Transcription elongation factor S-II is required for definitive hematopoiesis.
Transcription elongation factor S-II/TFIIS promotes readthrough of transcriptional blocks by stimulating nascent RNA cleavage activity of RNA polymerase II in vitro. The biologic significance of S-II function in higher eukaryotes, however, remains unclear. To determine its role in mammalian development, we generated S-II-deficient mice through targeted gene disruption. Homozygous null mutants died at midgestation with marked pallor, suggesting severe anemia. S-II(-/-) embryos had a decreased number of definitive erythrocytes in the peripheral blood and disturbed erythroblast differentiation in fetal liver. There was a dramatic increase in apoptotic cells in S-II(-/-) fetal liver, which was consistent with a reduction in Bcl-x(L) gene expression. The presence of phenotypically defined hematopoietic stem cells and in vitro colony-forming hematopoietic progenitors in S-II(-/-) fetal liver indicates that S-II is dispensable for the generation and differentiation of hematopoietic stem cells. S-II-deficient fetal liver cells, however, exhibited a loss of long-term repopulating potential when transplanted into lethally irradiated adult mice, indicating that S-II deficiency causes an intrinsic defect in the self-renewal of hematopoietic stem cells. Thus, S-II has critical and nonredundant roles in definitive hematopoiesis.
Division of Developmental Biochemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-0033.
Takahiro
T
Ito
Nagisa
N
Arimitsu
Masaki
M
Takeuchi
Nobuyuki
N
Kawamura
Makiko
M
Nagata
Kayoko
K
Saso
Nobuyoshi
N
Akimitsu
Hiroshi
H
Hamamoto
Shunji
S
Natori
Atsushi
A
Miyajima
Kazuhisa
K
Sekimizu
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003433:Crosses, Genetic; D005260:Female; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics* / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera; D020133:Reverse Transcriptase Polymerase Chain Reaction; D035602:Transcriptional Elongation Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*
D035602:Transcriptional Elongation Factors; C018648:transcription factor S-II; D049452:Green Fluorescent Proteins; D008156:Luciferases