Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis
Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis
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DOI：
10.1073/pnas.97.18.10132
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发表时间：
2000-08-29
影响因子：
11.1
通讯作者：
Jetten, AM
中科院分区：
文献类型：
--
作者：
Kurebayashi, S;Ueda, E;Jetten, AM
确定核受体超家族成员维甲酸相关孤儿受体γ（ROR γ）的生理功能。通过靶向破坏产生ROR γ功能缺陷的小鼠。ROR γ（-/-）小鼠缺乏外周和肠系膜淋巴结以及派伊尔集合淋巴结，表明ROR γ表达对于淋巴结器官形成是不可缺少的。虽然脾脏增大，但结构正常。外周血CD 3（+）和CD 4（+）淋巴细胞的数量分别减少6倍和10倍，而循环中的a细胞数量正常。ROR γ（-/-）小鼠的胸腺含有比野生型小鼠少74.4% +/- 8.9%的胸腺细胞。流式细胞术分析显示CD 4（+）CD 8（+）亚群减少。末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色显示ROR γ（-/-）小鼠胸腺皮质中的凋亡细胞增加了4倍。后者得到了所观察到的膜联蛋白V阳性细胞增加的支持。ROR γ（-/-）胸腺细胞置于培养物中表现出“自发”凋亡率的显著增加。这种增加在很大程度上与CD 4（+）CD 8（+）胸腺细胞有关，并且可能至少部分与抗凋亡基因Bcl-X-L表达水平的大幅降低有关。流式细胞术分析表明，在ROR γ（-/-）小鼠的胸腺细胞中，细胞周期5期的细胞百分比增加了C倍。我们的观察表明，ROR γ是淋巴器官发生所必需的，并在胸腺生成中起着重要的调节作用。我们的研究结果支持一个模型，其中ROR γ负控制胸腺细胞凋亡。
To identify the physiological functions of the retinoid-related orphan receptor gamma (ROR gamma), a member of the nuclear receptor superfamily. mice deficient in ROR gamma function were generated by targeted disruption. ROR gamma(-/-) mice lack peripheral and mesenteric lymph nodes and Peyer's patches, indicating that ROR gamma expression is indispensable for lymph node organogenesis. Although the spleen is enlarged, its architecture is normal. The number of peripheral blood CD3(+) and CD4(+) lymphocytes is reduced 6- and 10-fold, respectively, whereas the number of circulating a cells is normal. The thymus of ROR gamma(-/-) mice contains 74.4% +/- 8.9% fewer thymocytes than that of wild-type mice. Flow cytometric analysis showed a decrease in the CD4(+)CD8(+) subpopulation. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining demonstrated a 4-fold increase in apoptotic cells in the cortex of the thymus of ROR gamma(-/-) mice. The latter was supported by the observed increase in annexin V-positive cells. ROR gamma(-/-) thymocytes placed in culture exhibit a dramatic increase in the rate of "spontaneous" apoptosis. This increase is largely associated with CD4(+)CD8(+) thymocytes and may, at least in part, be related to the greatly reduced level of expression of the anti-apoptotic gene Bcl-X-L. Flow cytometric analysis demonstrated a C-fold rise in the percentage of cells in the 5 phase of the cell cycle among thymocytes from ROR gamma(-/-) mice. Our observations indicate that ROR gamma is essential for lymphoid organogenesis and plays an important regulatory role in thymopoiesis. Our findings support a model in which ROR gamma negatively controls apoptosis in thymocytes.