Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
Development. 2011 Jan;138(1):55-64. doi: 10.1242/dev.055533. Epub 2010 Nov 23.
The rostro-caudal polarity within a somite is primarily determined by the on/off state of Notch signaling, but the mechanism by which Notch is repressed has remained elusive. Here, we present genetic and biochemical evidence that the suppression of Notch signaling is essential for the establishment of rostro-caudal polarity within a somite and that Mesp2 acts as a novel negative regulator of the Notch signaling pathway. We generated a knock-in mouse in which a dominant-negative form of Rbpj is introduced into the Mesp2 locus. Intriguingly, this resulted in an almost complete rescue of the segmental defects in the Mesp2-null mouse. Furthermore, we demonstrate that Mesp2 potently represses Notch signaling by inducing the destabilization of mastermind-like 1, a core regulator of this pathway. Surprisingly, this function of Mesp2 is found to be independent of its function as a transcription factor. Together, these data demonstrate that Mesp2 is a novel component involved in the suppression of Notch target genes.
体节中的头尾极性主要由 Notch 信号的开启/关闭状态决定，但 Notch 被抑制的机制仍不清楚。在这里，我们提供了遗传和生化证据，表明 Notch 信号的抑制对于体节中头尾极性的建立是必不可少的，并且 Mesp2 作为 Notch 信号通路的一个新的负调控因子发挥作用。我们生成了一种敲入小鼠，其中将一种显性失活形式的 Rbpj 引入 Mesp2 基因座。有趣的是，这导致 Mesp2 缺失小鼠的节段性缺陷几乎完全得到挽救。此外，我们证明 Mesp2 通过诱导 Notch 信号通路的核心调节因子 mastermind-like 1 的不稳定性来强烈抑制 Notch 信号。令人惊讶的是，Mesp2 的这个功能与其作为转录因子的功能无关。总之，这些数据表明 Mesp2 是参与抑制 Notch 靶基因的一个新的组成部分。
