PUBLICATION

Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression

Authors
Jin, H., Li, L., Xu, J., Zhen, F., Zhu, L., Liu, P.P., Zhang, M., Zhang, W., and Wen, Z.
ID
ZDB-PUB-120412-13
Date
2012
Source
Blood   119(22): 5239-5249 (Journal)
Registered Authors
Li, Li, Liu, Pu Paul, Wen, Zilong, Zhang, Wenqing
Keywords
none
MeSH Terms
  • Animals
  • Core Binding Factor Alpha 2 Subunit/biosynthesis*
  • Core Binding Factor Alpha 2 Subunit/genetics
  • Gene Expression Regulation, Developmental/physiology*
  • Macrophages/cytology
  • Macrophages/metabolism
  • Myelopoiesis/physiology*
  • Neutrophils/cytology
  • Neutrophils/metabolism
  • Proto-Oncogene Proteins/biosynthesis*
  • Proto-Oncogene Proteins/genetics
  • Trans-Activators/biosynthesis*
  • Trans-Activators/genetics
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/biosynthesis*
  • Zebrafish Proteins/genetics
PubMed
22493295 Full text @ Blood
Abstract

Proper cell fate choice in myelopoiesis is essential for generating correct numbers of distinct myeloid subsets manifesting a wide spectrum of subset-specific activities during development and adulthood. Studies have suggested that myeloid fate choice is primarily regulated by transcription factors; however, new intrinsic regulators and their underlying mechanisms remain to be elucidated. Zebrafish embryonic myelopoiesis gives rise to neutrophils and macrophages and represents a promising system to derive new regulatory mechanisms for myeloid fate decision in vertebrates. Here we present an in vivo study of cell fate specification during zebrafish embryonic myelopoiesis through characterization of the embryos with altered Pu.1, Runx1 activity alone or their combinations. Genetic analysis shows that low and high Pu.1 activities determine embryonic neutrophilic granulocyte and macrophage fate, respectively. Inactivation and overexpression of Runx1 in zebrafish uncovers Runx1 as a key embryonic myeloid fate determinant that favors neutrophil over macrophage fate. Runx1 is induced by high Pu.1 level and in turn transrepresses pu.1 expression, thus constituting a negative feedback loop that fashions a favorable pu.1 level required for balanced fate commitment to neutrophils versus macrophages. Our findings define a Pu.1-Runx1 regulatory loop that governs the equilibrium between distinct myeloid fates by assuring an appropriate Pu.1 dosage.

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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping