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International Immunology, Vol. 14, No. 6, pp. 637-645, June 2002
© 2002 Japanese Society for Immunology

Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision

Hua Han1, Kenji Tanigaki1, Norio Yamamoto1, Kazuki Kuroda1, Momoko Yoshimoto2, Tatsutoshi Nakahata2, Koichi Ikuta1 and Tasuku Honjo1

Departments of 1 Medical Chemistry and 2 Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

Correspondence to: T Honjo; E-mail: honjo{at}mfour.med.kyoto-u.ac.jp
Transmitting editor: K. Sugamura

The transcription factor recombination signal binding protein-J (RBP-J) functions immediately downstream of the cell surface receptor Notch and mediates transcriptional activation by the intracellular domain of all four kinds of Notch receptors. To investigate the function of RBP-J, we introduced loxP sites on both sides of the RBP-J exons encoding its DNA binding domain. Mice bearing the loxP-flanked RBP-J alleles, RBP-Jf/f, were mated with Mx-Cre transgenic mice and deletional mutation of the RBP-J gene in adult mice was induced by injection of the IFN-{alpha} inducer poly(I)–poly(C). Here we show that inactivation of RBP-J in bone marrow resulted in a block of T cell development at the earliest stage and increase of B cell development in the thymus. Lymphoid progenitors deficient in RBP-J differentiate into B but not T cells when cultured in 2'-deoxyguanosine-treated fetal thymic lobes by hanging-drop fetal thymus organ culture. Competitive repopulation assay also revealed cell autonomous deficiency of T cell development from bone marrow of RBP-J knockout mouse. Myeloid and B lineage differentiation appears normal in the bone marrow of RBP-J-inactivated mice. These results suggest that RBP-J, probably by mediating Notch signaling, controls T versus B cell fate decision in lymphoid progenitors.

Keywords: gene targeting, Notch, RBP-J, T lymphocyte


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