Direct BMP2/4 signaling through BMP receptor IA regulates fetal thymocyte progenitor homeostasis and differentiation to CD4+CD8+ double-positive cell.
Direct BMP2/4 signaling through BMP receptor IA regulates fetal thymocyte progenitor homeostasis and differentiation to CD4+CD8+ double-positive cell.
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DOI：
10.4161/cc.27118
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Crompton T
中科院分区：
文献类型：
--
作者：
Hager-Theodorides AL;Ross SE;Sahni H;Mishina Y;Furmanski AL;Crompton T
BMP 2/4信号是胚胎发生所必需的，并参与胸腺形态发生和T细胞分化。体外实验表明，用外源性BMP 4处理胸腺外植体可负调节早期胸腺祖细胞的分化和从CD 4 − CD 8 −（DN）到CD 4 + CD 8+（DP）的转变。在这里，我们表明，在体内BMP 2/4信号是必需的胎儿胸腺祖细胞的稳态和扩增，但负调控从DN分化为DP细胞。出乎意料的是，从胎儿胸腺细胞中有条件地删除BMPRIA（使用Cre-loxP系统并用Vav启动子将切除定向到造血谱系细胞）证明，通过BMPRIA直接向胸腺细胞的BMP 2/4信号传导的生理水平是早期胎儿DN胸腺细胞正常分化和扩增所需的。相比之下，胸腺外植体的外源性BMP 4处理引起的早期胸腺细胞祖细胞分化的停滞部分由通过BMPRIA向胸腺细胞的直接信号传导诱导，部分由通过非造血细胞的间接信号传导诱导。通过条件性BMPRIA缺陷胸腺细胞的离体分析和通过用BMP 4抑制剂Noggin处理胸腺外植体，对从胎儿DN到DP细胞的转变的分析表明，BMP 2/4信号传导在该阶段是负调节剂。我们发现在胎儿T细胞发育的这个阶段，BMP 2/4通过BMPRIA直接向胸腺细胞发出信号。
BMP2/4 signaling is required for embryogenesis and involved in thymus morphogenesis and T-lineage differentiation. In vitro experiments have shown that treatment of thymus explants with exogenous BMP4 negatively regulated differentiation of early thymocyte progenitors and the transition from CD4−CD8− (DN) to CD4+CD8+ (DP). Here we show that in vivo BMP2/4 signaling is required for fetal thymocyte progenitor homeostasis and expansion, but negatively regulates differentiation from DN to DP cell. Unexpectedly, conditional deletion of BMPRIA from fetal thymocytes (using the Cre-loxP system and directing excision to hematopoietic lineage cells with the Vav promoter) demonstrated that physiological levels of BMP2/4 signaling directly to thymocytes through BMPRIA are required for normal differentiation and expansion of early fetal DN thymocytes. In contrast, the arrest in early thymocyte progenitor differentiation caused by exogenous BMP4 treatment of thymus explants is induced in part by direct signaling to thymocytes through BMPRIA, and in part by indirect signaling through non-hematopoietic cells. Analysis of the transition from fetal DN to DP cell, both by ex vivo analysis of conditional BMPRIA-deficient thymocytes and by treatment of thymus explants with the BMP4-inhibitor Noggin demonstrated that BMP2/4 signaling is a negative regulator at this stage. We showed that at this stage of fetal T-cell development BMP2/4 signals directly to thymocytes through BMPRIA.
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影响因子：
4.4
作者：
Hager-Theodorides, Ariadne L.;Furmanski, Anna L.;Crompton, Tessa
通讯作者：
Crompton, Tessa
影响因子：
20.3
作者：
Hidalgo, Laura;Martinez, Victor G.;Vicente, Angeles
通讯作者：
Vicente, Angeles
影响因子：
4.8
作者：
Mishina, Y;Starbuck, MW;Behringer, RR
通讯作者：
Behringer, RR
影响因子：
15.3
作者：
Graf, D;Nethisinghe, S;Merkenschlager, M
通讯作者：
Merkenschlager, M
影响因子：
4.3
作者：
Paschalidis, Nikolaos;Huggins, Anthony;D'Acquisto, Fulvio
通讯作者：
D'Acquisto, Fulvio