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：
9791777
负责人：
Hooman Troy Ghashghaei
金额：
$ 5.02万
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 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9791777
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 Home environment Image Lead Life Link MAP Kinase Gene Malignant Neoplasms Mammals Mental Retardation Microcephaly Mitosis Modeling Molecular Mouse Strains Natural regeneration Nervous System Physiology Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurons Pathologic Pathway interactions Patients Phase Phosphorylation Phosphotransferases Post-Translational Protein Processing Process Production Proteins Protocols documentation Publishing RNA RNA analysis Research Proposals Role Schizophrenia Signal Transduction Slice Specificity Stem cells Surface Testing Therapeutic Tight Junctions Tissues Transact Transcriptional Regulation Translations Ventricular Zinc Fingers base brain behavior cognitive task daughter cell epigenetic regulation in vivo member mgcRacGAP migration nerve stem cell network models neurodevelopment neuroepithelium neurogenesis novel overexpression public health relevance 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（由申请人提供）：神经元和神经胶质细胞是成熟大脑的运作单位，主要源自胚胎发育过程中的神经干细胞（NSC），神经干细胞在大脑皮层中产生神经元和神经胶质细胞，对哺乳动物尤其重要。因为它们最终会产生使我们能够执行高阶认知任务的组织，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，新神经元的生成和迁移的严重破坏可能会导致。小头畸形和无脑畸形，而较轻微的发育缺陷可能会导致神经元连接缺陷，例如自闭症谱系和精神分裂症中明显的神经元连接缺陷。调节皮质发育的分子和细胞信号的发育时序尤其重要，因为时间上不同的损伤可能会影响皮质。与影响神经干细胞胞质分裂的机制相关的许多缺陷是不同疾病的基础，因此了解干细胞如何分裂，以及在大脑过程中控制其分裂变化的因素。神经干细胞的发育和成熟对于理解神经发育障碍至关重要。在皮质发育过程中，神经干细胞必须在其细胞分裂中保持极其重要的平衡。它们可以通过不对称分裂产生神经元和神经胶质细胞，目前对调节这些重要分裂的细胞和分子机制的理解仍然支离破碎，并且关于这一过程的主要调节因子还有很多有待发现。的家人锌指特异性蛋白当我们仅在发育中的大脑皮层的神经干细胞中删除 Sp2 基因时，我们发现干细胞的积累会损害神经发生，相反，Sp2 的过度表达会迅速推动干细胞从心室的上皮细胞中剥离。我们发现了许多有趣的细胞生物学主题，这些主题是 Sp2 对 NSC 的有效影响的基础，我们在初步数据中介绍了这些研究结果。提议结合使用最先进的遗传小鼠品系、细胞和切片培养测定、实时成像协议、生化测定以及 Sp2 依赖的 RNA 和蛋白质景观图谱来测试 Sp2- 的中心假设依赖转录通过调节发育中的大脑皮质中 NSC 的对称和不对称分裂来调节增殖和分化的正确平衡，我们提供了初步证据表明 Sp2 可能通过其相互作用在 NSC 中发挥这一关键功能。因此，我们的研究建议探索一种新的机制模型，将驱动胞质分裂的分子机制与神经干细胞的不对称分裂联系起来，以产生大脑皮质中的神经元：我们理解的方法。皮质干细胞如何对称或不对称分裂具有广泛的影响。各种干细胞的对称和不对称决定是整个身体组织发育和再生的关键，干细胞分裂的这种平衡的破坏可能会导致一系列的后果。因此，了解控制这一关键神经干细胞功能的基本细胞机制对于理解干细胞在正常发育过程中如何进行适当的分裂以及它们的异常分裂是如何进行的至关重要。此外，我们研究的机制可用于更好地定义和完善重编程策略，以生成患者特异性干细胞、神经元和神经胶质细胞及其在各种脑部疾病中的潜在治疗应用。