Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression
- 31 May 2012
- journal article
- Published by American Society of Hematology in Blood
- Vol. 119 (22), 5239-5249
- https://doi.org/10.1182/blood-2011-12-398362
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 uncover 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.This publication has 51 references indexed in Scilit:
- Development of multilineage adult hematopoiesis in the zebrafish with a runx1 truncation mutationBlood, 2010
- Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBIDevelopment, 2009
- Identification and real-time imaging of a myc-expressing neutrophil population involved in inflammation and mycobacterial granuloma formation in zebrafishDevelopmental & Comparative Immunology, 2008
- Definitive hematopoiesis initiates through a committed erythromyeloid progenitor in the zebrafish embryoDevelopment, 2007
- Initiation of zebrafish haematopoiesis by the TATA-box-binding protein-related factor Trf3Nature, 2007
- The zebrafish lysozyme C promoter drives myeloid-specific expression in transgenic fishBMC Developmental Biology, 2007
- Targeting neural circuitry in zebrafish using GAL4 enhancer trappingNature Methods, 2007
- The 5′ zebrafish scl promoter targets transcription to the brain, spinal cord, and hematopoietic and endothelial progenitorsDevelopmental Dynamics, 2005
- Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1Nature Genetics, 2004
- Requirement of Transcription Factor PU.1 in the Development of Multiple Hematopoietic LineagesScience, 1994