Gng5 function in neural progenitors

Gng5 在神经祖细胞中的功能

• 批准号: 8501711
• 负责人: JANET D ROBISHAW
• 金额: $ 7.89万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 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/8501711
• 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

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.

描述（由申请人提供）：了解正常大脑如何发育以及疾病中出现的问题对于设计更好的方法来预防先天性疾病和治疗以神经元损失为特征的退行性疾病至关重要。与该应用特别相关的是，人们越来越认识到异源三聚体 G 蛋白对于 大脑的形成和维护。它们以 GTP 亚基和二聚体的形式产生分叉信号，调节磷脂酶、腺苷酸环化酶和离子通道，从而产生负责调节许多神经元过程的“第二信使”。当前的挑战是将各个 G 蛋白亚型与其对特定过程的调节联系起来。表达和功能证据均表明编码 G 蛋白 gamma5 亚基的 Gng5 基因在调节增殖、迁移或分化中发挥着关键作用。 Gng5 优先在神经祖细胞中表达。此外，我们还发现 Gng5 的整体缺失会导致小头畸形。然而，通过研究全局基因敲除小鼠可以获得的信息受到心脏缺陷导致的早期胚胎致死性的限制。与R03机制的既定目的一致，本申请建议开发一种条件敲除小鼠模型，其中神经祖细胞中的Gng5被特异性删除。这将通过将携带两个 floxed Gng5 等位基因的小鼠与在巢蛋白启动子控制下表达 Cre 重组酶的转基因小鼠杂交来实现。随后，将对条件性基因敲除大脑进行组织学分析，以确定 G 蛋白 ?5 亚基的缺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。揭示负责神经祖细胞扩增、迁移或分化的G蛋白α5亚基所需的信号通路可能为未来开发预防先天性疾病和治疗神经退行性疾病的有效策略提供分子基础。