, Jing-xia, Wan, Xiaoyang, Xiao, Wuhan
Keywords: development, gene regulation, hematopoiesis, leukemia, zebrafish, gadd45aa, hox, mll
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Biomarkers/metabolism
  • Blood Circulation/drug effects
  • Conserved Sequence/genetics
  • Embryonic Development/drug effects
  • Embryonic Development/genetics
  • Evolution, Molecular
  • Gene Expression Regulation, Developmental/drug effects
  • Gene Knockdown Techniques
  • Hematopoiesis/drug effects
  • Hematopoiesis/genetics*
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/drug effects
  • Hematopoietic Stem Cells/metabolism
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/metabolism
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Molecular Sequence Data
  • Morphogenesis/drug effects
  • Morphogenesis/genetics
  • Myeloid-Lymphoid Leukemia Protein/chemistry
  • Myeloid-Lymphoid Leukemia Protein/genetics*
  • Myeloid-Lymphoid Leukemia Protein/metabolism
  • Oligonucleotides, Antisense/pharmacology
  • Peptides/metabolism
  • Zebrafish/genetics*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed: 21784840 Full text @ J. Biol. Chem.
Studies implicate an important role for the mixed lineage leukemia (Mll) gene in haematopoiesis, mainly through maintaining Hox gene expression. However, the mechanisms underlying Mll-mediated haematopoiesis during embryogenesis remain largely unclear. Here, we investigate the role of mll during zebrafish embryogenesis, in particular, haematopoiesis. Mll depletion caused severe defects in haematopoiesis 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 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 haematopoiesis. 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 haematopoiesis and that gadd45αa may serve as a potential down-stream target for mediating mll function in haematopoiesis.