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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）：神经元和神经胶质是成熟大脑的操作单位，主要来源于胚胎发育期间的神经干细胞（NSC）。在大脑皮层中产生神经元和神经胶质的神经干细胞对哺乳动物特别重要，因为它们最终产生允许我们执行高级认知任务的组织。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严重中断可能导致小头畸形和无脑畸形，而轻度发育缺陷可能导致神经元连接的缺陷，例如自闭症谱系和精神分裂症中变得明显的缺陷。调节皮质发育的分子和细胞信号的发育时间是特别重要的，因为时间上不同的损伤可能会影响皮质、大脑活动和行为差异。与影响NSC中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，以及在大脑发育和NSC成熟过程中是什么控制其分裂变化，对于了解神经发育障碍至关重要。在皮质发育过程中，神经干细胞必须在细胞分裂中保持极其重要的平衡。它们必须首先通过对称分裂来扩大自己的细胞库，然后它们必须改变它们的分裂方式，这样它们就可以通过不对称分裂来产生神经元和神经胶质。目前对调节这些重要分裂的细胞和分子机制的理解仍然是支离破碎的，关于这一过程的主要调节因子还有很多有待发现。我们最近发现了一个新的调节这一过程属于一个家庭的锌指特异性蛋白转录因子Sp2。当我们只在发育中的大脑皮层的神经干细胞中删除Sp2基因时，我们发现了以神经发生为代价的干细胞积累。相反，Sp2的过表达迅速推动干细胞从发育中的皮质的心室表面中的上皮细胞家分层，并早熟地产生皮质神经元。我们已经发现了一些有趣的细胞生物学主题，这些主题是Sp2对NSC的有效作用的基础，我们在我们的初步数据中提出了这些主题。有了这些发现，我们建议使用最先进的遗传小鼠品系，细胞和切片培养测定，活体成像方案，生化测定，以及绘制依赖于Sp2的RNA和蛋白质景观图，以检验Sp2-依赖性转录通过调节发育中的大脑中NSC的对称和不对称分裂来调节增殖和分化的正确平衡。皮质我们提供的初步证据表明，Sp2可能通过其相互作用在神经干细胞中发挥这一关键作用。已知的细胞分裂机制和途径。因此，我们的研究提出探索一种新的机制模型，该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，以在大脑皮层中产生神经元。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分裂的方法具有广泛的影响。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。干细胞分裂中的这种平衡的破坏可导致从组织发育迟缓到肿瘤发生的一系列病理状况。因此，研究控制这一关键神经干细胞功能的基本细胞机制，不仅对理解正常发育过程中干细胞如何控制适当的分裂至关重要，而且对理解它们在病理条件下的异常分裂如何导致癌症等毁灭性疾病至关重要。此外，我们研究的机制可以用来更好地定义和完善重编程策略，以产生患者特异性干细胞，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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of cytokinesis during corticogenesis: focus on the midbody.

皮质生成过程中胞质分裂的调节：关注中体。

DOI：
10.1002/1873-3468.12676
发表时间：
2017
期刊：
FEBS letters
影响因子：
3.5
作者：
Johnson,CarolineA;Wright,CatherineE;Ghashghaei,HTroy
通讯作者：
Ghashghaei,HTroy

Detection and classification of neurons and glial cells in the MADM mouse brain using RetinaNet.

DOI：
10.1371/journal.pone.0257426
发表时间：
2021
期刊：
PloS one
影响因子：
3.7
作者：
Cai Y;Zhang X;Kovalsky SZ;Ghashghaei HT;Greenbaum A
通讯作者：
Greenbaum A

Developmentally defined forebrain circuits regulate appetitive and aversive olfactory learning.

DOI：
10.1038/nn.4452
发表时间：
2017-01
期刊：
NATURE NEUROSCIENCE
影响因子：
25
作者：
Muthusamy, Nagendran;Zhang, Xuying;Johnson, Caroline A.;Yadav, Prem N.;Ghashghaei, H. Troy
通讯作者：
Ghashghaei, H. Troy

Foxj1 expressing ependymal cells do not contribute new cells to sites of injury or stroke in the mouse forebrain.