Gng5 function in neural progenitors

Gng5 在神经祖细胞中的功能

基本信息

批准号：
8360905
负责人：
JANET D ROBISHAW
金额：
$ 8.18万
依托单位：
GEISINGER CLINIC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8360905
关键词：
Ablation Address Adenylate Cyclase Adult Affect Alleles American Amino Acids Animals Biological Process Brain Bypass Cell physiology Characteristics Child Communities Community Developments Congenital Disorders Congenital Heart Defects Defect Degenerative Disorder Development Disease Embryo Event Exhibits Foundations Future G Protein Gene G-Protein-Coupled Receptors GTP-Binding Proteins Gene Family Gene Targeting Genes Goals Guanosine Triphosphate Health Heterotrimeric GTP-Binding Proteins Human Genome Individual Ion Channel Knock-out Knockout Mice Maintenance Microcephaly Molecular Molecular Profiling Mus National Institute of Child Health and Human Development National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neurons Neurosciences Organism Phospholipase Play Post-Translational Protein Processing Process Production Protein Subunits Proteins Regulation Research Resources Role Second Messenger Systems Signal Pathway Signal Transduction Transgenic Mice Translating aging population base design dimer improved insight migration mouse genome mouse model nerve stem cell nervous system disorder nestin protein neural precursor cell neurodevelopment neurogenesis neuron loss neurotrophic factor novel prevent programs promoter recombinase relating to nervous system second messenger selective expression

项目摘要

DESCRIPTION (provided by applicant): Understanding how the normal brain develops and what goes wrong in disease is fundamental for designing better ways to prevent congenital diseases, and to treat degenerative disorders marked by neuronal loss. Of particular relevance to this application, there is a growing recognition that heterotrimeric G proteins are critical for formation and maintenance of the brain. They produce bifurcating signals in the form of a GTP- subunit and a dimer that regulate phospholipases, adenylyl cyclases, and ion channels to produce the "second messengers" responsible for modulating many neuronal processes. The current challenge is to relate the individual G-protein subtypes to their regulation of particular processes. Both expression and functional evidence suggest the Gng5 gene encoding the G-protein gamma5 subunit plays a critical role in modulating proliferation, migration, or differentiation. Gng5 is preferentially expressed in neural progenitor cells. Moreover, we have shown that global deletion of Gng5 causes microcephaly. However, the information that can be obtained from studying the global knockout mice has been limited by their early embryonic lethality resulting from a cardiac defect. Consistent with the stated purpose of the R03 mechanism, this application proposes to develop a conditional knockout mouse model in which Gng5 is specifically deleted in neural progenitor cells. This will be accomplished by crossing mice carrying two floxed Gng5 alleles with transgenic mice expressing Cre-recombinase under control of the nestin promoter. Subsequently, histological analyses of conditional knockout brains will be performed to identify how loss of the G-protein ?5 subunit affects cortical size and organization, while molecular strategies will be used to elucidate any underlying defects in proliferation, migration, or differentiation of neural progenitor cells. Revealing the signaling pathways requiring the G-protein ?5 subunit that is responsible for neural progenitor cell expansion, migration, or differentiation may provide a molecular basis for the future development of effective strategies to prevent congenital disorders and treat neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: To improve the health of the American people, the goal of both NINDS and NICHD are to gain a better understanding of how the normal brain develops, and to translate these discoveries into better strategies to prevent congenital disorders, and to more effectively treat neurodegenerative disorders. This R03 application addresses both goals by providing a novel mouse model for studying how heterotrimeric G proteins are involved in formation and maintenance of brain. This resource will have inherent value to both the neuroscience and development communities.

描述（由申请人提供）：了解正常大脑如何发展以及疾病中的问题是设计更好的方法来预防先天性疾病，并治疗以神经元损失标记的退行性疾病。与此应用特别相关，人们越来越认识到异三聚体G蛋白对大脑的形成和维护。它们以GTP亚基和一个调节磷脂酶，腺苷酸环化酶和离子通道的形式产生分叉信号，以产生负责调节许多神经元过程的“第二使者”。当前的挑战是将单个G蛋白亚型与对特定过程的调节联系起来。表达和功能证据都表明编码GNG5基因GNG5基因在调节增殖，迁移或分化中起着至关重要的作用。 GNG5在神经祖细胞中优先表达。此外，我们已经表明，GNG5的全局缺失会导致小头畸形。但是，从研究全球敲除小鼠可以获得的信息受到心脏缺陷引起的早期胚胎致死性的限制。与R03机制的既定目的一致，该应用建议开发有条件的基因敲除小鼠模型，其中GNG5在神经祖细胞中特异性删除。这将通过将携带两个Floxed GNG5等位基因的小鼠与在Nestin启动子控制下表达CRE聚集酶的转基因小鼠跨越小鼠来实现。随后，将对有条件敲除大脑进行组织学分析，以确定G蛋白的损失如何影响皮质大小和组织，而分子策略将用于阐明神经祖细胞增殖，迁移或分化中的任何潜在缺陷。揭示需要G蛋白的信号传导途径？5负责神经祖细胞扩张，迁移或分化的亚基可能为未来开发有效策略的发展提供了预防先天性疾病和治疗神经退行性疾病的分子基础。公共卫生相关性：为了改善美国人民的健康，NINDS和NICHD的目标是更好地了解正常大脑的发展方式，并将这些发现转化为更好的策略，以预防先天性疾病，并更有效地治疗神经退行性疾病。该R03应用程序通过提供了一种新型的小鼠模型来研究两个目标，以研究异构体G蛋白如何参与大脑的形成和维持。该资源将对神经科学和发展社区具有固有的价值。