Over-expression of Runx1 transcription factor impairs the development of thymocytes from the double-negative to double-positive stages.
Runx1 transcription factor is highly expressed at a CD4/CD8-double-negative (DN) stage of thymocyte development but is down-regulated when cells proceed to the double-positive (DP) stage. In the present study, we examined whether the down-regulation of Runx1 is necessary for thymocyte differentiation from the DN to DP stage. When Runx1 was artificially over-expressed in thymocytes by Lck-driven Cre, the DN3 population was unaffected, as exemplified by proper pre-T-cell receptor expression, whereas the DN4 population was perturbed as shown by the decrease in the CD27(hi) sub-fraction. In parallel, the growth rate of DN4 cells was reduced by half, as measured by bromodeoxyuridine incorporation. These events impaired the transition of DN4 cells to the DP stage, resulting in the drastic reduction of the number of DP thymocytes. The Runx1 gene has two promoters, a proximal and a distal promoter; and, in thymocytes, endogenous Runx1 was mainly transcribed from the distal promoter. Interestingly, only distal, but not proximal, Runx1 over-expression exhibited an inhibitory effect on thymocyte differentiation, suggesting that the distal Runx1 protein may fulfil a unique function. Our collective results indicate that production of the distal Runx1 protein must be adequately down-regulated for thymocytes to transit from the DN to the DP stage, a critical step in the massive expansion of the T-cell lineage.
Wong
Won F
WF
Institute of Development, Aging and Cancer, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
Nakazato
Megumi
M
Watanabe
Toshio
T
Kohu
Kazuyoshi
K
Ogata
Takehiro
T
Yoshida
Naomi
N
Sotomaru
Yusuke
Y
Ito
Mamoru
M
Araki
Kimi
K
Telfer
Janice
J
Fukumoto
Manabu
M
Suzuki
Daisuke
D
Sato
Takehito
T
Hozumi
Katsuto
K
Habu
Sonoko
S
Satake
Masanobu
M
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism
D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7