Gli3 in fetal thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of Shh.
Gli3 in fetal thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of Shh.
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DOI：
10.1242/dev.146910
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发表时间：
2018-01-31
期刊：
影响因子：
--
通讯作者：
Crompton T
中科院分区：
文献类型：
--
作者：
Solanki A;Yanez DC;Ross S;Lau CI;Papaioannou E;Li J;Saldaña JI;Crompton T
Gli3是一种Hedgehog （Hh）应答转录因子，可作为转录抑制因子或激活因子。我们发现小鼠胸腺上皮细胞（TECs）中的Gli3活性促进胎儿胸腺中CD4+ CD8+向CD4+ CD8−单阳性（SP4）细胞的阳性选择和分化，并且Gli3抑制Shh。Gli3的组成性缺失和TECs中Gli3的条件缺失会减少向SP4的分化，而胸腺细胞中Gli3的条件缺失则不会。从tec中条件删除Shh增加了向SP4的分化，并且在gli3缺陷胸腺中Shh的表达上调。转基因Hh报告基因的使用表明，Hh通路在胸腺细胞中是活跃的，并且在gli3缺陷的胎儿胸腺中增加。Gli3−/−胸腺中内源性Hh蛋白的中和恢复了SP4分化，表明TECs中的Gli3通过抑制Shh促进SP4分化。转录组分析显示，与野生型相比，hh介导的转录增加，而tcr介导的转录减少。摘要：胸腺上皮细胞中的Gli3活性通过减少Shh来促进从CD4+ CD8+到CD4+ CD8−胸腺细胞的成熟，Shh是小鼠胎儿胸腺库选择过程中t细胞受体介导的转录减少的信号。
Gli3 is a Hedgehog (Hh)-responsive transcription factor that can function as a transcriptional repressor or activator. We show that Gli3 activity in mouse thymic epithelial cells (TECs) promotes positive selection and differentiation from CD4+ CD8+ to CD4+ CD8− single-positive (SP4) cells in the fetal thymus and that Gli3 represses Shh. Constitutive deletion of Gli3, and conditional deletion of Gli3 from TECs, reduced differentiation to SP4, whereas conditional deletion of Gli3 from thymocytes did not. Conditional deletion of Shh from TECs increased differentiation to SP4, and expression of Shh was upregulated in the Gli3-deficient thymus. Use of a transgenic Hh reporter showed that the Hh pathway was active in thymocytes, and increased in the Gli3-deficient fetal thymus. Neutralisation of endogenous Hh proteins in the Gli3−/− thymus restored SP4 differentiation, indicating that Gli3 in TECs promotes SP4 differentiation by repression of Shh. Transcriptome analysis showed that Hh-mediated transcription was increased whereas TCR-mediated transcription was decreased in Gli3−/− thymocytes compared with wild type. Summary: Gli3 activity in thymic epithelial cells promotes maturation from CD4+ CD8+ to CD4+ CD8− thymocyte by reducing Shh, which signals to reduce T-cell receptor-mediated transcription during repertoire selection in mouse fetal thymus.
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通讯作者：
Crompton T
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通讯作者：
Crompton, T