FUNCTION OF MERLIN, A DROSOPHILA NF2 GENE HOMOLOGUE

2型神经纤维瘤病(NF2)是一种主要遗传的疾病，已被 被证明是由梅林(Schwannomin)突变引起的，梅林是 蛋白质4.1超家族。NF2的症状，通常在早期出现 成人生活，都是由双侧前庭形成的 神经鞘瘤和其他良性肿瘤。梅林和梅林的细胞功能 它在肿瘤抑制中的作用在很大程度上仍不清楚。识别 与Merlin相互作用的特异性蛋白质和信号转导途径 尤其重要，因为这些伴侣可能扮演着遗传的角色 NF2疾病表型的修饰因子并提供潜在的靶点 治疗剂。常见的果蝇，果蝇，已经被证明是一种 用于识别基因功能的遗传修饰因子的实用模型系统。 因此，这项提案的总体目标是检查细胞 Merlin和果蝇的功能，鉴定其与之相关的蛋白质 互动，并考察梅林与 与Ezrin/Radisin/Moesin相关的蛋白质。 在下一个资助期，我们计划继续对梅林进行研究 在个体细胞中发育生物体的功能。具体地说， 拟议的实验将： 1)研究梅林功能的调节机制 体外诱变与细胞NAD生化分析相结合 蛋白质的功能。 2)通过筛选确定Merlin功能的第二位点修饰 增强或抑制显性-负性表型的突变 梅林转基因。 3)阐明ERM蛋白的功能及其功能 通过分离和表征基因突变与梅林的关系 果蝇Moesin基因。 这些实验有望为深入了解细胞的功能提供帮助 梅林和ERM蛋白。因此，他们将为我们的 了解人类NF2，肿瘤抑制的一般情况，以及 致癌。此外，拟议的实验应该会导致 更好地理解发生在根尖的细胞过程 连接域。最后，这些研究应该有助于 细胞相互作用控制细胞生长的机制 并决定细胞在发育过程中的命运。

Neurofibromatosis type 2 (NF2), a dominantly inherited disease, has been shown to be caused by mutations in Merlin (Schwannomin), a member of the protein 4.1 superfamily. Symptoms of NF2, which usually appear by early adult life, are caused by the formation of bilateral vestibular Schwannomas and other benign tumors. The cellular functions of Merlin and its role in tumor suppression are still largely unknown. Identifying specific proteins and signal transduction pathways with Merlin interacts is especially important because these partners may act as genetic modifiers of NF2 disease phenotypes and provide potential targets for therapeutic agents. The common fruit fly, Drosophila, has proven to be a useful model system for identifying genetic modifiers of gene function. The overall goal of this proposal is therefore to examine the cellular functions of Merlin and Drosophila, identify the proteins with which it interacts, and examine the relationship between Merlin and the closely related Ezrin/Radixin/Moesin proteins. In the next funding period, we plan to continue our studies of Merlin function in developing organisms in individual cells. Specifically, the proposed experiments will: 1) Examine the mechanisms by which Merlin function is regulate using a combination of in vitro mutagenesis and cellular nad biochemical analysis of protein function. 2) Identify second site modifiers of Merlin function by screening for mutations that enhance or suppress the phenotypes of dominant-negative Merlin transgenes. 3) Elucidate the functions of ERM proteins and their functional relationship with Merlin by isolating and characterizing mutations in the Drosophila Moesin gene. These experiments are expected to provide insights into the functions of Merlin and the ERM proteins. Thus they will contribute to our understanding of human NF2, tumor suppression in general, and carcinogenesis. In addition, the proposed experiments should lead to a better understanding of cellular processes that occur in the apical junctional domain. Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control cell growth and determine cell fate during development.