Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis

Deborah J. Stumpo, Hal E. Broxmeyer, Toni Ward, Scott Cooper, Giao Hangoc, Jo Chung Yang, William C. Shelley, Eric K. Richfield, Manas K. Ray, Mervin C. Yoder, Peter D. Aplan, Perry J. Blackshear

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81 Scopus citations

Abstract

Members of the tristetraprolin family of tandem CCCH finger proteins can bind to AU-rich elements in the 3′-untranslated region of mRNAs, leading to their deadenylation and subsequent degradation. Partial deficiency of 1 of the 4 mouse tristetraprolin family members, Zfp36l2, resulted in complete female infertility because of early embryo death. We have now generated mice completely deficient in the ZFP36L2 protein. Homozygous Zfp36l2 knockout (KO) mice died within approximately 2 weeks of birth, apparently from intestinal or other hemorrhage. Analysis of peripheral blood from KO mice showed a decrease in red and white cells, hemoglobin, hematocrit, and platelets. Yolk sacs from embryonic day 11.5 (E11.5) Zfp36l2 KO mice and fetal livers from E14.5 KO mice gave rise to markedly reduced numbers of definitive multilineage and lineage-committed hematopoietic progenitors. Competitive reconstitution experiments demonstrated that Zfp36l2 KO fetal liver hematopoietic stem cells were unable to adequately reconstitute the hematopoietic system of lethally irradiated recipients. These data establish Zfp36l2 as a critical modulator of definitive hematopoiesis and suggest a novel regulatory pathway involving control of mRNA stability in the life cycle of hematopoietic stem and progenitor cells.

Original languageEnglish (US)
Pages (from-to)2401-2410
Number of pages10
JournalBlood
Volume114
Issue number12
DOIs
StatePublished - Nov 20 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Stumpo, D. J., Broxmeyer, H. E., Ward, T., Cooper, S., Hangoc, G., Yang, J. C., Shelley, W. C., Richfield, E. K., Ray, M. K., Yoder, M. C., Aplan, P. D., & Blackshear, P. J. (2009). Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis. Blood, 114(12), 2401-2410. https://doi.org/10.1182/blood-2009-04-214619