Function of Merlin, a Drosophila NF2 Gene Homologue

描述（申请人提供）：2型神经纤维瘤病（NF 2）是一种显性遗传性疾病，由蛋白质4.1超家族成员Merlin（Schwannomin）突变引起。NF 2的症状通常在成年早期出现，由双侧前庭神经鞘瘤（导致耳聋）和其他良性肿瘤的形成引起。Merlin的细胞功能及其在肿瘤抑制中的作用在很大程度上仍然是未知的，尽管我们实验室和其他实验室最近的研究取得了重大进展。鉴定Merlin相互作用的特定蛋白质和信号转导途径尤其重要，因为这些伴侣可能作为NF 2疾病表型的遗传修饰剂，并为治疗剂提供潜在靶点。常见的果蝇，果蝇，已被证明是一个有用的模型系统，了解基因功能的背景下，发展中的有机体。因此，本提案的总体目标是研究Merlin及其功能伴侣在果蝇中的细胞功能，特别是与Hippo途径控制细胞增殖有关。 在下一个资助期内，我们计划继续研究Merlin和Expanded在发育中的生物体和单个细胞中的功能。具体而言，所提出的实验将：1）阐明Merlin/Expanded和HSW途径之间的功能相互作用。 具体来说，我们将测试的假设，扩展的功能下游的河马调节转录辅激活Yorkie。 2)了解Merlin和Expanded在调节质膜上受体定位和可用性方面的作用。 3)检查通过Hippo、萨尔瓦多、Warts途径的信号传导对调节细胞表面受体丰度的作用。 这些实验有望为Merlin、Expanded和Hippo通路在调节增殖中的功能提供见解。因此，他们将有助于我们了解人类NF 2，肿瘤抑制一般，和致癌作用。此外，拟议的实验应该导致更好地了解细胞过程，建立专门的上皮细胞和神经元的膜域。最后，这些研究应有助于研究细胞相互作用控制细胞生长和决定发育过程中细胞命运的机制。

DESCRIPTION (provided by applicant): Neurofibromatosis type 2 (NF2), a dominantly inherited disease, is 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 (resulting in deafness) and other benign tumors. The cellular functions of Merlin and its role in tumor suppression are still largely unknown, though recent studies in our laboratory and others have made significant progress. Identifying specific proteins and signal transduction pathways with which 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 understanding gene function in the context of a developing organism. The overall goal of this proposal is therefore to examine the cellular functions of Merlin and its functional partner Expanded in Drosophila, particularly in relation to the control of cell proliferation by the Hippo pathway. In the next funding period, we plan to continue our studies of Merlin and Expanded function in developing organisms and in individual cells. Specifically, the proposed experiments will: 1) Elucidate functional interactions between Merlin/Expanded and the HSW pathway. Specifically we will test the hypothesis that Expanded functions downstream of Hippo to regulate the transcriptional coactivator Yorkie. 2) Understand the role of Merlin and Expanded in regulating receptor localization and availability at the plasma membrane. 3) Examine the role of signaling by the Hippo, Salvador, Warts pathway on regulating receptor abundance at the cell surface. These experiments are expected to provide insights into the functions of Merlin, Expanded and the Hippo pathway in regulating proliferation. 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 the cellular processes that establish specialized membrane domains in epithelial cells and neurons. 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.