TY - JOUR
T1 - Over-expression of Runx1 transcription factor impairs the development of thymocytes from the double-negative to double-positive stages
AU - Wong, Won F.
AU - Nakazato, Megumi
AU - Watanabe, Toshio
AU - Kohu, Kazuyoshi
AU - Ogata, Takehiro
AU - Yoshida, Naomi
AU - Sotomaru, Yusuke
AU - Ito, Mamoru
AU - Araki, Kimi
AU - Telfer, Janice
AU - Fukumoto, Manabu
AU - Suzuki, Daisuke
AU - Sato, Takehito
AU - Hozumi, Katsuto
AU - Habu, Sonoko
AU - Satake, Masanobu
PY - 2010/6/1
Y1 - 2010/6/1
N2 - 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 CD27hi 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.
AB - 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 CD27hi 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.
KW - Double negative
KW - Double positive
KW - Runx1
KW - Thymocyte development
KW - Transgenic mice
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U2 - 10.1111/j.1365-2567.2009.03230.x
DO - 10.1111/j.1365-2567.2009.03230.x
M3 - Article
C2 - 20102410
AN - SCOPUS:77952066320
VL - 130
SP - 243
EP - 253
JO - Immunology
JF - Immunology
SN - 0019-2805
IS - 2
ER -