Pilon Nicolas, Oh Karen, Sylvestre Jean-René, Savory Joanne G A, Lohnes David
Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
Development. 2007 Jun;134(12):2315-23. doi: 10.1242/dev.001206.
In the mouse, Cdx1 is essential for normal anteroposterior vertebral patterning through regulation of a subset of Hox genes. Retinoic acid (RA) and certain Wnts have also been implicated in vertebral patterning, although the relationship between these signaling pathways and the regulation of mesodermal Hox gene expression is not fully understood. Prior work has shown that Cdx1 is a direct target of both Wnt and retinoid signaling pathways, and might therefore act to relay these signals to the Hox genes. Wnt and RA are believed to impact on Cdx1 through an atypical RA-response element (RARE) and Lef/Tcf-response elements (LRE), respectively, in the proximal promoter. To address the roles of these regulatory motifs and pathways, we derived mice mutated for the LRE or the LRE plus the RARE. In contrast to RARE-null mutants, which exhibit limited vertebral defects, LRE-null and LRE+RARE-null mutants exhibited vertebral malformations affecting the entire cervical region that closely phenocopied the malformations seen in Cdx1-null mutants. Mutation of the LRE also greatly reduced induction of Cdx1 by RA, demonstrating a requirement for Wnt signaling in the regulation of this gene by retinoids. LRE and LRE+RARE mutants also exhibited vertebral fusions, suggesting a defect in somitogenesis. As Wnt signaling is implicated in somitogenesis upstream of the Notch pathway, it is conceivable that Cdx1 might play a role in this process. However, none of the Notch pathway genes assessed was overtly affected.
在小鼠中，Cdx1通过调控一部分Hox基因，对正常的前后椎体模式形成至关重要。视黄酸（RA）和某些Wnt信号通路也与椎体模式形成有关，尽管这些信号通路与中胚层Hox基因表达调控之间的关系尚未完全明确。先前的研究表明，Cdx1是Wnt和视黄酸信号通路的直接靶点，因此可能起到将这些信号传递给Hox基因的作用。据信，Wnt和RA分别通过近端启动子中的非典型视黄酸反应元件（RARE）和Lef/Tcf反应元件（LRE）影响Cdx1。为了研究这些调控基序和信号通路的作用，我们培育了LRE或LRE加RARE发生突变的小鼠。与表现出有限椎体缺陷的RARE缺失突变体不同，LRE缺失突变体和LRE + RARE缺失突变体表现出影响整个颈椎区域的椎体畸形，与Cdx1缺失突变体中所见的畸形极为相似。LRE的突变还大大降低了RA对Cdx1的诱导作用，表明在视黄酸对该基因的调控中Wnt信号通路是必需的。LRE和LRE + RARE突变体还表现出椎体融合，提示体节发生存在缺陷。由于Wnt信号通路在Notch信号通路的上游参与体节发生，因此可以想象Cdx1可能在此过程中发挥作用。然而，所评估的Notch信号通路基因均未受到明显影响。
