Expression profiling of immature thymocytes revealed a novel homeobox gene that regulates double-negative thymocyte development.
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(low)CD25(+) 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(high)CD25(+) to CD44(low)CD25(+) in DN thymocytes, while constitutive expression of Duxl inhibits expression of TCR beta-chains and leads to impaired beta selection and greatly reduced production of CD4/CD8 double-positive thymocytes, indicating its critical roles in DN thymocyte development.
Kawazu
Masahito
M
Department of Hematology and Oncology, University of Tokyo, Japan.
Yamamoto
Go
G
Yoshimi
Mayumi
M
Yamamoto
Kazuki
K
Asai
Takashi
T
Ichikawa
Motoshi
M
Seo
Sachiko
S
Nakagawa
Masahiro
M
Chiba
Shigeru
S
Kurokawa
Mineo
M
Ogawa
Seishi
S
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005801:Genes, Homeobox / Q000276:immunology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D050676:Core Binding Factor Alpha 2 Subunit; C115599:DUX1 protein, human; D018398:Homeodomain Proteins; C493726:Runx1 protein, mouse