Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis.
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.
Stumpo
Deborah J
DJ
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Broxmeyer
Hal E
HE
Ward
Toni
T
Cooper
Scott
S
Hangoc
Giao
G
Chung
Yang Jo
YJ
Shelley
William C
WC
Richfield
Eric K
EK
Ray
Manas K
MK
Yoder
Mervin C
MC
Aplan
Peter D
PD
Blackshear
Perry J
PJ
D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D001853:Bone Marrow / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005333:Fetus / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010198:Pancytopenia / Q000235:genetics* / Q000473:pathology; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014018:Tissue Distribution; D051816:Tristetraprolin / Q000502:physiology*
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; C118208:ZFR protein, mouse; C497553:Zfp36 protein, mouse