Hematopoiesis in the fetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor

Hematopoiesis in the fetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor

^*Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Seiryo-machi, Aoba-ku, Sendai 980; ^†Department of Cell Biology, Cancer Institute, Toshima-ku, Tokyo 170; ^‡Department of Hematology-Oncology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108; and ^§Department of Viral Oncology, Institute for Virus Research, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606, Japan

Abstract

The Pebpb2 gene encodes a non-DNA binding subunit of the heterodimeric transcription factor, polyomavirus enhancer binding protein 2/core binding factor (PEBP2/CBF), and is rearranged in inversion of chromosome 16 associated with human acute myeloid leukemia. To investigate its physiological function, Pebpb2 was mutated by a targeting strategy to generate a null mutant. The homozygous mutation in mice proved lethal in embryos around embryonic day 12.5, apparently due to massive hemorrhaging in the central nervous system. In addition, definitive hematopoiesis in the liver was severely impaired. The observed phenotype was indistinguishable from that reported for homozygous disruption of AML1, which encodes a DNA binding subunit of PEBP2/CBF. Thus, the results indicate that the two subunits function together as a heterodimeric PEBP2/CBF in vivo and that PEBP2/CBF plays an essential role in the development of definitive hematopoiesis.

Footnotes

↵ ¶ To whom reprint requests should be addressed.
Ed Harlow, Harvard Medical School, Charlestown, MA
ABBREVIATIONS:

E,

embryonic day;

PEBP2,

polyomavirus enhancer binding protein 2;

CBF,

core binding factor;

ES cell,

embryonic stem cell;

RT-PCR,

reverse transcription–PCR