Laboratory of Gene Regulation Research, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
Mol Biol Cell. 2011 Sep;22(18):3541-9. doi: 10.1091/mbc.E11-02-0139. Epub 2011 Jul 27.
The number of vertebrae is defined strictly for a given species and depends on the number of somites, which are the earliest metameric structures that form in development. Somites are formed by sequential segmentation. The periodicity of somite segmentation is orchestrated by the synchronous oscillation of gene expression in the presomitic mesoderm (PSM), termed the "somite segmentation clock," in which Notch signaling plays a crucial role. Here we show that the clock period is sensitive to Notch activity, which is fine-tuned by its feedback regulator, Notch-regulated ankyrin repeat protein (Nrarp), and that Nrarp is essential for forming the proper number and morphology of axial skeleton components. Null-mutant mice for Nrarp have fewer vertebrae and have defective morphologies. Notch activity is enhanced in the PSM of the Nrarp(-/-) embryo, where the ~2-h segmentation period is extended by 5 min, thereby forming fewer somites and their resultant vertebrae. Reduced Notch activity partially rescues the Nrarp(-/-) phenotype in the number of somites, but not in morphology. Therefore we propose that the period of the somite segmentation clock is sensitive to Notch activity and that Nrarp plays essential roles in the morphology of vertebrae and ribs.
脊椎的数量是严格为特定物种定义的，取决于体节的数量，体节是发育过程中最早形成的分节结构。体节是通过连续的分段形成的。体节分段的周期性由前体节中基因表达的同步振荡协调，称为“体节分段时钟”，其中 Notch 信号发挥着关键作用。在这里，我们表明时钟周期对 Notch 活性敏感，而 Notch 活性由其反馈调节剂 Notch 调节的锚蛋白重复蛋白（Nrarp）进行微调，并且 Nrarp 对于形成适当数量和形态的轴骨骼成分是必不可少的。Nrarp 缺失突变体小鼠的脊椎数量较少，形态缺陷。Nrarp(-/-)胚胎的 PSM 中 Notch 活性增强，其中约 2 小时的分段周期延长了 5 分钟，从而形成的体节和由此产生的脊椎数量减少。降低 Notch 活性可部分挽救 Nrarp(-/-)表型在体节数量上，但不能在形态上。因此，我们提出体节分段时钟的周期对 Notch 活性敏感，而 Nrarp 在脊椎和肋骨的形态中发挥着重要作用。
