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

doi:10.1016/j.celrep.2021.108905

Ogt controls neural stem/progenitor cell pool and adult neurogenesis through modulating Notch signaling

Cell Rep. 2021 Mar 30;34(13):108905. doi: 10.1016/j.celrep.2021.108905.

Authors

Junchen Chen¹, Xiaoxue Dong¹, Xuejun Cheng², Qiang Zhu³, Jinyu Zhang¹, Qian Li¹, Xiaoli Huang², Min Wang⁴, Liping Li⁵, Weixiang Guo⁴, Binggui Sun⁶, Qiang Shu⁷, Wen Yi⁸, Xuekun Li⁹

Affiliations

¹ 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.
² The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China.
³ 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.
⁴ State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
⁵ 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.
⁶ 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.
⁷ The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China. Electronic address: [email protected].
⁸ 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. Electronic address: [email protected].
⁹ 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. Electronic address: [email protected].

PMID: 33789105
DOI: 10.1016/j.celrep.2021.108905

Abstract

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.

Keywords: O-GlcNAcylation; Ogt; cognition; neural stem/progenitor cells; neurogenesis; notch; ubiquitin ligase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylglucosamine / metabolism
Aging / metabolism*
Animals
Biocatalysis
Cell Differentiation
Cell Proliferation
Gene Deletion
Glycosylation
HEK293 Cells
Humans
Memory
Mice, Transgenic
N-Acetylglucosaminyltransferases / deficiency
N-Acetylglucosaminyltransferases / metabolism*
Neurogenesis*
Proteolysis
Receptors, Notch / chemistry
Receptors, Notch / metabolism*
Signal Transduction*
Stem Cells / cytology
Stem Cells / enzymology*
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

Substances

Receptors, Notch
Itch protein, mouse
Ubiquitin-Protein Ligases
N-Acetylglucosaminyltransferases
Ogt protein, mouse
Acetylglucosamine