Gng5 function in neural progenitors

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丢失为特征的退行性疾病至关重要。与该应用特别相关的是，越来越多的人认识到异源三聚体G蛋白对于 大脑的形成和维持。它们以GTP-亚基和二聚体的形式产生分叉信号，所述二聚体调节磷脂酶、腺苷酸环化酶和离子通道以产生负责调节许多神经元过程的“第二信使”。目前的挑战是将单个G蛋白亚型与它们对特定过程的调节联系起来。表达和功能证据都表明，编码G蛋白γ 5亚基的Gng 5基因在调节增殖、迁移或分化方面发挥着关键作用。gng 5优先在神经前体细胞中表达。此外，我们已经表明，Gng 5的整体缺失导致小头畸形。然而，从研究整体基因敲除小鼠中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R 03机制的所述目的一致，本申请提出开发条件性敲除小鼠模型，其中Gng 5在神经祖细胞中特异性缺失。这将通过将携带两个floxed Gng 5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，将进行条件性敲除脑的组织学分析，以确定G蛋白是如何丢失的？5亚基影响皮质大小， 组织，而分子策略将用于阐明神经祖细胞的增殖，迁移或分化中的任何潜在缺陷。揭示需要G蛋白的信号通路？负责神经祖细胞扩增、迁移或分化的5亚基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。 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育方式，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。R 03的这一应用通过提供一种新的小鼠模型来研究异源三聚体G蛋白如何参与大脑的形成和维持，从而实现了这两个目标。这种资源将对神经科学和发展社区具有内在价值。

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.