Runx1可通过一个抑制Pu.1表达的负反馈环路来调节胚胎髓细胞命运选择

State Key Laboratory of Molecular Neuroscience, Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

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.

Zhang, W.; Guangdong Higher Education Institutes, Department of Cell Biology, Southern Medical University, Guangzhou 510515, China; email: zzwwqq@smu.edu.cn