Ishitani Tohru, Matsumoto Kunihiro, Chitnis Ajay B, Itoh Motoyuki
Unit on Nervous System Development, Laboratory of Cell Regulation, Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
Nat Cell Biol. 2005 Nov;7(11):1106-12. doi: 10.1038/ncb1311.
Nrarp (Notch-regulated ankyrin repeat protein) is a small protein that has two ankyrin repeats. Although Nrarp is known to be an inhibitory component of the Notch signalling pathway that operates in different developmental processes, the in vivo roles of Nrarp have not been fully characterized. Here, we show that Nrarp is a positive regulator in the Wnt signalling pathway. In zebrafish, knockdown of Nrarp-a expression by an antisense morpholino oligonucleotide (MO) results in altered Wnt-signalling-dependent neural-crest-cell development. Nrarp stabilizes LEF1 protein, a pivotal transcription factor in the Wnt signalling cascade, by blocking LEF1 ubiquitination. In accordance with this, the knockdown phenotype of lef1 is similar to that of nrarp-a, at least in part, in its effect on the development of multiple tissues in zebrafish. Furthermore, activation of LEF1 does not affect Notch activity or vice versa. These findings reveal that Nrarp independently regulates canonical Wnt and Notch signalling by modulating LEF1 and Notch protein turnover, respectively.
Nrarp（Notch调节的锚蛋白重复蛋白）是一种含有两个锚蛋白重复序列的小蛋白。尽管已知Nrarp是Notch信号通路的抑制成分，在不同的发育过程中发挥作用，但Nrarp在体内的作用尚未完全明确。在此，我们表明Nrarp是Wnt信号通路中的一个正向调节因子。在斑马鱼中，通过反义吗啉代寡核苷酸（MO）敲低Nrarp-a的表达会导致依赖Wnt信号的神经嵴细胞发育改变。Nrarp通过阻断LEF1泛素化来稳定LEF1蛋白，LEF1是Wnt信号级联反应中的关键转录因子。与此一致的是，lef1的敲低表型至少在部分程度上与nrarp-a的敲低表型相似，对斑马鱼多个组织的发育产生影响。此外，LEF1的激活不影响Notch活性，反之亦然。这些发现揭示了Nrarp分别通过调节LEF1和Notch蛋白的周转来独立调节经典Wnt和Notch信号。
