Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation

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Abstract

Reactive oxygen species (ROS), produced during various electron transfer reactions in vivo, are generally considered to be deleterious to cells1. In the mammalian haematopoietic system, haematopoietic stem cells contain low levels of ROS. However, unexpectedly, the common myeloid progenitors (CMPs) produce significantly increased levels of ROS2. The functional significance of this difference in ROS level in the two progenitor types remains unresolved2,3. Here we show that Drosophila multipotent haematopoietic progenitors, which are largely akin to the mammalian myeloid progenitors4, display increased levels of ROS under in vivo physiological conditions, which are downregulated on differentiation. Scavenging the ROS from these haematopoietic progenitors by using in vivo genetic tools retards their differentiation into mature blood cells. Conversely, increasing the haematopoietic progenitor ROS beyond their basal level triggers precocious differentiation into all three mature blood cell types found in Drosophila, through a signalling pathway that involves JNK and FoxO activation as well as Polycomb downregulation. We conclude that the developmentally regulated, moderately high ROS level in the progenitor population sensitizes them to differentiation, and establishes a signalling role for ROS in the regulation of haematopoietic cell fate. Our results lead to a model that could be extended to reveal a probable signalling role for ROS in the differentiation of CMPs in mammalian haematopoietic development and oxidative stress response.

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Figure 1: ROS profile of third-instar lymph glands.
Figure 2: Increased ROS production triggers precocious differentiation of the multipotent progenitors.
Figure 3: Disrupting JNK signalling suppresses the ROS-dependent differentiation phenotype.
Figure 4: FoxO activation and Polycomb downregulation phenocopy aspects of the ROS-induced differentiation.

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Acknowledgements

We thank I. Ando and H. Muller for antibodies, and E. Hafen, A. Martinez-Arias, F. Missirlis, S. Noselli, R. Paro, S Sinenko, the National Institute of Genetics Fly Stock Center (Japan) and the Bloomington Stock Center for fly stocks. We acknowledge M. Kulkarni and C. Pitsouli of the Perrimon laboratory for technical assistance. Owing to space limitations, we apologize to our colleagues whose work is not referenced. This study was supported by US National Institutes of Health grant R01HL067395 to U.B. and a T32 institutional postdoctoral fellowship T32-HL069766 to E.O.-A.

Author Contributions U.B. supervised the project. E.O.-A. conceived, designed and performed all experiments. E.O.-A. and U.B. discussed results and wrote the manuscript.

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Correspondence to Utpal Banerjee.

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Owusu-Ansah, E., Banerjee, U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537–541 (2009) doi:10.1038/nature08313

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