Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis
Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis
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DOI：
10.1101/gad.932601
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发表时间：
2001-12-01
影响因子：
10.5
通讯作者：
Rosenfeld, MG
中科院分区：
文献类型：
--
作者：
Dasen, JS;Barbera, JPM;Rosenfeld, MG
了解特定辅阻遏物和 DNA 结合转录因子协调表达的功能意义仍然是哺乳动物发育中的一个关键问题。在垂体发育过程中，两个高度相关的成对样同源域因子，即阻遏物 Hesx1/Rpx 和激活物 Prop-1，以连续、重叠的时间模式表达。在这里，我们表明，虽然最初的垂体器官定型可能需要 Hesx1/Rpx 的抑制作用，但超越第一垂体 (POMC) 谱系的出现需要 Hesx1 表达和 Prop-1 作用的丧失。尽管Hesx1在不同的域上募集了Groucho相关的辅阻遏物TLE1和N-CoR/Sin3/HDAC复合物，但Hesx1在体内的阻遏功能证明需要TLE1的特异性募集，而TLE1在垂体器官发生过程中表现出共表达的空间和时间模式。此外，Hesx1 介导的抑制与腹侧间脑中的 FGF8/FGF10 信号传导协调负反馈回路，这是防止口腔外胚层诱导多个垂体所必需的。我们的数据表明，两个结构相关的DNA结合配对样同源域转录因子与相似的同源元件结合，在关键的共表达TLE辅阻遏物的作用基础上，通过以时间特异性方式相互抑制和激活靶基因来协调垂体器官发生。
Understanding the functional significance of the coordinate expression of specific corepressors and DNA-binding transcription factors remains a critical question in mammalian development. During the development of the pituitary gland, two highly related paired-like homeodomain factors, a repressor, Hesx1/Rpx and an activator, Prop-1, are expressed in sequential, overlapping temporal patterns. Here we show that while the repressive actions of Hesx1/Rpx may be required for initial pituitary organ commitment, progression beyond the appearance of the first pituitary (POMC) lineage requires both loss of Hesx1 expression and the actions of Prop-1. Although Hesx1 recruits both the Groucho-related corepressor TLE1 and the N-CoR/Sin3/HDAC complex on distinct domains, the repressor functions of Hesx1 in vivo prove to require the specific recruitment of TLE1, which exhibits a spatial and temporal pattern of coexpression during pituitary organogenesis. Furthermore, Hesx1-mediated repression coordinates a negative feedback loop with FGF8/FGF10 signaling in the ventral diencephalon, required to prevent induction of multiple pituitary glands from oral ectoderm. Our data suggest that the opposing actions of two structurally-related DNA-binding paired-like homeodomain transcription factors, binding to similar cognate elements, coordinate pituitary organogenesis by reciprocally repressing and activating target genes in a temporally specific fashion, on the basis of the actions of a critical, coexpressed TLE corepressor.