Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Development. 2011 Dec;138(23):5235-46. doi: 10.1242/dev.062802.
Mastermind (Mam) is one of the elements of Notch signaling, a system that plays a pivotal role in metazoan development. Mam proteins form transcriptionally activating complexes with the intracellular domains of Notch, which are generated in response to the ligand-receptor interaction, and CSL DNA-binding proteins. In mammals, three structurally divergent Mam isoforms (MamL1, MamL2 and MamL3) have been identified. There have also been indications that Mam interacts functionally with various other transcription factors, including the p53 tumor suppressor, β-catenin and NF-κB. We have demonstrated previously that disruption of MamL1 causes partial deficiency of Notch signaling in vivo. However, MamL1-deficient mice did not recapitulate total loss of Notch signaling, suggesting that other members could compensate for the loss or that Notch signaling could proceed in the absence of Mam in certain contexts. Here, we report the generation of lines of mice null for MamL3. Although MamL3-null mice showed no apparent abnormalities, mice null for both MamL1 and MamL3 died during the early organogenic period with classic pan-Notch defects. Furthermore, expression of the lunatic fringe gene, which is strictly controlled by Notch signaling in the posterior presomitic mesoderm, was undetectable in this tissue of the double-null embryos. Neither of the single-null embryos exhibited any of these phenotypes. These various roles of the three Mam proteins could be due to their differential physical characteristics and/or their spatiotemporal distributions. These results indicate that engagement of Mam is essential for Notch signaling, and that the three Mam isoforms have distinct roles in vivo.
主脑蛋白（Mam）是 Notch 信号通路的组成部分之一，该信号通路在后生动物的发育中起着至关重要的作用。Mam 蛋白与 Notch 的细胞内域以及 CSL DNA 结合蛋白形成转录激活复合物，这些细胞内域是对配体-受体相互作用的反应而产生的。在哺乳动物中，已经鉴定出三种结构上不同的 Mam 同种型（MamL1、MamL2 和 MamL3）。也有迹象表明，Mam 与各种其他转录因子（包括 p53 肿瘤抑制因子、β-连环蛋白和 NF-κB）在功能上相互作用。我们之前已经证明，MamL1 的破坏会导致体内 Notch 信号的部分缺陷。然而，MamL1 缺陷小鼠并没有完全 recapitulate Notch 信号的缺失，这表明其他成员可以弥补缺失，或者在某些情况下， Notch 信号可以在没有 Mam 的情况下进行。在这里，我们报告了 MamL3 缺失的小鼠系的生成。尽管 MamL3 缺失的小鼠没有明显的异常，但 MamL1 和 MamL3 都缺失的小鼠在早期器官发生期死亡，具有典型的全 Notch 缺陷。此外，lunatic fringe 基因的表达，该基因在后部体节间 mesoderm 中严格受 Notch 信号控制，在双缺失胚胎的该组织中无法检测到。这两种单缺失的胚胎都没有表现出任何这些表型。这三种 Mam 蛋白的各种作用可能是由于它们的物理特性和/或时空分布的差异。这些结果表明，Mam 的参与对于 Notch 信号是必不可少的，并且这三种 Mam 同种型在体内具有不同的作用。
