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

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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.