Mechanisms of cytokinesis and delamination in the cerebral cortices

大脑皮质胞质分裂和分层的机制

基本信息

批准号：
9134875
负责人：
Hooman Troy Ghashghaei
金额：
$ 32.23万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9134875
关键词：
Adherens Junction Adhesions Adhesives Anencephaly Apical Autistic Disorder Biochemical Bioinformatics Biological Biological Assay Brain Brain Diseases Cell Cycle Cell Cycle Stage Cell Maturation Cell Therapy Cell division Cell physiology Cells Cerebral cortex ChIP-seq Complex Cytokinesis DNA Binding Domain Data Defect Development Developmental Process Disease Embryonic Development Epithelial Equilibrium Event Excision Exhibits Failure Family Generations Genes Genetic Genetic Transcription Health Home environment Image Lead Life Link MAP Kinase Gene Malignant Neoplasms Mammals Maps Mental Retardation Microcephaly Mitosis Modeling Molecular Mouse Strains Natural regeneration Nervous System Physiology Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurons Pathway interactions Patients Phase Phosphorylation Phosphotransferases Post-Translational Protein Processing Process Production Proteins Protocols documentation Publishing RNA Research Proposals Role Schizophrenia Signal Transduction Slice Specificity Stem cells Surface Testing Therapeutic Tight Junctions Time Tissues Transact Transcriptional Regulation Translations Ventricular Work Zinc Fingers base brain behavior cognitive task daughter cell epigenetic regulation in vivo member mgcRacGAP migration nerve stem cell network models neuroepithelium neurogenesis novel overexpression receptor self-renewal stem cell division trafficking transcription factor transcriptome transcriptome sequencing tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Neurons and glia, the operating units of the mature brain, are derived from neural stem cells (NSCs) largely during embryonic development. NSCs that give rise to neurons and glia in the cerebral cortex are particularly important to mammals as they ultimately generate the tissue that allows us to perform high-order cognitive tasks. Many neurodevelopmental disorders are caused by abnormalities in molecular and cellular machinery involved in various NSC functions. For example severe disruptions in generation and migration of new neurons can cause microcephaly and anencephaly, whereas milder developmental defects may result in imperfections in connectivity of neurons such as those becoming apparent in Autism spectrum and schizophrenia. The developmental timing of molecular and cellular signals that regulate cortical development are particularly important as temporally distinct insult may impact the cortex, activity in the brain, and behavior differentially. A number of defects associated with mechanisms that impact cytokinesis in NSCs underlie distinct diseases. Therefore understanding how stem cells divide, and what governs changes in their division during the course of brain development and NSC maturation is critical to understanding neurodevelopmental disorders. In the course of cortical development NSCs must maintain an extremely important balance in their cellular divisions. They must first expand their own pool through symmetric divisions, after which they must switch how they divide so that they can generate neurons and glia through asymmetric divisions. The current understanding of cellular and molecular mechanisms that regulate these important divisions remains fragmented and much remains to be discovered regarding master regulators of this process. We recently discovered a novel regulator of this process belongs to a family of zinc-finger specificity protein transcription factors, called Sp2. We found accumulation of stem cells at the expense of neurogenesis when we deleted the Sp2 gene only in NSCs of the developing cerebral cortex. In contrast overexpression of Sp2 rapidly pushes stem cells to delaminate from their epithelial home in the ventricular surface of the developing cortex, and precociously generate cortical neurons. We have discovered a number of intriguing cell biological themes that underlie the potent effects of Sp2 on NSCs, which we present in our preliminary data. With these findings, we propose to use a combination of state-of-the-art genetic mouse strains, cell and slice culture assays, live imaging protocols, biochemical assays, and mapping of RNA and protein landscapes that are Sp2-depenent to test the central hypothesis that Sp2-dependent transcription regulates the correct balance of proliferation and differentiation by regulating symmetric and asymmetric divisions of NSCs in the developing cerebral cortices. We provide preliminary evidence that Sp2 may carry out this critical function in NSCs through its interactions with known mechanisms and pathways of cell division. Thus, our study proposes to explore a novel mechanistic model that links molecular machineries that drive cytokinesis with asymmetric division of NSCs for production of neurons in the cerebral cortices. Potential for Broader Impact: Our approaches to understand how cortical stem cells divide symmetrically or asymmetrically have wide implications. Symmetric and asymmetric decisions in various stem cells are key to tissue development and regeneration throughout the body. Disruption of this balance in division of stem cells can lead to a range of pathological conditions from developmental retardation of tissues to oncogenesis. Therefore, undertaking the basic cellular mechanisms that control this key neural stem cell function is critical to understanding not only how appropriate divisions are controlled in stem cells during normal development, but also how their abnormal divisions in pathological conditions lead to devastating diseases such as cancer. Moreover, the mechanisms we study can be harnessed to better define and refine reprogramming strategies for generation of patient-specific stem cells, neurons, and glia and their potential therapeutic application in various brain diseases.

描述（由适用提供）：成熟大脑的工作单位神经元和神经胶质在胚胎发育过程中源自神经元细胞（NSC）。引起大脑皮质中神经元和神经胶质的NSC对哺乳动物尤为重要，因为它们最终会产生组织，从而使我们能够执行高阶认知任务。许多神经发育障碍是由参与各种NSC功能的分子和细胞机制异常引起的。例如，新神经元的产生和迁移的严重破坏会导致小头畸形和异常，而米勒发育缺陷可能会导致神经元的连通性不完美，例如在自闭症和精神分裂症中显而易见的神经元。调节皮质发育的分子和细胞信号的发育时机尤为重要，因为暂时不同的侮辱可能会影响大脑的皮质，活性和行为不同。与影响NSC中细胞因子的机制有关的许多缺陷是不同的疾病。因此，了解干细胞如何分裂，以及在大脑发育和NSC成熟过程中的分裂变化的原因对于理解神经发育障碍至关重要。在皮层发展过程中，NSC必须在其细胞分裂中保持极为重要的平衡。他们必须首先通过对称分区扩大自己的池，之后他们必须切换分裂的方式，以便可以通过不对称的划分产生神经元和神经胶质。当前对调节这些重要分裂的细胞和分子机制的理解仍然分散，并且有关此过程的主调节剂仍有许多待发现。我们最近发现了一个新的过程调节剂属于锌指特异性蛋白家族转录因子，称为SP2。我们发现，仅在发育中的大脑皮质的NSC中删除SP2基因时，干细胞的积累是以神经发生为代价的。相比之下，SP2的过表达迅速推动干细胞从其在发育中皮质的心室表面上的上皮家中分层，并早熟产生皮质神经元。我们已经发现了许多有趣的细胞生物学主题，这些主题是SP2对NSC的潜在影响的基础，我们在初步数据中提出了SP2。有了这些发现，我们建议将最先进的遗传小鼠菌株，细胞和切片培养测定法，实时成像协议，生化测定法以及RNA和蛋白质景观的映射与SP2相关的SP2依赖于SP2依赖性转录的核心假设的依赖性和依赖于SP2依赖性的依赖性划分的中心差异的依赖性疾病的群体依赖的质量分化的质量分化的质量依赖的中心假设的映射以及脑皮质。我们提供了初步证据，表明SP2可以通过其相互作用在NSC中执行此关键功能具有已知机制和细胞分裂途径。这是我们的研究提案，探讨了一种新型的机械模型，该模型将驱动细胞因子的分子机器与NSC的不对称分裂联系起来，以生产大脑皮质中的神经元。产生更广泛影响的潜力：我们了解皮质干细胞如何对称或不对称地划分具有广泛意义的方法。各种干细胞中的对称和不对称决策是整个人体组织发育和再生的关键。干细胞分裂平衡的破坏可能导致一系列病理条件，从时间的发育迟缓到肿瘤发生。因此，采取控制此关键神经干细胞功能的基本细胞机制不仅要理解正常发育过程中干细胞中适当的分裂如何控制适当的分裂，而且对病理状况中的异常分裂如何导致诸如癌症等毁灭性疾病。此外，我们可以利用我们研究的机制来更好地定义和完善重编程策略，以生成患者特异性干细胞，神经元和神经胶质的生成及其在各种脑部疾病中的潜在治疗应用。