Cell Identity Determination In Human Brain: Somatic Mutation and Cell Lineage

人脑中细胞身份的确定：体细胞突变和细胞谱系

• 批准号: 10673781
• 负责人: Christopher A. Walsh
• 金额: $ 68万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673781
• 关键词: Adult; Aging; Algorithms; Animal Model; Architecture; Autopsy; Bar Codes; Birth; Brain; Brain region; Brodmann' s area; Cell Cycle; Cell Lineage; Cell division; Cells; Cerebral cortex; Cognitive; Communities; Copy Number Polymorphism; DNA; DNA Integration; DNA Mutational Analysis; DNA Sequence Alteration; DNA analysis; Data; Development; Disease; Epilepsy; Fetal Development; Forensic Medicine; Funding; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Genome; Goals; Grant; Hippocampus; Human; Human Development; Human body; Inherited; Intellectual functioning disability; Life; Malignant Neoplasms; Maps; Measures; Mental disorders; Methods; Mosaicism; Mutation; Neocortex; Nerve Degeneration; Neurodevelopmental Disorder; Neuroglia; Neurons; Neurosciences; Pattern; Predisposition; Prefrontal Cortex; Primates; Publishing; RNA; RNA analysis; Retrotransposon; Sampling; Single Nucleotide Polymorphism; Somatic Cell; Somatic Mutation; Structure; Surface; Technology; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Visual Cortex; Work; autism spectrum disorder; brain cell; brain size; brain surgery; cell type; childhood epilepsy; dentate gyrus; disease-causing mutation; excitatory neuron; expectation; experimental study; genome sequencing; human disease; inhibitory neuron; insight; mosaic; neocortical; nervous system disorder; neural; postmitotic; postnatal development; prenatal; tool

Somatic mutations, present in some but not all cells of the brain, are increasingly implicated in neurological and psychiatric diseases. Somatic mutations that arise during the cell divisions of prenatal brain development are inherited in clonal fashion and can cause neurodevelopmental diseases such as epilepsy and intellectual disability, even when present at low levels of mosaicism. The previous funding period of this grant developed new methods and algorithms to analyze somatic mutations in postmortem human brain, and technologies to sequence the genomes of single neurons, and has shown that each neuron has a unique genome, with hundreds of developmental mutations present at birth, and dozens more mutations being added each year of life. During prenatal life, 2-3 mutations mark each cell division, so that mutations make in principal a permanent record of each cell division. Integrating the analysis of DNA marks of cell lineage with patterns of gene expression that identify the different neural types in human brain potentially now enables the discovery of the first systematic picture of the pattern of cell divisions that generates the cells of the human brain. In this project, we will apply our existing methods to provide several scientific discoveries not otherwise attainable, providing tools of widespread utility to the genetics and neuroscience communities. Our three Specific Aims will be to 1) use simultaneous analysis of DNA mutations and RNA gene expression to map the lineage of neural cell types in cerebral cortex; 2) map clonal patterns across the surface of the human cerebral cortex to see how they relate to functional subdivisions of the cortex; and 3) focus on the analysis of development of human temporal lobe, which is subject to many unique conditions like temporal lobe epilepsy. These data provide three major discoveries which have all been major goals of neuroscience and which are not presently obtainable by other means: 1) the first direct cell lineage data from the adult human brain, 2) a preliminary lineage map connecting neuronal cell classes, and 3) unique insight into temporal lobe development.

体细胞突变存在于大脑的一些细胞中，但不是全部，越来越多地与 神经和精神疾病。产前大脑细胞分裂过程中出现的体细胞突变 发育以克隆方式遗传，可导致神经发育疾病，例如癫痫和 智力障碍，即使存在低水平的镶嵌现象。本次资助的上一资助期 开发了新的方法和算法来分析死后人脑中的体细胞突变，并且 对单个神经元的基因组进行测序的技术，并表明每个神经元都有独特的 基因组，出生时就存在数百个发育突变，并且还添加了数十个突变 生命中的每一年。在产前生命中，每次细胞分裂都会有 2-3 个突变，因此突变会导致 负责每次细胞分裂的永久记录。将细胞谱系 DNA 标记分析与 识别人脑中不同神经类型的基因表达模式现在可能使 发现了产生人类细胞的细胞分裂模式的第一张系统图 脑。在这个项目中，我们将应用我们现有的方法来提供一些原本没有的科学发现 可以实现，为遗传学和神经科学界提供广泛实用的工具。 我们的三个具体目标是 1) 同时分析 DNA 突变和 RNA 基因 表达以绘制大脑皮层神经细胞类型谱系； 2) 绘制整个表面的克隆模式 人类大脑皮层的结构，了解它们与皮层功能细分的关系； 3) 重点关注 分析人类颞叶的发育，该发育受颞叶等许多独特条件的影响 癫痫。 这些数据提供了三个重大发现，它们都是神经科学的主要目标，并且 目前无法通过其他方式获得：1）来自成人大脑的第一个直接细胞谱系数据，2） 连接神经元细胞类别的初步谱系图，以及 3) 对颞叶的独特见解 发展。

项目成果

Genomic variants and variations in malformations of cortical development.

• DOI: 10.1016/j.pcl.2015.03.002
• 发表时间: 2015-06
• 期刊: PEDIATRIC CLINICS OF NORTH AMERICA
• 影响因子: 2.6
• 作者: Jamuar, Saumya S.;Walsh, Christopher A.
• 通讯作者: Walsh, Christopher A.

Aging and neurodegeneration are associated with increased mutations in single human neurons.

• DOI: 10.1126/science.aao4426
• 发表时间: 2018-02-02
• 期刊: Science (New York, N.Y.)
• 作者: Lodato MA;Rodin RE;Bohrson CL;Coulter ME;Barton AR;Kwon M;Sherman MA;Vitzthum CM;Luquette LJ;Yandava CN;Yang P;Chittenden TW;Hatem NE;Ryu SC;Woodworth MB;Park PJ;Walsh CA
• 通讯作者: Walsh CA

The cerebrospinal fluid provides a proliferative niche for neural progenitor cells.

• DOI: 10.1016/j.neuron.2011.01.023
• 发表时间: 2011-03-10
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Lehtinen MK;Zappaterra MW;Chen X;Yang YJ;Hill AD;Lun M;Maynard T;Gonzalez D;Kim S;Ye P;D'Ercole AJ;Wong ET;LaMantia AS;Walsh CA
• 通讯作者: Walsh CA

Isolation of cerebrospinal fluid from rodent embryos for use with dissected cerebral cortical explants.

• DOI: 10.3791/50333
• 发表时间: 2013-03
• 期刊: Journal of visualized experiments : JoVE
• 作者: Mauro W. Zappaterra;A. LaMantia;C. Walsh;Maria K. Lehtinen

The apical complex couples cell fate and cell survival to cerebral cortical development.

• DOI: 10.1016/j.neuron.2010.03.019
• 发表时间: 2010-04-15
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Kim S;Lehtinen MK;Sessa A;Zappaterra MW;Cho SH;Gonzalez D;Boggan B;Austin CA;Wijnholds J;Gambello MJ;Malicki J;LaMantia AS;Broccoli V;Walsh CA
• 通讯作者: Walsh CA