Ogt controls neural stem/progenitor cell pool and adult neurogenesis through modulating Notch signaling
Junchen Chen,
Xiaoxue Dong,
Xuejun Cheng,
Qiang Zhu,
Jinyu Zhang,
Qian Li,
Xiaoli Huang,
Min Wang,
Liping Li,
Weixiang Guo,
Binggui Sun,
Qiang Shu,
Wen Yi,
Xuekun Li
Affiliations
Junchen Chen
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
Xiaoxue Dong
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
Xuejun Cheng
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
Qiang Zhu
MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058; The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China
Jinyu Zhang
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
Qian Li
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
Xiaoli Huang
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
Min Wang
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
Liping Li
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
Weixiang Guo
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
Binggui Sun
The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
Qiang Shu
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; Corresponding author
Wen Yi
MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058; The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China; Corresponding author
Xuekun Li
The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310029, China; Corresponding author
Summary: Ogt catalyzed O-linked N-acetylglucosamine (O-GlcNAcylation, O-GlcNAc) plays an important function in diverse biological processes and diseases. However, the roles of Ogt in regulating neurogenesis remain largely unknown. Here, we show that Ogt deficiency or depletion in adult neural stem/progenitor cells (aNSPCs) leads to the diminishment of the aNSPC pool and aberrant neurogenesis and consequently impairs cognitive function in adult mice. RNA sequencing reveals that Ogt deficiency alters the transcription of genes relating to cell cycle, neurogenesis, and neuronal development. Mechanistic studies show that Ogt directly interacts with Notch1 and catalyzes the O-GlcNAc modification of Notch TM/ICD fragment. Decreased O-GlcNAc modification of TM/ICD increases the binding of E3 ubiquitin ligase Itch to TM/ICD and promotes its degradation. Itch knockdown rescues neurogenic defects induced by Ogt deficiency in vitro and in vivo. Our findings reveal the essential roles and mechanisms of Ogt and O-GlcNAc modification in regulating mammalian neurogenesis and cognition.
