Involvement of a co-factor of Notch signaling, Mastermind, into Schizophrenia

在Notch信号传导期间，配体刺激诱导Notch细胞内结构域的产生，其随后被转运到细胞核。与DNA结合蛋白RBP-J和转录共激活因子Mastermind（Mam）一起，Notch细胞内结构域形成三聚体复合物，其激活来自靶启动子的转录。我们发现，Mam基因之一MamL 1的杂合敲除小鼠表现出对多巴胺的敏感性增加，模仿人类精神分裂症的部分症状。我们已经发现Rbp-j的杂合敲除小鼠也表现出非常相似的表型。此外，通过检测精神分裂症患者和健康对照者的血液基因组DNA，我们发现在RBP-J和MAML 1基因的编码区中存在精神分裂症特异性错义多态性。我们正在研究这些多态性对这些蛋白质功能的影响。

During Notch signaling, ligand stimulation induces generation of Notch intracellular domain, which is subsequently transported to the nuclei. With a DNA-binding protein RBP-J and a transcriptional co-activator Mastermind (Mam), the Notch intracellular domain forms a trimeric complex that activates transcription from the target promoters. We had found that heterozygous knockout mice of one of Mam genes, MamL1, exhibit increased sensitivity to dopamine, mimicking a part of symptoms of schizophrenia in humans. We have found heterozygous knockout mice of Rbp-j also exhibit very similar phenotype. Furthermore, by examining blood-derived genomic DNA from schizophrenic patients and healthy controls, we have found schizophrenia-specific missense polymorphisms in coding regions of both RBP-J and MAML1 genes. We are examining effects of these polymorphisms on the functions of these proteins.