Induction and dorsal restriction of Paired-box 3 (Pax3) gene expression in the caudal neuroectoderm is mediated by integration of multiple pathways on a short neural crest enhancer.
Induction and dorsal restriction of Paired-box 3 (Pax3) gene expression in the caudal neuroectoderm is mediated by integration of multiple pathways on a short neural crest enhancer.
复制标题
DOI：
10.1016/j.bbagrm.2014.04.023
复制
发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Oraly Sanchez-Ferras;Guillaume Bernas;Emilie Laberge-Perrault;N. Pilon
中科院分区：
文献类型：
--
作者：
Oraly Sanchez-Ferras;Guillaume Bernas;Emilie Laberge-Perrault;N. Pilon
Pax 3编码一个配对盒转录因子，在神经嵴和神经管的个体发育中起关键作用。Pax 3神经表达的鲁棒控制由两组冗余的顺式调节模块（CRM）确保，所述顺式调节模块（CRM）整合前后（例如Wnt-β连环蛋白信号传导）以及背腹（例如Shh-Gli信号传导）指导性线索。在以前的工作中，我们试图表征Wnt介导的Pax 3表达调控，并确定Cdx转录因子（Cdx 1/2/4）作为这一过程中的关键中间体。我们从Pax 3的5′-侧翼区域鉴定出神经嵴增强子2（NCE 2）作为Cdx依赖的CRM，其重现了Pax 3在小鼠尾神经外胚层中的限制性表达。虽然这与传递来自后处理Wnt配体的诱导信号的关键作用一致，但Cdx蛋白在尾芽区域中的广泛表达与NCE 2的受限活性不一致。这意味着，其他积极和/或消极的输入是必需的，在这里，我们报告了一个新的作用，转录因子Zic 2在这种调节。我们的数据有力地表明，Zic 2参与诱导（作为直接Pax 3 NCE 2激活剂和Cdx神经辅因子）以及维持Pax 3背侧限制（作为腹侧Shh抑制性输入的靶点）。我们还提供了证据表明，诱导Cdx-Zic 2相互作用是集成在NCE 2与神经特异性转录因子Sox 2的正输入。总而言之，我们的数据提供了重要的机制的见解不同的信号通路的协调整合的shortPax 3CRM。
Pax3encodes a paired-box transcription factor with key roles in neural crest and neural tube ontogenesis. Robust control ofPax3neural expression is ensured by two redundant sets of cis-regulatory modules (CRMs) that integrate anterior–posterior (such as Wnt–βCatenin signaling) as well as dorsal–ventral (such as Shh–Gli signaling) instructive cues. In previous work, we sought to characterize the Wnt-mediated regulation ofPax3expression and identified the Cdx transcription factors (Cdx1/2/4) as critical intermediates in this process. We identified the neural crest enhancer-2 (NCE2) from the 5′-flanking region ofPax3as a Cdx-dependent CRM that recapitulates the restricted expression ofPax3in the mouse caudal neuroectoderm. While this is consistent with a key role in relaying the inductive signal from posteriorizing Wnt ligands, the broad expression of Cdx proteins in the tailbud region is not consistent with the restricted activity of NCE2. This implies that other positive and/or negative inputs are required and, here, we report a novel role for the transcription factor Zic2 in this regulation. Our data strongly suggests that Zic2 is involved in the induction (as a directPax3NCE2 activator and Cdx neural cofactor) as well as the maintenance ofPax3dorsal restriction (as a target of the ventral Shh repressive input). We also provide evidence that the inductive Cdx–Zic2 interaction is integrated on NCE2 with a positive input from the neural-specific transcription factor Sox2. Altogether, our data provide important mechanistic insights into the coordinated integration of different signaling pathways on a shortPax3CRM.