Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation
Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation
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DOI：
10.1128/mcb.25.19.8507-8519.2005
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发表时间：
2005-10-01
影响因子：
5.3
通讯作者：
Cooney, AJ
中科院分区：
文献类型：
--
作者：
Gu, PL;LeMenuet, D;Cooney, AJ
胚胎干（ES）细胞的多能性和分化由转录因子和信号分子网络控制。 Oct4和Nanog等转录因子是ES细胞自我更新和维持未分化状态所必需的。这些因子表达的减少表明 ES 细胞分化的开始。编码孤儿核受体GCNF的基因失活表明，它在早期胚胎发育过程中体细胞Oct4表达的抑制中发挥着重要作用。分离GCNF(-/-) ES细胞以研究GCNF在分化过程中下调多能性基因的功能。用视黄酸处理 GCNF(-/-) ES 细胞后，观察到 ES 细胞标记基因 Oct4、Nanog、Sox2、FGF4 和 Stella 的抑制消失。多能性基因抑制的丧失是 GCNF 丧失的直接或间接后果。 Oct4 和 Nanog 基因都是 ES 细胞分化和早期小鼠胚胎发育过程中 GCNF 抑制的直接目标。相比之下，Sox2 和 FGF4 通过 Oct4 间接受 GCNF 调节。这些发现确立了 GCNF 在视黄酸诱导的 ES 细胞分化过程中抑制多能性基因表达中的核心作用。
Embryonic stem (ES) cell pluripotency and differentiation are controlled by a network of transcription factors and signaling molecules. Transcription factors such as Oct4 and Nanog are required for self-renewal and maintain the undifferentiated state of ES cells. Decreases in the expression of these factors indicate the initiation of differentiation of ES cells. Inactivation of the gene encoding the orphan nuclear receptor GCNF showed that it plays an important role in the repression of Oct4 expression in somatic cells during early embryonic development. GCNF(-/-) ES cells were isolated to study the function of GCNF in the down-regulation of pluripotency genes during differentiation. Loss of repression of ES cell marker genes Oct4, Nanog, Sox2, FGF4, and Stella was observed upon treatment of GCNF(-/-) ES cells with retinoic acid. The loss of repression of pluripotency genes is either a direct or indirect consequence of loss of GCNF. Both the Oct4 and Nanog genes are direct targets of GCNF repression during ES cell differentiation and early mouse embryonic development. In contrast Sox2 and FGF4 are indirectly regulated by GCNF through Oct4. These findings establish a central role for GCNF in the repression of pluripotency gene expression during retinoic acid-induced ES cell differentiation.