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Expression Profiling of Immature Thymocytes Revealed a Novel Homeobox Gene That Regulates Double-Negative Thymocyte Development¹

Masahito Kawazu^*,, Go Yamamoto^*, Mayumi Yoshimi^*, Kazuki Yamamoto^*, Takashi Asai^*, Motoshi Ichikawa^*, Sachiko Seo^*, Masahiro Nakagawa^*, Shigeru Chiba, Mineo Kurokawa^* and Seishi Ogawa^2,*,,,¶

^* Department of Hematology and Oncology, Cell Therapy and Transplantation Medicine, and Regeneration Medicine for Hematopoiesis; 21st Century Core of Excellence (COE) program, Graduate School of Medicine, University of Tokyo, University of Tokyo Hospital, Tokyo, Japan; and ^¶ Core Research for Evolutional Science and Technology, Japan Science and Technology Agency

Intrathymic development of CD4/CD8 double-negative (DN) thymocytes can be tracked by well-defined chronological subsets of thymocytes, and is an ideal target of gene expression profiling analysis to clarify the genetic basis of mature T cell production, by which differentiation of immature thymocytes is investigated in terms of gene expression profiles. In this study, we show that development of murine DN thymocytes is predominantly regulated by largely repressive rather than inductive activities of transcriptions, where lineage-promiscuous gene expression in immature thymocytes is down-regulated during their differentiation. Functional mapping of genes showing common temporal expression profiles implicates previously uncharacterized gene regulations that may be relevant to early thymocytes development. A small minority of genes is transiently expressed in the CD44^lowCD25⁺ subset of DN thymocytes, from which we identified a novel homeobox gene, Duxl, whose expression is up-regulated by Runx1. Duxl promotes the transition from CD44^highCD25⁺ to CD44^lowCD25⁺ in DN thymocytes, while constitutive expression of Duxl inhibits expression of TCR -chains and leads to impaired selection and greatly reduced production of CD4/CD8 double-positive thymocytes, indicating its critical roles in DN thymocyte development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Research on Measures for Intractable Diseases, Health and Labor, Sciences Research Grants, Ministry of Health, Labor and Welfare, Research on Health Sciences focusing on Drug Innovation, the Japan Health Sciences Foundation, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency.

² Address correspondence and reprint requests to Dr. Seishi Ogawa, Department of Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan. E-mail address: sogawa-tky{at}umin.ac.jp

³ Abbreviations used in this paper: DN, double negative; DP, double positive; FL, fetal liver; rh, recombinant human; shRNA, small hairpin RNA; iTCR, intracellular TCR; qPCR, quantitative PCR; NGFRt, nerve growth factor receptor; OP9-DL1, OP9-delta-like-1.

⁴ The online version of this article contains supplemental material.