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 tria...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-associ-ated 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-P-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.展开更多
基金supported by the National Natural Science Foundation of China(31770929 and 31522029)the Beijing Municipal Science and Technology Commission(Z181100001518001 and Z161100000216154)of China.
文摘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-associ-ated 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-P-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.
