The 140th Annual Meeting of the Pharmaceutical Society of Japan (Kyoto)

Presentation information


[S04] Notch signaling: context dependency, niche, and diseases

Thu. Mar 26, 2020 9:00 AM - 11:00 AM [Room D] Room D (1F)

Organizers: Motoyuki Itoh (Grad Sch Pharm, Chiba Univ), Takashi Minami (Inst Res Dev Anal, Kumamoto Univ)

9:05 AM - 9:20 AM

[S04-1] Functions and regulation of Notch signaling during neural development and brain diseases

○Motoyuki Itoh1 (1. Grad Sch Pharm, Chiba Univ)

The Notch signaling pathway has crucial functions in determining cell fates, stem cell maintenance, and homeostasis in neuronal tissues within metazoan organisms. Our recent studies provide evidence about the context-dependent regulation/ functions of Notch signaling and Notch-related disease mechanisms in the brain. First, progenitor proliferation and cell fate determination involve signaling through different sets of Notch ligand-receptor combinations that occur concurrently during development in zebrafish. Two ligands, DeltaA and DeltaD, and three receptors, Notch1a, Notch1b, and Notch3 redundantly contribute to interneuron progenitor maintenance. On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the differentiated interneuron V2a/V2b cell fate determination. Second, Notch signaling regulates effectors of glycolysis in a context-dependent manner. We found Notch signaling regulates glycolysis-related gene expression in neural tissues at different developmental stages. Notch signaling positively regulates glut1a and glut3a expression and negatively regulates hk2 expression. Third, different Notch3 mutations which are responsible for the brain disease, CADASIL leading to early-onset dementia, exhibited different metabolisms for each mutation. The C185R mutant protein is less susceptible to degradation than the wild type, while the C428S mutation did not undergo ligand binding-induced Notch3 extracellular domain degradation.