Blood Journal
Leading the way in experimental and clinical research in hematology

miR-142-3p acts as an essential modulator of neutrophil development in zebrafish

  1. Hong-Bo Fan1,2,
  2. Yi-Jie Liu1,3,
  3. Lei Wang1,2,
  4. Ting-Ting Du1,2,
  5. Mei Dong1,2,
  6. Li Gao1,2,
  7. Zhao-Zheng Meng1,2,
  8. Yi Jin1,2,
  9. Yi Chen1,2,
  10. Min Deng1,2,
  11. Huang-Tian Yang1,2,
  12. Qing Jing1,2,
  13. Ai-Hua Gu4,
  14. Ting-Xi Liu1,2, and
  15. Yong Zhou1,2
  1. 1Key Laboratory of Stem Cell Biology and State Key Laboratory for Medical Genomics and Laboratory of Development and Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and
  2. 2Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
  3. 3Department of Laboratory Medicine, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China; and
  4. 4State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China

Key Points

  • The miR-142-3p double mutant zebrafish displayed aberrant neutrophil hypermaturation and homeostasis in myelopoiesis.

  • Abnormal activation of IFN-γ signaling mediated the impaired neutrophil development in miR-142-3p–deficient zebrafish.

Abstract

Neutrophils play critical roles in vertebrate innate immune responses. As an emerging regulator in normal myelopoiesis, the precise roles of microRNA in the development of neutrophils have yet to be clarified. Using zinc-finger nucleases, we have successfully generated heritable mutations in miR-142a and miR-142b and showed that hematopoietic-specific miR-142-3p is completely deleted in miR-142 double mutant zebrafish. The lack of miR-142-3p resulted in aberrant reduction and hypermaturation of neutrophils in definitive myelopoiesis, as well as impaired inflammatory migration of neutrophils in the fetal stage. Furthermore, the adult myelopoiesis in the miR-142-3p–deficient zebrafish was also affected, producing irregular hypermature neutrophils with increased cell size and a decreased nucleocytoplasmic ratio. Additionally, miR-142-3p–deficient zebrafish are expected to develop a chronic failure of myelopoiesis with age. Transcriptome analysis showed an aberrant activation of the interferon γ (IFN-γ) signaling pathway in myelomonocytes after miR-142-3p deletion. We found that the reduced number and hypermaturation of neutrophils caused by loss of miR-142-3p was mainly mediated by the abnormally activated IFN-γ signaling, especially the upregulation of stat1a and irf1b. Taken together, we uncovered a novel role of miR-142-3p in maintaining normal neutrophil development and maturation.

  • Submitted December 17, 2013.
  • Accepted June 19, 2014.
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