Developmental dependence on NurRE and EboxNeuro for expression of pituitary proopiomelanocortin
Developmental dependence on NurRE and EboxNeuro for expression of pituitary proopiomelanocortin
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DOI：
10.1210/me.2007-0567
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发表时间：
2008-07-01
影响因子：
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通讯作者：
Drouin, Jacques
中科院分区：
文献类型：
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作者：
Lavoie, Pierre-Luc;Budry, Lionel;Drouin, Jacques
垂体前阿黑皮素（POMC）基因的细胞特异性表达依赖于大量DNA结合转录因子（TF）的组合作用。这些包括一般和细胞限制性因子，以及作为信号传导途径效应物的因子。我们先前已经在远端POMC启动子中定义了一种复合调控元件，该元件包含赋予细胞特异性的碱性螺旋-环-螺旋TF和对CRH信号传导和糖皮质激素负反馈有反应的NGFI-B孤儿核受体的靶点。这些因子分别作用于相邻的调节元件Ebox（Neuro）和NurRE。目前，Ebox（Neuro）被认为是胎儿发育期间NeuroD 1的靶点，但该因子可能无法解释成人垂体的活性; NurRE和NGFI-B相关因子在下丘脑-垂体门脉系统建立之前是否活跃也是未知的。为了评估这些调控元件及其同源转录因子在整个垂体器官发生和成人中的重要性，我们评估了突变体POMC启动子在转基因小鼠整个发育过程中的活性。这些实验表明，Ebox（神经）和同源的基本螺旋-环-螺旋因子需要在整个发展和成人腺体，超出NeuroD 1的表达。同样，数据显示持续的重要性，NurRE及其同源因素在整个垂体发育。这些数据对比的持续依赖性在整个发展过程中相同的调节元件与TF表达的高度动态模式和调制其活动响应信号通路。
Cell-specific expression of the pituitary proopiomelanocortin (POMC) gene depends on the combinatorial action of a large number of DNA-binding transcription factors (TFs). These include general and cell-restricted factors, as well as factors that act as effectors of signaling pathways. We have previously defined in the distal POMC promoter a composite regulatory element that contains targets for basic helix-loop-helix TFs conferring cell specificity and for NGFI-B orphan nuclear receptors that are responsive to CRH signaling and to glucocorticoid negative feedback. These factors act on neighboring regulatory elements, the Ebox(Neuro) and NurRE, respectively. Currently, the Ebox(Neuro) is thought to be the target of NeuroD1 during fetal development, but this factor may not account for activity in the adult pituitary; it is also unknown whether the NurRE and NGFI-B-related factors are active before establishment of the hypothalamic-pituitary portal system. In order to assess the importance of these regulatory elements and their cognate TFs throughout pituitary organogenesis and in the adult, we have assessed the activity of mutant POMC promoters in transgenic mice throughout development. These experiments indicate that the Ebox(Neuro) and cognate basic helix-loop-helix factors are required throughout development and in the adult gland, beyond expression of NeuroD1. Similarly, the data reveal sustained importance of the NurRE and its cognate factors throughout pituitary development. These data contrast the sustained dependence throughout development on the same regulatory elements with the highly dynamic patterns of TF expression and the modulation of their activity in response to signaling pathways.