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mecp2突变导致Rett综合征的发病机制及临床治疗研究进展

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中国优生与遗传杂志 2024年第7期 1529-1533页

作者：王慧敏崔向荣胡先明山西医科大学儿科医学系山西医科大学附属儿童医院

位于Xq28上的甲基-CpG结合蛋白2(mecp2)基因突变可导致多种严重的呈X连锁遗传的神经系统疾病。其中，mecp2突变主要与Rett综合征（RTT）相关。目前尚无治愈Rett综合征的方法，现有的主要治疗手段仍停留于对症治疗，以缓解症状，延长寿... 详细信息

位于Xq28上的甲基-CpG结合蛋白2(mecp2)基因突变可导致多种严重的呈X连锁遗传的神经系统疾病。其中，mecp2突变主要与Rett综合征（RTT）相关。目前尚无治愈Rett综合征的方法，现有的主要治疗手段仍停留于对症治疗，以缓解症状，延长寿命。通过逐渐深入的研究及小鼠模型的应用，Rett综合征的发病机制更加明确，针对Rett综合征的治疗思路不断更新。Rett综合征不是一种不可逆转的疾病，这一突破性的想法推动了对先进基因和RNA疗法有益效果的研究。基因替代、基因编辑、失活的X染色体再激活及IGF-1的内源性神经肽合成类似物等开始应用于Rett综合征的治疗。本文将回顾Rett综合征相关的发病机制及治疗手段，为Rett综合征的治疗提供更多思路。

关键词： Rett综合征 mecp2 基因编辑曲非奈肽

Loss of O-GlcNAcylation on mecp2 at Threonine 203 Leads to Neurodevelopmental Disorders

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Neuroscience Bulletin 2022年第2期38卷 113-134页

作者： Juanxian Cheng Zhe Zhao Liping Chen Ying Li Ruijing Du Yan Wu Qian Zhu Ming Fan Xiaotao Duan Haitao Wu Department of Neurobiology Beijing Institute of Basic Medical SciencesBeijing 100850China Chinese Institute for Brain Research Beijing 102206China Key Laboratory of Neuroregeneration Co-innovation Center of NeuroregenerationNantong UniversityNantong 226019China State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China

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 *** 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 *** 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 *** 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 ***,genetic disruption of O-GlcNAcylation at T203 on mecp2 decreased the neuronal activity-induced induction of Bdnf *** study highlights the critical role of mecp2 T203 O-GlcNAcylation in neural development and synaptic transmission potentially via brain-derived neurotrophic factor.

关键词： mecp2 O-GlcNAcylation-Dendrite development Synaptic transmission Braiderived neurotrophic factor

Extension of the Lifespan of a Mouse Model of Rett Syndrome by Intracerebroventricular Delivery of mecp2

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Neuroscience Bulletin 2023年第2期39卷 297-302页

作者： Kan Yang Cheng Cheng Yiting Yuan Yuefang Zhang Shifang Shan Zilong Qiu Center for Excellence in Brain Science and Intelligence Technology Institute of NeuroscienceState Key Laboratory of NeuroscienceCAS Key Laboratory of Primate NeurobiologyChinese Academy of SciencesShanghai 200031China Belief BioMed(Shanghai) Co.Ltd.Shanghai 200032China National Clinical Research Center for Aging and Medicine Huashan HospitalFudan UniversityShanghai 200040China

DearEditors,Rett Syndrome(RTT)is a severe neurodevelopmental disorder characterized by neural dysfunctions and a reduced lifespan,mainly in female patients,involving loss-of-function mutations in the methyl-CpG bindin... 详细信息

关键词： mecp2 Extension neural

Abnormal Prefrontal Neural Oscillations are Associated with Social Deficits in mecp2 Duplication Syndrome

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Neuroscience Bulletin 2022年第12期38卷 1598-1602页

作者： Xiao Li Yingnan Nie Qiyu Niu Xuanjun Guo Zilong Qiu Shouyan Wang Institute of Intelligent Robotics Academy for Engineering and TechnologyFudan UniversityShanghai 200433China Institute of Science and Technology for Brain-Inspired Intelligence Fudan UniversityShanghai 200433China Center for Excellence in Brain Science and Intelligence Technology Institute of NeuroscienceState Key Laboratory of NeuroscienceCAS Key Laboratory of Primate NeurobiologyChinese Academy of SciencesShanghai 200031China National Clinical Research Center for Aging and Medicine Huashan HospitalFudan UniversityShanghai 200040China

DearEditor,Methyl-CpG-binding protein 2(mecp2)participates in regulating the expression of the CREB,TDP-43 and Dnmtl genes[1,2].Recent studies have shown that mecp2 is essential for maintaining normal neural functions in the mammalian *** of mecp2causes mecp2 duplication syndrome[3],a type of autism spectrum disorder that results in a core phenotype of social deficits in human patients[4],nonhuman primates[5],and rodents[6].

关键词： mecp2 mecp2 patients

mecp2 deficiency promotes cell reprogramming by stimulating IGF1/AKT/mTOR signaling and activating ribosomal protein-mediated ceil cycle gene translation

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Journal of Molecular Cell Biology 2018年第6期10卷 515-526页

作者： Wei Zhang Guihai Feng Libin Wang Fei Teng Liu Wang Wei Li Ying Zhang Qi Zhou State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China

The generation of induced pturipotent stem cells (iPSCs)offers a great opportunity in research and regenerative *** current poor efficiency and incomplete mechanistic understanding of the reprogramming process hamper the clinical application of iPSCs. mecp2 connects histone modification and DNA methyiation,which are key changes of somatic cell ***,the rote of mecp2 in celt reprogramming has not been *** this study,we found that mecp2 deficiency enhanced reprogramming efficiency and stimulated cell proliferation through regulating cell cycle protein expression in the earLy stage of ***2 deficiency enhanced the expression of ribosomal protein genes,thereby enhancing reprogramming efficiency through promoting the translation of ceLl cycle *** the end,mecp2 deficiency stimulated IGF1/AKT/mTOR signaling and activated ribosomal protein gene *** together,our data indicate that mecp2 deficiency promoted cell reprogramming through stimulating IGF1/AKT/mTOR signaling and activating ribosomal protein-mediated cell cycle gene translation in the early stage of reprogramming.

关键词： mecp2 cell reprogramming IGFI/AKT/mTOR signaling ribosomal protein cell cycle

mecp2:multifaceted roles in gene regulation and neural development

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Neuroscience Bulletin 2014年第4期30卷 601-609页

作者： Tian-Lin Cheng Zilong Qiu Institute of Neuroscience Shanghai Institutes for Biological SciencesChinese Academy of Sciences

Methyl-CpG-binding protein 2 （mecp2） is a classic methylated-DNA-binding protein, dysfunctions of which lead to various neurodevelopmental disorders such as Rett syndrome and autism spectrum disorder. Initially recognized as a transcriptional repressor, mecp2 has been studied extensively and its functions have been expanded dramatically in the past two decades. Recently, it was found to be involved in gene regulation at the post-transcriptional level. mecp2 represses nuclear microRNA processing by interacting directly with the Drosha/DGCR8 complex. In addition to its multifaceted functions, mecp2 is remarkably modulated by post- translational modifications such as phosphorylation, SUMOylation, and acetylation, providing more regulatory dimensions to its functions. The role of mecp2 in the central nervous system has been studied extensively, from neurons to glia. Future investigations combining molecular, cellular, and physiological methods are necessary for defining the roles of mecp2 in the brain and developing efficient treatments for mecp2-related brain disorders.

关键词： mecp2 Rett syndrome central nervous system gene expression regulation post-translationalmodification post-transcriptional regulation glia

Visualization and correction of social abnormalities-associated neural ensembles in adult mecp2 duplication mice

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Science Bulletin 2020年第14期65卷 1192-1202,M0004页

作者： Le Sun Ruiguo Chen Long Li Bo Yuan Kun Song Na Pan Tian-Lin Cheng Shiyang Chang Kunzhang Lin Xiaobin He Qian Wu Fuqiang Xu Zilong Qiu Xiaoqun Wang State Key Laboratory of Brain and Cognitive Science CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of Brain-Intelligence Technology(Shanghai)Institute for Stem Cell and RegenerationInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Institute of Neuroscience CAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China The College of Life Science University of Chinese Academy of SciencesBeijing 100049China The College of Life Science Hebei Normal UniversityShijiazhuang 050016China State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics Wuhan Institute of Physics and MathematicsCAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesWuhan 430071China Advanced Innovation Center for Human Brain Protection Beijing Institute for Brain DisordersCapital Medical UniversityBeijing 100069China

Duplications of mecp2-containing genomic segments led to severe autistic symptoms in male. Transgenic mice overexpressing the human mecp2 gene exhibit autistic-like behaviors. Neural circuits underlying social defects in mecp2 transgenic(mecp2-TG) mice remain unknown. To observe neural activity of mecp2-TG mice in vivo, we performed calcium imaging by implantation of microendoscope in the hippocampal CA1 regions of mecp2-TG and wild type(WT) mice. We identified neurons whose activities were tightly associated with social interaction, which activity patterns were compromised in mecp2-TG mice. Strikingly, we rescued the social-related neural activity in CA1 and social defects in mecp2-TG mice by deleting the human mecp2 transgene using the CRISPR/Cas9 method during *** data points to the neural circuitry responsible for social interactions and provides potential therapeutic targets for autism in adulthood.

关键词： mecp2 CRISPR/Cas9 In vivo calcium imaging Social activity Autism

Generation of a monkey with mecp2 mutations by TALEN-based gene targeting

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Neuroscience Bulletin 2014年第3期30卷 381-386页

作者： Zhen Liu Xue Zhou Ying Zhu Zhi-Fang Chen Bin Yu Yan Wang Chen-Chen Zhang Yan-Hong Nie Xiao Sang Yi-Jun Cai Yue-Fang Zhang Chen Zhang Wen-Hao Zhou Qiang Sun Zilong Qiu Institute of Neuroscience Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Department of Neonatology Children’s Hospital of Fudan University State Key Laboratory of Biomembrane and Membrane Biotechnology School of Life Sciences PKU-IDG/McGovern Institute for Brain Research Peking University

Gene editing in model organisms has provided critical insights into brain development and diseases. Here, we report the generation of a cynomolgus monkey （Macaca fascicularis） carrying mecp2 mutations using transcription activator-like effector nucleases （TALENs）-mediated gene targeting. After injecting TALENs mRNA into monkey zygotes achieved by in vitro fertilization and embryo transplantation into surrogate monkeys, we obtained one male newborn monkey with an mecp2 deletion caused by frame- shifting mutation in various tissues. The monkey carrying the mecp2 mutation failed to survive after birth, due to either the toxicity of TALENs or the critical requirement of mecp2 for neural development. The level of mecp2 protein was essentially depleted in the monkey＇s brain. This study demonstrates the feasibility of introducing genetic mutations in non-human primates by site-specific gene-editing methods.

关键词： monkey TALEN mecp2 Rett syndrome

Expression of Phospho-mecp2s in the Developing Rat Brain and Function of Postnatal mecp2 in Cerebellar Neural Cell Development

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Neuroscience Bulletin 2017年第1期33卷 1-16页

作者： Fang Liu Jing-Jing Ni Feng-Yan Sun Department of Neurobiology Institute of Biomedical SciencesState Key Laboratory of Medical NeurobiologyShanghai Medical CollegeFudan UniversityShanghai 200032China Research Center on Aging and Medicine Shanghai Medical CollegeFudan UniversityShanghai 200032China

Abnormal expression and dysfunction of methyl-CpG binding protein 2 （mecp2） cause Rett syndrome （RTT）. The diverse phosphorylation modifications modulate mecp2 function in neural cells. Using western blot and immunohistochemistry, we examined the expression patterns of mecp2 and three phospho-mecp2s （pmecp2s） in the developing rat brain. The expression of mecp2 and phospho-S80 （pS80） mecp2 increased while pS421 mecp2 and pS292 mecp2 decreased with brain maturation. In contrast to the nuclear localization of mecp2 and pS80 mecp2, pS421 mecp2 and pS292 mecp2 were mainly expressed in the cytoplasmic com- partment. Apart from their distribution in neurons, they were also detected at a low level in astrocytes. Postnatallyinitiated mecp2 deficiency affected cerebellar neural cell development, as determined by the abnormal expression of GFAP, DCX, Tuj 1, MAP-2, and calbindin-D28k. Together, these results demonstrate that mecp2 and diverse pmecp2s have distinct features of spatio-temporal expression in the rat brain, and that the precise levels of mecp2 in the postnatal period are vital to cerebellar neural cell development.

关键词： mecp2 Phospho-mecp2 Braindevelopment Cytoplasm Astrocyte Cerebellum