Schwann Cells in Neurofibromatosis Type 2 (NF2)

描述（由申请人提供）：约10%的颅内肿瘤为神经鞘瘤，由双等位基因NF2突变的雪旺细胞组成的良性肿瘤。NF2突变或缺失被认为是神经鞘瘤形成的原因。一些证据表明NF2蛋白merlin参与小g蛋白信号传导。生化证据和我们对原发性神经鞘瘤细胞的分析表明，merlin在Rac信号传导中起作用。正常的雪旺细胞是极化的，一个表面附着在轴突上，另一个表面附着在基底层，而神经鞘瘤细胞与轴突无关。这种极性的丧失很可能是由Rac信号改变引起的。由于Rac信号通路与雪旺细胞的相关性尚不清楚，我们建议评估梅林-Rac级联在雪旺细胞生长和肿瘤发生中的作用。我们的具体假设是梅林限制了雪旺细胞中Rac信号传导的持续时间。我们进一步假设，Rac信号的失调解释了神经鞘瘤特征的轴突-胶质相互作用失败。我们计划使用功能获得和功能丧失小鼠模型和来自人类神经鞘瘤的原代细胞的组合来验证这些假设。我们相信，对原发性神经鞘瘤细胞的分析为研究纯早期人类癌细胞提供了难得的机会。所提出的研究有望为正常轴突-神经胶质相互作用的调控提供见解，并导致理解和最终治疗人类神经鞘瘤的策略。

DESCRIPTION (provided by applicant): About 10% of all intracranial tumors are schwannomas, benign tumors comprised of Schwann cells with biallelelic NF2 mutations. NF2 mutation or loss is believed to cause schwannoma formation. Several lines of evidence implicate merlin, the NF2 protein, in small G-protein signaling. Biochemical evidence and our analysis of primary schwannoma cells suggest that merlin functions in Rac signaling. While normal Schwann cells are polarized, with one surface attached to axons and the other to basal lamina, schwannoma cells are unassociated with axons. This loss of polarity is likely to arise secondary to altered Rac signaling. Because the relevance of the Rac signaling pathway to Schwann cells is not known, we propose to evaluate a merlin-Rac cascade in Schwann cell growth and tumorigenesis. Our specific hypothesis is that merlin limits the duration of Rac signaling in Schwann cells. We further postulate that deregulated Rac signaling accounts for the failed axon-glial interactions characteristic of schwannomas. We plan to use a combination of gain-of-function and loss-of-function mouse models and primary cells from human schwannomas to test these hypotheses. We believe that analysis of primary schwannoma cells offers a rare opportunity to study a pure population of early stage human cancer cells. The proposed studies are expected to provide insight into regulation of normal axon-glial interactions, and to lead to strategies to understand and ultimately treat human schwannomas.