Loss of O-GlcNAcylation on MeCP2 at Threonine 203 Leads to Neurodevelopmental Disorders.
10.1007/s12264-021-00784-8
- Author:
Juanxian CHENG
1
;
Zhe ZHAO
1
;
Liping CHEN
1
;
Ying LI
1
;
Ruijing DU
1
;
Yan WU
1
;
Qian ZHU
1
;
Ming FAN
1
;
Xiaotao DUAN
2
;
Haitao WU
3
Author Information
1. Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
2. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. xduan@ncba.ac.cn.
3. Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. wuht@bmi.ac.cn.
- Publication Type:Journal Article
- Keywords:
Brain-derived neurotrophic factor;
Dendrite development;
MeCP2;
O-GlcNAcylation;
Synaptic transmission
- MeSH:
Animals;
Humans;
Methyl-CpG-Binding Protein 2/metabolism*;
Mice;
Neurodevelopmental Disorders/genetics*;
Rett Syndrome/genetics*;
Synaptic Transmission;
Threonine
- From:
Neuroscience Bulletin
2022;38(2):113-134
- CountryChina
- Language:English
-
Abstract:
Mutations of the X-linked methyl-CpG-binding protein 2 (MECP2) gene in humans are responsible for most cases of Rett syndrome (RTT), an X-linked progressive neurological disorder. While genome-wide screens in clinical trials have revealed several putative RTT-associated mutations in MECP2, their causal relevance regarding the functional regulation of MeCP2 at the etiologic sites at the protein level requires more evidence. In this study, we demonstrated that MeCP2 was dynamically modified by O-linked-β-N-acetylglucosamine (O-GlcNAc) at threonine 203 (T203), an etiologic site in RTT patients. Disruption of the O-GlcNAcylation of MeCP2 specifically at T203 impaired dendrite development and spine maturation in cultured hippocampal neurons, and disrupted neuronal migration, dendritic spine morphogenesis, and caused dysfunction of synaptic transmission in the developing and juvenile mouse cerebral cortex. Mechanistically, genetic disruption of O-GlcNAcylation at T203 on MeCP2 decreased the neuronal activity-induced induction of Bdnf transcription. Our study highlights the critical role of MeCP2 T203 O-GlcNAcylation in neural development and synaptic transmission potentially via brain-derived neurotrophic factor.
