O-GlcNAc transferase Ogt regulates embryonic neuronal development through modulating Wnt/ß-catenin signaling.

Ogt-mediated O-GlcNAcylation is enriched in the nervous system and involves in neuronal development, brain function and neurological diseases. However, the roles of Ogt and O-GlcNAcylation in embryonic neurogenesis have remained largely unknown. Here, we show that Ogt is highly expressed in embryonic brain, and Ogt depletion reduces the proliferation of embryonic neural stem cells and migration of new born neurons. Ogt depletion in cultured hippocampal neurons impairs neuronal maturation, including reduced dendritic numbers and length, and immature development of spines. Mechanistically, Ogt depletion decreases the activity of Wnt/ß-catenin signaling. Ectopic ß-catenin rescues neuronal developmental deficits caused by Ogt depletion. Ogt also regulates human cortical neurogenesis in forebrain organoids derived from induced pluripotent stem cells. Our findings reveal the essential roles and mechanisms of Ogt-mediated O-GlcNAc modification in regulating mammalian neuronal development.

Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway.

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3ß binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aß plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.

m6A Modification Involves in Enriched Environment-Induced Neurogenesis and Cognition Enhancement.

Although previous studies have shown that an enriched environment (EE) promotes neurogenesis and alters DNA and histone modifications, it remains largely unknown whether an EE affects epitranscriptome in the context of neuronal development. Here, we showed that EE exposure enhanced the pool of adult neural stem/progenitor cells (aNSPCs) and promoted neuronal differentiation of aNSPCs. EE exposure also improved cognitive capabilities and altered the expression of genes relating to neuronal development, neurogenesis, and memory. N 6-Methyladenosine (m6A) immunoprecipitation combined with deep sequencing (MeRIP-seq) data analysis revealed that EE exposure increased the global level of m6A and led to differential m6A mRNA modification. Differential m6A modification-associated genes are involved in neuronal development, neurogenesis, and so on. Notably, EE exposure decreased the protein level of m6A eraser Fto, but did not affect the protein level of m6A writers METTL3 and METTL14. Taken together, our results suggest that enriched environment exposure induces differential m6A mRNA modification and adds a novel layer to the interaction between the environment and epigenetics in the context of postnatal neuronal development.

FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development.

N6-methyladenosine (m6A) is the most abundant internal modification on mammalian messenger RNA. It is installed by a writer complex and can be reversed by erasers such as the fat mass and obesity-associated protein FTO. Despite extensive research, the primary physiological substrates of FTO in mammalian tissues and development remain elusive. Here, we show that FTO mediates m6A demethylation of long-interspersed element-1 (LINE1) RNA in mouse embryonic stem cells (mESCs), regulating LINE1 RNA abundance and the local chromatin state, which in turn modulates the transcription of LINE1-containing genes. FTO-mediated LINE1 RNA m6A demethylation also plays regulatory roles in shaping chromatin state and gene expression during mouse oocyte and embryonic development. Our results suggest broad effects of LINE1 RNA m6A demethylation by FTO in mammals.

RYBP modulates embryonic neurogenesis involving the Notch signaling pathway in a PRC1-independent pattern.

RYBP (Ring1 and YY1 binding protein), an essential component of the Polycomb repressive complex 1 (PRC1), plays pivotal roles in development and diseases. However, the roles of Rybp in neuronal development remains completely unknown. In the present study, we have shown that the depletion of Rybp inhibits proliferation and promotes neuronal differentiation of embryonic neural progenitor cells (eNPCs). In addition, Rybp deficiency impairs the morphological development of neurons. Mechanistically, Rybp deficiency does not affect the global level of ubiquitination of H2A, but it inhibits Notch signaling pathway in eNPCs. The direct interaction between RYBP and CIR1 facilitates the binding of RBPJ to Notch intracellular domain (NICD) and consequently activated Notch signaling. Rybp loss promotes CIR1 competing with RBPJ to bind with NICD, and inhibits Notch signaling. Furthermore, ectopic Hes5, Notch signaling downstream target, rescues Rybp-deficiency-induced deficits. Collectively, our findings show that RYBP regulates embryonic neurogenesis and neuronal development through modulating Notch signaling in a PRC1-independent manner.

Mutation-induced DNMT1 cleavage drives neurodegenerative disease.

Specific mutations within the replication foci targeting sequence (RFTS) domain of human DNMT1 are causative of two types of adult-onset neurodegenerative diseases, HSAN1E and ADCA-DN, but the underlying mechanisms are largely unknown. We generated Dnmt1-M1 and Dnmt1-M2 knock-in mouse models that are equivalent to Y495C and D490E-P491Y mutation in patients with HSAN1E, respectively. We found that both mutant heterozygous mice are viable, have reduced DNMT1 proteins, and exhibit neurodegenerative phenotypes including impaired learning and memory. The homozygous mutants die around embryonic day 10.5 and are apparently devoid of DNMT1 proteins. We present the evidence that the mutant DNMT1 proteins are unstable, most likely because of cleavage within RFTS domain by an unidentified proteinase. Moreover, we provide evidence that the RFTS mutation­induced cleavage of DNMT1, but not mutation itself, is responsible for functional defect of mutant DNMT1. Our study shed light on the mechanism of DNMT1 RFTS mutation causing neurodegenerative diseases.

Autism spectrum disorders: autistic phenotypes and complicated mechanisms.

BACKGROUND: Autism spectrum disorder (ASD), a pervasive developmental neurological disorder, is characterized by impairments in social interaction and communication, and stereotyped, repetitive patterns of interests or behaviors. The mechanism of ASDs is complex, and genetic components and epigenetic modifications play important roles. In this review, we summarized the recent progresses of ASDs focusing on the genetic and epigenetic mechanisms. We also briefly discussed current animal models of ASD and the application of high-throughput sequencing technologies in studying ASD. DATA SOURCES: Original research articles and literature reviews published in PubMed-indexed journals. RESULTS: Individuals with ASDs exhibit a set of phenotypes including neurological alteration. Genetic components including gene mutation, copy-number variations, and epigenetic modifications play important and diverse roles in ASDs. The establishment of animal models and development of new-generation sequencing technologies have contributed to reveal the complicated mechanisms underlying autistic phenotypes. CONCLUSIONS: Dramatic progress has been made for understanding the roles of genetic and epigenetic components in ASD. Future basic and translational studies should be carried out towards those candidate therapeutic targets.

Long Non-coding RNA in Neuronal Development and Neurological Disorders.

Long non-coding RNAs (lncRNAs) are transcripts which are usually more than 200 nt in length, and which do not have the protein-coding capacity. LncRNAs can be categorized based on their generation from distinct DNA elements, or derived from specific RNA processing pathways. During the past several decades, dramatic progress has been made in understanding the regulatory functions of lncRNAs in diverse biological processes, including RNA processing and editing, cell fate determination, dosage compensation, genomic imprinting and development etc. Dysregulation of lncRNAs is involved in multiple human diseases, especially neurological disorders. In this review, we summarize the recent progress made with regards to the function of lncRNAs and associated molecular mechanisms, focusing on neuronal development and neurological disorders.