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The generation and properties of human cortical organoids as a disease model for malformations of cortical development

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Neural Regeneration Research 2023年第10期18卷 2119-2126页

作者： Xiu-Ping Zhang Xi-Yuan Wang Shu-Na Wang Chao-Yu Miao Department of Pharmacology Second Military Medical University/Naval Medical UniversityShanghaiChina

As three-dimensional“organ-like”aggregates,human cortical organoids have emerged as powerful models for studying human brain evolution and brain disorders with unique advantages of humanspecificity,fidelity and *** cortical organoids derived from human pluripotent stem cells can elaborately replicate many of the key properties of human cortical development at the molecular,cellular,structural,and functional levels,including the anatomy,functional neural network,and interaction among different brain regions,thus facilitating the discovery of brain development and *** addition to studying the neuro-electrophysiological features of brain cortex development,human cortical organoids have been widely used to mimic the pathophysiological features of cortical-related disease,especially in mimicking malformations of cortical development,thus revealing pathological mechanism and identifying effective *** this review,we provide an overview of the generation of human cortical organoids and the properties of recapitulated cortical development and further outline their applications in modeling malformations of cortical development including pathological phenotype,underlying mechanisms and rescue strategies.

关键词： cortical development disease models human cortical organoids human cortical spheroids human pluripotent stem cells malformations of cortical development telencephalon organoids whole brain organoids

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Regulation of cortical development by Anaplastic Lymphoma Kinase

Regulation of Cortical Development by Anaplastic Lymphoma Ki...

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中国神经科学学会第十二届全国学术会议

作者： Rui Mao Guo Wang Rui Deng Zhengping Jia Zikai Zhou The Key Laboratory of developmental Genes and Human Disease Ministry of Education Institute of Life Sciences Southeast University Neurosciences and Mental Health The Hospital for Sick Children Department of Physiology University of Toronto

Anaplastic lymphoma kinase（Alk） is a receptor-type protein tyrosine kinase that is transiently and specifically expressed in the nervous systems during embryonic stages. Studies in Drosophila, Caenorhabditis elegans and mice have reported that Alk signaling plays important role in learning and neurogenesis while its physiological function in the development of mammalian brain remains unclear. In this study, we focused on the role of Alk in the cerebral cortical development in mice. We employed RNAi and pharmacological inhibition in cultured human neural progenitor cells（h NPCs） derived from embryonic stem cells and C57/B6 wild-type embryonic mice to inhibit Alk signaling, respectively. We examined the effects of Alk inhibition on neuronal proliferation, apoptosis and cell cycle in cultured h NPCs by FACS and immunocytochemistry. In addition, we analyzed the neuronal proliferation, differentiation and migration in embryonic mouse brain by immunohistochemistry after Alk signaling disruption. The results indicate that Alk regulates cortical development by promoting the proliferation and survival of neural progenitor cells.

关键词： Anaplastic lymphoma kinase cortical development neural progenitor cells

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Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins

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Neural Regeneration Research 2025年第1期20卷 242-252页

作者： Daiyu Hu Yuanqing Cao Chenglin Cai Guangming Wang Min Zhou Luying Peng Yantao Fan Qiong Lai Zhengliang Gao Fundamental Research Center Shanghai Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center)School of MedicineTongji UniversityShanghaiChina Institute of Geriatrics(Shanghai University) Affiliated Nantong Hospital of Shanghai University(The Sixth People’s Hospital of Nantong)Shanghai University School of MedicineNantongJiangsu ProvinceChina Shanghai Engineering Research Center of Organ Repair Shanghai University School of MedicineShanghaiChina Key Laboratory of Arrhythmias Ministry of EducationShanghai East HospitalSchool of MedicineTongji UniversityShanghaiChina

Human brain development is a complex process,and animal models often have significant *** address this,researchers have developed pluripotent stem cell-derived three-dimensional structures,known as brain-like organoids,to more accurately model early human brain development and *** enable more consistent and intuitive reproduction of early brain development,in this study,we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid *** involved embedding organoids in matrigel for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrigel for further cultivation,resulting in a new type of human brain organoid *** cerebral organoid system replicated the temporospatial characteristics of early human brain development,including neuroepithelium derivation,neural progenitor cell production and maintenance,neuron differentiation and migration,and cortical layer patterning and formation,providing more consistent and reproducible organoids for developmental modeling and toxicology *** a proof of concept,we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental *** organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns,including bursts of cortical cell death and premature *** exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity,accompanied by compensatory cell proliferation at ectopic *** convenience,flexibility,and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental,neurological,and neurotoxicological studies.

关键词： cadmium cell death cell proliferation cortical development environmental toxins neural progenitor cells neurogenesis neurotoxicology organoids stem cells

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Transcriptome Analysis Identifies SenZfp536,a Sense LncRNA that Suppresses Self-renewal of cortical Neural Progenitors

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Neuroscience Bulletin 2021年第2期37卷 183-200页

作者： Kuan Tian Andi Wang Junbao Wang Wei Li Wenchen Shen Yamu Li Zhiyuan Luo Ying Liu Yan Zhou College of Life Sciences Renmin Hospital of Wuhan UniversityWuhan UniversityWuhan430072China Frontier Science Center for Immunology and Metabolism Medical Research InstituteSchool of MedicineWuhan UniversityWuhan430071China Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China

Long non-coding RNAs(lncRNAs)regulate transcription to control development and homeostasis in a variety of tissues and ***,their roles in the development of the cerebral cortex have not been well ***,a bioinformatics pipeline was applied to delineate the dynamic expression and potential cis-regulating effects of mouse lncRNAs using transcriptome data from 8 embryonic time points and sub-regions of the developing cerebral *** further characterized a sense lncRNA,SenZfp536,which is transcribed downstream of and partially overlaps with the protein-coding gene *** SenZfp536 and Zfp536 were predominantly expressed in the proliferative zone of the developing ***536 was cis-regulated by SenZfp536,which facilitates looping between the promoter of Zfp536 and the genomic region that transcribes ***,knocking down or activating the expression of SenZfp536 increased or compromised the proliferation of cortical neural progenitor cells(NPCs),***,overexpressing Zfp536 in cortical NPCs reversed the enhanced proliferation of cortical NPCs caused by SenZfp536 *** study deepens our understanding of how lncRNAs regulate the propagation of cortical NPCs through cis-regulatory mechanisms.

关键词： Zfp536 Sense lncRNA Self-renewal cortical development Neural progenitor

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Transcriptome analysis of human embryonic cortex development by single cell RNA-seq

Transcriptome analysis of human embryonic cortex development...

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中国神经科学学会第十二届全国学术会议

作者： Suijuan Zhong Xiaoying Fan Qian Wu Wensu Liu Fuchou Tang Xiaoqun Wang Institute of Biophysics CAS Beijing Advanced Innovation Center for Genomics (ICG) College of Life Sciences Peking University

The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitors. Subtypes of progenitors that are common in humans but virtually absent in rodents, called outer radial glia（ORG）, have been proposed to be crucial to the evolutionary expansion of the human cortex. Combined progenitor subtype-specific sorting with single cell transcriptome-wide RNA sequencing to identify genes enriched in human ORG. In summary, single-cell transcriptional profiling in human revealed the transcriptional heterogeneity of cortical progenitors.

关键词： Single cell sequence cortical development Neural stem cell

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Myosin X is required for the migration of cortical neurons through regulating cytoskeleton

Myosin X is required for the migration of cortical neurons t...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Xing-Da JU,Ye GUO,Hua-Li YU,Yu-Ting LI,Xiao-Juan ZHU~* Laboratory of Neural Plasticity,Key Laboratory of Molecular Epigenetics of Ministry of Education,Institute of Cytology and Genetics,Northeast Normal University,Changchun 130024

＜正＞Objective cortical development is an important process during the establishment of nervous *** generation of cortical layers relies on the proliferation,differentiation,migration and projection of cortical neurons with an inside-out mode,and nearly all these processes are closely related with the regulation of *** X（Myo X）,an untraditional member of myosin families,was found to interact directly with both microfilaments and microtubules,and had been identified as a functional factor during nerve cells migration of Xenopus and zebrafish. Research has previously shown that Myo X is highly expressed during brain development,however,little is known of the role that Myo X is required for neuronal migration in cerebral *** we report that Myo X promotes neuronal migration by regulating the dynamics of *** Firstly,we analyzed the expression pattern of Myo X in the developing cortex with in situ hybridization and immunohistochemistry ***,to determine the function of Myo X in the expressed area,in utero electroporation was performed with Myo X miRNA at E15.5 and brains were analyzed at E18.5,a period of time when neuronal migration is ***,to further explore the mechanism that Myo X regulates neuronal migration,we cultured neurons from electroporated brains. Results（1） Myo X is mainly expressed in the VZ,SVZ and IZ zones.（2） Knocking down the expression of Myo X resulted in a migration defect in the cortical plate,which was caused by morphological changes of migrating neurons, cells lacking Myo X failed to adopt the bipolar morphology that Myo X-expressing cells acquired.（3） Being the same as the morphological analysis in vivo,cells lacking Myo X have changed dynamic regulation of cytoskeleton. Conclusion Our data suggested that Myo X mediated neuronal migration by regulating cellular morphology through modulation of the cytoskeleton dynamics.

关键词： cortical development neuronal migration Myosin X cytoskeleton dynamic

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Characterization of the Frizzled10-CreERTM transgenic mouse:an inducible cre line for the study of Cajal-Retzius cell development

Characterization of the Frizzled10-CreERTM transgenic mouse:...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Samuel J.Pleasure Department of Neurology Programs in NeuroscienceDevelopmental Biology and Biomedical SciencesSan FranciscoCalifornia

＜正＞Cajal-Retzius（CR） cells are among the earliest born cortical neurons and are located in the marginal zone of the cerebral cortex,the most superficial cortical layer adjacent to the pial *** cells play a major role in regulating both migration of other neurons and cortical network maturation by regulating synapse and dendrite formation during murine and human cortical development.A number of studies have indicated that CR cells and their best characterized gene product,the secreted glycoprotein reelin,are involved in neuronal *** plays a key role in the normal inside-out formation of neocortical *** layers are inverted and cells are abnormally dispersed in reeler mice,which lack normal reelin *** defects are observed in mice lacking the two reelin receptors,the very-low-density lipoprotein receptor and the apolipoprotein E receptor *** considerable research effort has been devoted to CR cells since their discovery by *** y Cajal and *** more than a century ago,the function of these cells during cortical development is still not fully ***,the precise molecular and cellular mechanisms by which these intriguing neurons regulate the development of the cerebral cortex remain to be *** of the difficulty is that CR cells do not serve a single function but instead exert several disparate effects at distinct stages of development,and tools have been lacking to dissect these *** recent years,the Cre recombinase from bacteriophage PI has become an essential tool for conditional gene activation and inactivation in the mouse for the study of gene functions and the downstream molecular ***,to allow conditional modification of gene activity at distinct stages of development,a fusion protein composed of Cre and a mutated form of the ligand binding domain of the estrogen receptor（Cre-ERTM） have been generated in which the Cre activity can be induced efficiently

关键词： Cajal-Retzius cell reelin CreERTM Frizzled 10 Wnt cortical hem cortical development neuron migration

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The role and mechanism of autophagy on the regulation of embryonic brain development and neural stem cell differentiation

The role and mechanism of autophagy on the regulation of emb...

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中国神经科学学会第十届全国学术会议

作者： Xiaohui Lv Huihui Jiang Baoguo Li Qingli Liang Yanli Liu Shukun Wang Qianwei Zhao Yaqing Wang Wei Li Jianwei Jiao State Key Laboratory of Reproductive Biology Institute of ZoologyChinese Academy of Sciences Key Laboratory of Animal Ecology and Conservation Biology Institute of ZoologyChinese Academy of Sciences Center for developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of Sciences

Autophagy as a bulk degradation pathway plays important roles in ***,it is still unknown that how autophagy regulates cortical neurogenesis during brain *** we report that the regulatory roles of autophagy-related 5(Atg5),which is essential for autophagosome formation,in embryonic cortical *** observed that Atg5 and microtubule-associated protein 1 light chain 3(LC3) expression increased with the brain development and the differentiation *** of Atg5 expression inhibited neural progenitor differentiation,and affected proliferation and cell-cycle exit *** deletion of Atg5 by Cre in Atg5 mice showed that Atg5 regulated neural progenitor ***,Atg5 knockdown caused neuronal migration delay and neuronal cell morphology ***,we found Atg5 regulated β-catenin signaling ***5cooperates with β-catenin to mediate neural progenitor *** findings show that crucial roles of Atg5 in neurogenesis during embryonic cortical development,which may contribute to the explanation of neurodegenerative disorders caused by autophagy dysregulation.

关键词： autophagy Atg5 neurogenesis cortical development

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